Aim: Prostate cancer (PCa) is the most commonly diagnosed non-skin cancer among men. Serum prostate-specific antigen level is used as a standard PCa biomarker for over 20 years. However, it has only 33% specificity and 86% sensitivity (for the cutoff value for prostate biopsy of > 4 ng/mL). This leads to overdiagnosis and overtreatment. In-depth insight into PCa metabolomics enables discovery of novel PCa biomarkers.

Methods: Metabolomic alternation in PCa serum, urine and interstitial fluid was examined using gold-nanoparticle-based laser mass spectrometry imaging. This study included 5 patients who underwent prostate biopsy with positive result, 5 patients with negative result and 10 healthy controls.

Results: Over two hundred differentiating metabolites (87 in urine, 54 in serum and 78 in interstitial fluid) were detected. Four, twenty two and ten metabolites from urine, serum and interstitial fluid respectively showed statistical significant differential abundance between cancer and control group.

Conclusion: Comprehensive metabolomic profile of PCa has been identified. Out of 36 metabolites, 20 were identified and should be further evaluated in clinical trials as a potential PCa biomarker. Urine concentration of triglyceride (12:0/20:1) showed over 10 times higher abundance in PCa samples in comparison to healthy controls and is considered the most promising potential biomarker.

Axillary recurrence is a rare event in patients treated with sentinel lymph node biopsy alone with the majority occurring in the first 5 years after surgery. Intramammary lymph node (IMLN) can be the primary sites of metastasis and sentinel lymph nodes, but the clinical significance, including prognosis and therapeutic approach is yet unclear, even more with capsular extravasation. IMLN metastases are strongly correlated with axillary lymph nodes involvement and therefore a guide for further surgical management of the axillary nodes.

Few studies have reported on the analyses of drugs targeting enriched populations of cancer stem cells (CSCs) as a means for identifying potent anti-CSC agents. This review evaluates recent information on the identification and functions of specific CSC surface markers, with particular emphasis on colorectal cancers and the screening of drugs to eliminate such cells. Many of these CSC markers are found commonly expressed on CSCs from different cancer types as well as embryonic stem cells. These markers are often related to hypoxic activation of the WNT/b-catenin pathway, cyclooxygenase-2/prostaglandin E signalling and their relationship to LGR5. By effectively using drugs that inhibit these pathways to kill the CSC population, or otherwise forcing them out of dormancy into active cell division, cancers should become more susceptible to chemotherapy. Such combinational therapies targeting both CSCs and proliferating tumor cells should greatly improve upon the current basis for treatment.

Aim: The aim of the study is to test visible resonance Raman (VRR) spectroscopy for rapid skin cancer diagnosis, and evaluate its effectiveness as a new optical biopsy method to distinguish basal cell carcinoma (BCC) from normal skin tissues.

Methods: The VRR spectroscopic technique was undertaken using 532 nm excitation. Normal and BCC human skin tissue samples were measured in seconds. The molecular fingerprints of various native biomolecules as biomarkers were analyzed. A principal component analysis - support vector machine (PCA-SVM) statistical analysis method based on the molecular fingerprints was developed for differentiating BCC from normal skin tissues.

Results: VRR provides a rapid method and enhanced Raman signals from biomolecules with resonant and near-resonant absorption bands as compared with using a near-infrared excitation light source. The VRR technique revealed chemical composition changes of native biomarkers such as tryptophan, carotenoids, lipids and proteins. The VRR spectra from BCC samples showed a strong enhancement in proteins including collagen type I combined with amide I and amino acids, and a decrease in carotenoids and lipids. The PCA-SVM statistical analysis based on the molecular fingerprints of the biomarkers yielded a 93.0% diagnostic sensitivity, 100% specificity, and 94.5% accuracy compared with histopathology reports.

Conclusion: VRR can enhance molecular vibrational modes of various native biomarkers to allow for very fast display of Raman modes in seconds. It may be used as a label-free molecular pathology method for diagnosis of skin cancer and other diseases and be used for combined treatment with Mohs surgery for BCC.

Aim: Breast cancer (BCA) in women is a leading cause of mortality and morbidity; distant metastases occur in ~40% of cases. Here, as an alternative to ionizing radiation therapy and chemotherapy and their associated side effects, we explored a new combination approach using capecitabine (CPBN) and aminolevulinate-based photodynamic therapy (PDT). We had previously developed a combination PDT approach in which 5-fluorouracil (5FU), a differentiation-promoting agent, increases the levels of protoporphyrin IX (PpIX) in cancer cells when given as a neoadjuvant prior to aminolevulinic acid (ALA). However, 5FU can be toxic when administered systemically at high levels. We reasoned that CPBN, a known chemotherapeutic for BCA and less toxic than 5FU (because CPBN is metabolized to 5FU specifically within tumor tissues), might work equally well as a PDT neoadjuvant.

Methods: Murine 4T1 BCA cells harboring a luciferase transgene were injected into breast fat pads of female nude mice. CPBN (600 mg/kg/day) was administered by oral gavage for 3 days followed by intraperitoneal ALA administration and PDT with red light (633 nm) on day 4. Tumor growth and regression were monitored in vivo using bioluminescence imaging. Histological changes in primary tumors and metastases were assessed by immunohistochemistry after necropsy.

Results: CPBN pretreatment of 4T1 tumors increased cellular differentiation, reduced proliferation, raised PpIX levels, enhanced tumor cell death, and reduced metastatic spread of 4T1 cells post-PDT, relative to vehicle-only controls.

Conclusion: The use of CPBN as a non-toxic PDT neoadjuvant for treatment of BCA represents a novel approach with significant potential for translation into the clinic.

Retrograde trafficking is a well-regulated, multi-component pathway that can result in endosomal trafficking to the trans-Golgi network, the perinuclear space, or the nucleus. Either clathrin or the retromer complex can travel with proteins endocytosed from the plasma membrane, guided by Rabs (including 5, 6, 7, 9, 22A), interacting with a host of sorting nexin proteins, and fusing with Golgi-specific anchors to allow transport of activated receptor tyrosine kinases to a potential end within the nucleus. Amplification in these constituents is common in cancer, leading to increased retrotranslocation and a reduction in degradation of receptor tyrosine kinases, an event highly associated with cancer metastasis. Here, we review the role of retrograde trafficking in altering transmembrane receptor localization and activity and the relationship to metastasis, focusing on all four members of the ErbB family, with comparison to other receptor tyrosine kinases including the insulin receptor and fibroblast growth factor receptor, as well as other transmembrane proteins dysregulated in metastasis. By examining how these receptors are being alternatively trafficked and the cancer-associated events resulting from this process, we hope to identify novel therapeutic targets.

Breast cancer is a common malignancy among women. Due to the improvement of social awareness and advances in imaging technologies, significant achievements are obtained at its diagnosis and treatment each passing day. A 54-year-old, multiparous and postmenopausal woman, who presented with a palpable lymph node in the right supraclavicular region and a right adnexal mass but had no findings from the breast examination, is reported in this article. Following advanced assessment, metastatic carcinoma was identified in the lymph node biopsy and the adnexal mass. During the exploration for the primary origin, microinvasive breast cancer was diagnosed following mammographic imaging and an excisional biopsy from the right breast. Microinvasive breast cancer, which did present itself with clinical findings with metastases despite the lack of local findings, was discussed with the review of the literature.

Postpartum involution is the process by which the lactating mammary gland returns to the pre-pregnant state after weaning. Expression of tumor-promotional collagen, upregulation of matrix metalloproteinases, infiltration of M2 macrophages, and remodeling of blood and lymphatic vasculature are all characteristics shared by the involuting mammary gland and breast tumor microenvironment. The tumor promotional nature of the involuting mammary gland is perhaps best evidenced by cases of postpartum breast cancer (PPBC), or those cases diagnosed within 10 years of most recent childbirth. Women with PPBC experience more aggressive disease and higher risk of metastasis than nulliparous patients and those diagnosed outside the postpartum window. Semaphorin 7a (SEMA7A), cyclooxygenase-2 (COX-2), and collagen are all expressed in the involuting mammary gland and, together, predict for decreased metastasis free survival in breast cancer. Studies investigating the role of these proteins in involution have been important for understanding their contributions to PPBC. Postpartum involution thus represents a valuable model for the identification of novel molecular drivers of PPBC and classical cancer hallmarks. In this review, we will highlight the similarities between involution and cancer in the mammary gland, and further define the contribution of SEMA7A/COX-2/collagen interplay to postpartum involution and breast tumor progression and metastasis.

Brain metastases risk at the time of diagnosis or during the course of disease is high in non-small cell lung cancer (NSCLC). Even the incidence of brain metastases has increased in recent years, due to detection of smaller asymptomatic lesions with MRI screening as well as improved survival as a consequence of developments in systemic therapies. In the last decade, there have been many trials in the management of NSCLC patients with brain metastases, questioning the role of adjuvant whole brain radiotherapy (WBRT) after surgery or stereotactic radiosurgery (SRS), WBRT, compared to best supportive care in patients not amenable to surgery, aggressive local therapies in solitary brain metastases, postsurgical cavity SRS, SRS in non-oligometastatic patients, cranial radiotherapy in patients with driver mutations, thyrosine kinase inhibitors, immune check point inhibitors and the impact of therapies on neurocognitive functions and quality of life. The main objective of this review is to provide an update on current trends in radiotherapy in the management of newly diagnosed brain metastases from NSCLC.

Brain metastasis is a major cause of death in patients with solid cancers. Breast cancer cells have high tendency to migrate towards brain. Cancer cells within brain are characterized by severe aggressiveness and inaccessibility. Currently, breast cancer and its metastasis are the second leading cause of death among women. Tumor microenvironment and blood brain barrier (BBB) represent great obstacles in targeting breast cancer and its metastasis. Chemotherapy is a safer treatment modality for brain metastasis compared with risky surgical resection and brain radiotherapy. Unfortunately, conventional chemotherapy lack penetration of BBB and suffer from multiple resistance mechanisms. Current treatment technologies for brain metastases of breast cancer have limited long-term success and numerous side effects, illustrating the urgent need for novel smart strategies. Various novel drug entities and nanosystems have been employed to improve diagnosis and targeted treatment of breast cancer and its metastasis. Immunotherapy agents and small tyrosine kinase inhibitors have been shown to reduce tumor size and increase survival in patients with breast cancer, but still poorly penetrate BBB. Tailored sized nanoparticles to some extent crossed brain tumor barrier and enhanced drug accumulation in tumors by taking advantage of enhanced permeability and retention. Furthermore, various active targeting strategies have been adopted to improve accessibility to brain malignancies. Therefore, to achieve enhanced antitumor therapy against breast cancer and its brain metastasis, multi-talented delivery systems are urgently needed for optimal treatment. This review focuses on the various active and passive targeting technologies for the treatment of breast cancer brain metastases in the past decade. A comprehensive summary and examples along with pros and cons of each system will be discussed. Different treatment modalities and nanotechnology facilities will be demonstrated to aid in designing the optimal smart, safe, targeted and effective systems to combat brain metastases of breast cancer.

The carcinogenic mechanism proposed considers that stem cells committed to repair tissues and differentiated cells, acquire different metabolic properties, if there is an associated GABA deficiency suppressing a control system of the endocrine pancreas. This control system mediated by GABA, released with insulin, normally turns off glucagon and somatostatin release when insulin is released. A consequence of the GABA deficiency in pancreas and adrenals is a hybrid insulin-glucagon-somatostatin message, received by new mitotic stem cells displaying then a hybrid metabolic rewiring. This gives them a selective metabolic advantage over differentiated cells that become insulin resistant and only receive the glucagon- somatostatin part of the hormonal message. Indeed, their insulin receptors are desensitized by the persistent leakage of insulin resulting from the GABA deficiency that fails to close the insulin release mechanism. Thus differentiated cells are simply rewired to be plundered by stem cells. The metabolic advantage gained by stem cells blocks their own differentiation and maintains their mitotic capacity. Inevitable mutations of mitotic cells follow, the immune system is unable to eliminate a geometrically increasing number of altered stem cells, a selection of the most aggressive but metabolically successful population takes place when cancer is declared.

Ovarian cancer (OC) is a serious condition that often presents at advanced stages and has high mortality rates, with the current mode of early-stage screening lacking sensitivity and specificity. OC often presents asymptomatically, which renders early diagnosis difficult. Furthermore, many patients lack significant risk factors or family history of the disease. Five-year survival rates differ between patients with OC among racial, ethnic, and social groups as a result of different social barriers. This review article aims to present the currently existing data regarding health care disparities among OC patients of different ethnic, demographic, and socioeconomic backgrounds, and what next steps should be taken to better understand and eventually eliminate these potentially devastating health care disparities. Increasing data support the notion that a combination of genomic, socioeconomic status, social factors, and cultural differences lead to differential treatments and therefore health care disparities. While genomic and biological factors are important, language barriers, geographic and travel barriers, differences in comorbidity likelihood between populations, and different treatment plans seem to have a greater impact on 5-year survival rates of patients from diverse backgrounds. Language barriers limit a shared-decision model of care. Transportation limitations and geographic differences can lead to limited follow-up and insufficient care in resource and equipment restrictive settings. Patients with these barriers also tend to have a higher incidence of comorbidities that raise the mortality rate of OC. Further research needs to explore effective solutions to bridge health care disparities and understand why they occur.

Aim: Bisphosphonates are used as an adjuvant treatment in breast cancer bone metastasis patients, often simultaneously with chemotherapeutic agents. Interestingly, their sequential combination has been reported to have synergistic anti-tumor effects on bone metastases in preclinical models. We studied the effects of doxorubicin (DOX) and zoledronic acid (ZOL) and their combination on established bone metastases in the MDA-MB-231(SA)GFP bone metastasis model.

Methods: Tumor burden and osteolytic bone lesions were quantitated by fluorescence imaging and radiography, respectively. The mice were randomized in four groups receiving vehicle, DOX, ZOL or both DOX and ZOL in a sequential combination on day 14. Serum marker of osteoclast number was followed weekly, and blood ionized calcium was measured at sacrifice. Bone and tumor area, apoptosis and proliferation of tumor cells were analyzed from histological sections.

Results: ZOL prevented hypercalcemia and osteolytic lesion progression, whereas DOX induced apoptosis in the MDA-MB-231(SA)GFP cells. However, neither of the treatments alone nor in sequential combination were able to reduce tumor burden in bone. Furthermore, no additive effects on tumor cell apoptosis were observed in the combination group.

Conclusion: No additive effects in combination of DOX and ZOL were observed in this aggressive model of breast cancer bone metastasis.

Epithelial-mesenchymal transition (EMT) is a plastic and reversible process, essential for development and tissue homeostasis. Under pathological conditions, EMT causes induction of tumor growth, angiogenesis and metastasis. According to its reversible nature, the EMT program is associated with vast epigenetic changes. Targeting the epigenetic network that controls the EMT pathway in disease progression is a novel promising strategy to fight cancer metastasis. The impact of alterations in histone methylation in cancer has led to the identification of histone methyltransferases and demethylases as promising novel targets for therapy. Specifically, the lysine specific demethylase 1 (LSD1, also known as KDM1A) plays a pivotal role in the regulation of EMT. Here we present an overview of the causative role of LSD1 in the EMT process, summarizing recent findings on its emerging functions in cell migration and invasion in breast cancer.

The epithelial-mesenchymal transition (EMT), in which cells undergo a switch from a polarized, epithelial phenotype to a highly motile fibroblastic or mesenchymal phenotype is fundamental during embryonic development and can be reactivated in a variety of diseases including cancer. Spatio-temporally-regulated mechanisms are constantly orchestrated to allow cells to adapt to their constantly changing environments when disseminating to distant organs. Although numerous transcriptional regulatory factors are currently well-characterized, the post-transcriptional control of EMT requires continued investigation. The hnRNP E1 protein displays a major role in the control of tumor cell plasticity by regulating the translatome through multiple non-redundant mechanisms, and this role is exemplified when E1 is absent. hnRNP E1 binding to RNA molecules leads to direct or indirect translational regulation of specific sets of proteins: (1) hnRNP E1 binding to specific targets has a direct role in translation by preventing elongation of translation; (2) hnRNP E1-dependent alternative splicing can prevent the generation of a competing long non-coding RNA that acts as a decoy for microRNAs (miRNAs) involved in translational inhibition of EMT master regulators; (3) hnRNP E1 binding to the 3’ untranslated region of transcripts can also positively regulate the stability of certain mRNAs to improve their translation. Globally, hnRNP E1 appears to control proteome reprogramming during cell plasticity, either by direct or indirect regulation of protein translation.

Aim: To investigate whether AF1q, overexpressed in metastatic cells compared with the primary tumor cells, plays a pivotal role in breast cancer metastasis.

Methods: To investigate whether AF1q has a responsibility in the acquisition of a metastatic phenotype, we performed RNA-sequencing (RNA-Seq) to identify the gene signature and applied the Metacore direct interactions network building algorithm with the top 40 amplicons of RNA-Seq.

Results: Most genes were directly linked with intercellular adhesion molecule-1 (ICAM-1). Likewise, we identified that ICAM-1 expression is attenuated in metastatic cells compared to primary tumor cells. Moreover, overexpression of AF1q attenuated ICAM-1 expression, whereas suppression of AF1q elicited the opposite effect. AF1q had an effect on ICAM-1 promoter region and regulated its transcription. Decreased ICAM-1 expression affected the attachment of T cells to a breast cancer cell monolayer. We confirmed the finding by performing the analysis on Burkitt’s lymphoma.

Conclusion: Attenuation of ICAM-1 by AF1q on tumor cells disadvantages host anti-tumor defenses through the trafficking of lymphocytes, which affects tumor progression and metastasis.

Head and neck squamous cell carcinoma (HNSCC) has a large global burden of disease and poor survival outcomes. Recent targeted therapies and immunotherapies have been explored in HNSCC, but there has been limited translation to clinical practice outside of recurrent or metastatic cases. Window of opportunity settings, where novel agents are administered between cancer diagnosis and planned definitive therapy, have begun to be employed in HNSCC. Tumor tissue biopsies are obtained at diagnosis and after the investigation treatment, along with other biospecimens and radiographic exams. Thus, this study design can characterize the safety profiles, pharmacodynamics, and initial tumor responses to novel therapies in a treatment-naïve subject. Early window studies have also identified potential biomarkers to predict sensitivity or resistance to treatments. However, these early investigations have revealed multiple challenges associated with this trial design. In this review, we discuss recent window of opportunity trials in HNSCC and how they inform design considerations for future studies.

Aim: The convergence of tumorigenic and embryonic signaling pathways drives us to exploit the embryonic stem cell (ESC) microenvironment to restrict metastatic potential of cancer cells. We have previously demonstrated that bioengineered ESC microenvironments could restrict growth and metastatic potential of highly aggressive breast cancer cell (BCC). This study aims to further understand the regulation of convergent EGFR and canonical Wnt/β-catenin signaling pathway function in triple negative metastatic BCCs using the 3D in vitro ESC microenvironment created by encapsulating ESCs in alginate hydrogel microstrands.

Methods: Co-culture with ESC-microstrands increased sensitivity to two chemotherapeutic drugs in metastatic BCCs. To test whether these changes were due to restored signaling pathway regulation in BCCs, we probed for changes in gene expression of key molecules related to the EGFR and canonical Wnt/β-catenin signaling pathways using quantitative reverse transcription polymerase chain reaction and Western blot analysis.

Results: ESC-microstrands are able to alter the gene expression of highly aggressive BCCs at both mRNA and protein levels. These changes are indicative of a reversal of EGFR and canonical Wnt/β-catenin signaling pathway hyperactivation following co-culture. Increased NKD2 mRNA and protein expression coinciding with dual signaling pathway inhibition within co-cultured BCCs suggests that this reversal may be attributable to restored regulation of NKD2 within these pathways.

Conclusion: ESC-microstrands are able to reverse oncogenic signaling pathway hyperactivation and restore signaling pathway regulation in metastatic BCCs. Further studies could provide insight into what role NKD2 up-regulation plays in BCC inhibition, leading to the development of a new targeted therapy for metastatic breast cancer.

Aim: Metastasis to the brain has become a major limitation to the life expectancy and quality of life for many patients with breast cancer. Unfortunately, other than radiation and palliative treatments with trastuzumab, and pertuzumab, no effective therapy for brain metastases is currently available. This study seeks to identify novel gene targets and pharmaceutical Intervention against breast cancer brain metastasis.

Methods: The detailed methods applied to this study, including comparative RNA sequencing and bioinformatics analysis of sequence data, ingenuity pathway analysis, protein-protein interaction analysis, high throughput screening of clinical and pre-clinical drugs, cell viability and proliferation assay, toxicity and apoptosis assay using fluorescence-activated cell sorting, real-time PCR, western blotting, statistical analysis of data.

Results: The study reveals critical roles for SRC, ERBB2, PIK3CA, and GABA in the proliferation and survival of breast cancer brain metastatic (BBM) cells and showed that SRC- and ERBB2-mediated activation of PIK3-AKT/mTOR signaling regulates BBM cell survival. Selective inhibition of these candidate genes alone or in combination induces robust apoptosis in BBM cells

Conclusion: The findings of this study provide a rationale for further preclinical evaluation of SRC-targeting regimens in combination with ERBB2 inhibitors and/or GABA agonists to target breast cancer brain metastasis.

Alternative splicing is a major contributor to transcriptome and proteome diversity in eukaryotes. Comparing to normal samples, about 30% more alternative splicing events were recently identified in 32 cancer types included in The Cancer Genome Atlas database. Some alternative splicing isoforms and their encoded proteins contribute to specific cancer hallmarks. In this review, we will discuss recent progress regarding the contributions of alternative splicing to breast cancer metastasis. We plan to dissect the role of MTDH, CD44 and their interaction with other mRNA splicing factors. We believe an in-depth understanding of the mechanism underlying the contribution of splicing to breast cancer metastasis will provide novel strategies to the management of breast cancer.

Aim: The progression free survival of non-small cell lung cancer (NSCLC) patients has been doubled over the last years, but still single epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) lead to incomplete responses. Compensatory signaling pathways are activated upon single EGFR TKIs. We have shown that compounds, which inhibit these pathways, are synergistic with EGFR TKIs. Proviral integration site for Moloney murine leukemia virus (PIM) has been connected to cancer therapy resistance, being involved in receptor tyrosine kinase, signal transducer and activator of transcription 3 (STAT3) and interleukin-6 signaling. We hypothesized that combined PIM and EGFR inhibition may improve the upfront therapy of EGFR-mutation positive NSCLC.

Methods: We reviewed the literature on PIM kinases, and performed cell viability assays, gene expression analyses, and immunoblotting experiments to reveal the mechanisms of action of the PIM inhibitor (AZD1208) alone and combined with osimertinib in five EGFR-mutation positive NSCLC cell lines.

Results: Osimertinib alone induced the activation of signal transducer and activator of transcription 3 (STAT3) as well as other signaling nodes. Combined osimertinib and AZD1208 yielded moderate synergistic effects in all NSCLC cell lines investigated. Among the EGFR-mutation positive cell lines examined, the H1975 and PC9 cell lines had the highest PIM1 and STAT3 mRNA expression. The combination decreased the osimertinib-induced STAT3 phosphorylation.

Conclusion: This study provides a short review on PIM kinases, and shows our results of combined PIM and EGFR inhibition in EGFR-mutation positive NSCLC cell lines. The combination was moderately synergistic but decreased STAT3 phosphorylation, an important signaling node in therapy resistance.

Cancer is a systemic disease. In order to fully understand it, we must take a holistic view on how cancer interacts with its host. The brain monitors and responds to natural and aberrant signals arriving from the periphery, particularly those of metabolic or immune origin. As has been well described, a hallmark of cancer is marked disruption of metabolic and inflammatory processes. Depending on the salience and timing of these inputs, the brain responds via neural and humoral routes to alter whole-body physiology. These responses have consequences for tumor growth and metastasis, directly influencing patient quality of life and subsequent mortality. Additionally, environmental inputs such as light, diet, and stress, can promote inappropriate neural activity that benefits cancer. Here, I discuss evidence for brain-tumor interactions, with special emphasis on subcortical neuromodulator neural populations, and potential ways of harnessing this cross-talk as a novel approach for cancer treatment.

Obesity has the far reaching consequence on cancer pathogenesis and immune reactions. In particular, adiponectin (APN) produced by adipocytes played an important role in modulating obesity related malignancies. Via its interaction with corresponding receptors and their downstream signalling pathways, it regulates cells survival, apoptosis and cancer metastasis. Our review dissects the clinical evidence on how hypoadiponectinaemia associated with the increased risks of several cancers and the long-term prognosis and also addresses the controversies. APN also has its indirect effect on anti-cancer immune response which may influence the disease process. We also analyse the impact of APN on the immune system, the anti-tumour responses and the controversies surrounding this area. Targeting therapeutics on APN and its receptor axis represents a promising and novel anti-cancer treatment. Biological understanding of how APN and its interaction with its receptors may affect the immune reactivity. Careful strategizing the use of APN therapeutics in cancer treatment is important, as the APN receptor signalling on the immune cells can blunt anti-tumour response. Targeting APN or its receptors has an enormous implication for the treatment of cancers.

Cancer remains a worldwide health problem, being the disease with the highest impact on global health. Even with all the recent technological improvements, recurrence and metastasis still are the main cause of death. Since photodynamic therapy (PDT) does not compromise other treatment options and presents reduced long-term morbidity when compared with chemotherapy or radiotherapy, it appears as a promising alternative treatment for controlling malignant diseases. In this review, we set out to perform a broad up-date on PDT in cancer research and treatment, discussing how this approach has been applied and what it could add to breast cancer therapy. We covered topics going from the photochemical mechanisms involved, the different cell death mechanisms being triggered by a myriad of photosensitizers up to the more recent-on-going clinical trials.

Metabolism is defined as the collection of complex biochemical processes that living cells use to generate energy and maintain their growth and survival. Metabolism encompasses the synthesis and breakdown of glucose, fatty acids, and amino acids; the generation of energy (ATP); and oxidative phosphorylation. In cancer cells, metabolism can be commandeered to promote tumor growth and cellular proliferation. These alterations in metabolism have emerged as an additional hallmark of various cancers. In this review we focus on metabolic alterations in multiple myeloma (MM) - a malignancy of plasma cells - including derangements in glycolysis, gluconeogenesis, the tricarboxylic acid cycle, oxidative phosphorylation, and fatty acid/amino acid synthesis and degradation. Particular focus is given to metabolic alterations that contribute to myeloma cell growth, proliferation and drug resistance. Finally, novel approaches that target metabolic pathways for the treatment of MM are discussed.

The emergence of novel systemic therapies has spurred a dramatic paradigm shift in lung cancer treatment. Research has revealed greater intracranial efficacy in targeted agents and immune checkpoint inhibitors (ICI) compared to conventional chemotherapy. Concurrently, advances in stereotactic radiosurgery (SRS) have contributed to the increased use of this highly localized, minimally-invasive treatment modality for local tumor control. In this era of precision medicine, the combination of these novel agents and SRS demands further prospective exploration - particularly as questions regarding their sequence of administration and the risk of neurotoxicity remain unanswered. Presently, although data are limited and largely retrospective, literature supports the concurrent administration of ICI and radiation, with no observed increases in immune-related adverse events or acute neurologic toxicities. In the case of patients with driver mutations, newer generations of tyrosine kinase inhibitors (TKI) display improved intracranial efficacy and are currently preferred alone upfront in patients with asymptomatic brain metastases (BM) due to lack of data. Evidence of combining TKI and SRS is limited with mixed results. In this review, we explore the evidence regarding the use of novel systemic agents and SRS for treatment of lung cancer BM. Clinical practice will continue to be refined as larger, prospective studies yield results.

Contralateral axillary metastasis (CAM) is a rare entity normally treated as a systemic disease. Recent publications have proposed aggressive surgical treatment with benefits to the patients in terms of survival. We present a case of a 74-year-old patient with a history of unilateral breast cancer, recurrence on the ipsilateral breast and then development of a CAM. The patient was treated with aggressive surgical treatment, but she developed an early recurrence of the disease with distant metastasis. There is limited evidence of the correct management of CAM, although proposed to treat it as a loco regional disease, individualized and multidisciplinary management is the best option for these patients.

Aim: To correlate the microcalcifications’ characteristics, such as morphology and elemental compositions, with the occurrence of bone metastatic lesions at 5 years from diagnosis.

Methods: In this retrospective study, we enrolled 70 patients from which we collected one breast biopsy each. From each biopsy, paraffin serial sections were obtained to perform histological classifications, immunohistochemical analyses and Energy Dispersive X-ray evaluation.

Results: Microcalcifications analysis showed a significant association between the presence of calcium crystals made of magnesium substituted hydroxyapatite and the development of bone metastasis from 5 years from diagnosis. No significant association was observed by evaluation the morphological appearance of microcalcifications. Immunohistochemical analysis displayed a significant association between the expression of bone morphogenetic proteins 2 and pentraxin-3, two osteoblast induction factors, and the formation of bone metastatic lesions.

Conclusion: Results here reported highlighted the possible use of breast microcalcifications as a negative prognostic marker of bone metastatic diseases. In particular, the association between elemental composition of breast microcalcifications and the formation of bone lesions can lay the foundation for the development of new in vivo diagnostic tools based on the analysis of microcalcifications and capable to predict the formation of bone metastasis.

Aim: This study focuses on the stomach as an unusual but not rare site of metastasis of breast cancer.

Methods: We performed a literature search on gastric metastasis from breast cancer searching for reviews from 2000 to 2018 and case reports from 2013 to 2018. We found 11 reviews and 36 case reports and we compared their findings about important aspects of gastric metastasis, such as disease free survival, overall survival, symptoms, endoscopic findings, therapy, histology, and immunohistochemistry.

Results: The incidence of stomach as site of metastasis of breast cancer ranges from 5% to 18%. Reviews and case reports reached similar conclusions about several of the aforementioned aspects: invasive lobular breast cancer (ILC) is mainly responsible for gastric metastases; disease free survival can vary greatly ranging from 0.5 months to 30 years; gastric metastases usually present with non-specific symptoms, even though five patients in case reports were asymptomatic; linitis plastica is the most common endoscopic finding; immunohistochemistry is essential for differentiating primary gastric cancer from metastasis; the preferred treatment is systemic therapy, but surgery is still an option in case of emergency; median overall survival of patients with gastric metastasis from breast cancer is 24 months.

Conclusion: Breast metastasis to the stomach should be considered in any patient suspecting gastric neoplasm previously treated for breast carcinoma, especially if the treated carcinoma was ILC.

Autophagy is a conserved lysosomal-dependent catabolic process that maintains the cellular homeostasis by recycling misfolded proteins and damaged organelles. It involves a series of ordered events (initiation, nucleation, elongation, lysosomal fusion and degradation) that are tightly regulated/controlled by diverse cell signals and stress. It is like a double-edged sword that can play either a protective or destructive role in cancer, by pro-survival or apoptotic cues. Recently, modulating autophagy by pharmacological agents has become an attractive strategy to treat cancer. Currently, a number of small molecules that inhibit autophagy initiation (e.g., ULK kinase inhibitors), nucleation (e.g., Vps34 inhibitors), elongation (e.g., ATG4 inhibitors) and lysosome fusion (e.g., chloroquine, hydroxyl chloroquine, etc.) are reported in pre-clinical and clinical study. Also a number of small molecules reported to induce autophagy by targeting mammalian target of rapamycin (e.g., rapamycin analogs) or adenosine 5’-monophosphate-activated protein kinase (e.g., sulforaphane). The study results suggest that many potential “druggable” targets exist in the autophagy pathway that could be harnessed for developing new cancer therapeutics. In this review, we discuss the reported autophagy modulators (inhibitors and inducers), their molecular mode of action and their applications in cancer therapy.

Circulating biomarkers - nucleic acids, proteins, and metabolites - have been used in several adult oncologic processes to affect early detection, measure response to treatment, and offer prognostic information. The identification and validation of biomarkers for pediatric brain tumors, however, has been meager by comparison. Early detection and serial screening of pediatric brain tumors has the potential to improve outcomes by allowing for rapid therapeutic interventions and more targeted therapies. This is particular resonant for pediatric brain tumors where treatment success is heavily dependent on early surgical intervention. This highlights the need for biomarker development in pediatric neuro-oncology. The authors reviewed current circulating biomarker targets in various biofluid reservoirs and discuss the current barriers to biomarker development in pediatric neuro-oncology patients.

Circulating tumor cells (CTCs) have the potential to provide genetic information for heterogeneous tumors, which may be useful for monitoring disease progression and developing personalized therapies. However, the isolation of CTCs for molecular analysis is challenging due to their extreme rarity and phenotypic heterogeneity, which hinders the transformation of CTCs into traditional clinical applications. In order to achieve clinically significant CTC detection, devices utilizing novel microfluidics and nanotechnology have been developed to achieve high sensitivity and specificity capture of CTCs. In this review, we discuss these newly developed devices for CTC capture and molecular characterization for early diagnosis and determining ideal treatment regimen to better manage these cancers clinically. In addition, the potential prognostic values of CTCs as treatment guidelines and that ultimately contribute to realize personalized treatment are also discussed.

Breast cancer (BC) is the leading cause of cancer-related deaths in women worldwide. However, the majority of cancer mortalities can be attributed to cancer cell metastasis to distal organs/tissues rather than the primary tumor mass itself. The microenvironment surrounding the main tumor mass, as well as its final migration destination, plays a crucial role in the survival, growth, proliferation, and progression of BC. Intercellular stromal cells and components of the microenvironment surrounding a tumor comprise a nurturing cubicle that provides a communication network of cross-talk and signaling between the tumor cells and the extracellular matrix (ECM) and interstitial cells. This network connection enables the tumor cells to engage in metastatic-associated activities such as cell adhesion, invasiveness, mobility, migration, cell shape change, cell-to-cell contact, and basement membrane degradation. An untapped therapeutic approach that might disable the communication network between cancer and stromal cells could possibly aid in providing this unmet need in treating metastatic disease. The intravenous administration of select protein-derived peptides to patients might have the potential to occupy, saturate, and block receptors and binding proteins at the interstitial/ECM communication interface with tumors.

Aim: We have recently identified a cancer stem cell (CSC) subpopulations within the tumor nests (TNs) and another within the peritumoral stroma (PTS) in liver metastasis from colon adenocarcinoma (LMCA). This study investigated the expression of components of the renin-angiotensin (RAS): pro-renin receptor (PRR), angiotensin converting enzyme (ACE), and angiotensin II receptor 1 (ATIIR1) and angiotensin II receptor 2 (ATIIR2) in LMCA.

Methods: 3,3-Diaminobenzidine (DAB) immunohistochemical (IHC) staining was performed on 16 LMCA samples for PRR, ACE, ATIIR1 and ATIIR2. Immunofluorescence (IF) IHC staining was performed to investigate co-expression of these components of the RAS with SOX2 or OCT4. NanoString analysis (n = 6) and Western blotting (WB, n = 3) were performed on snap-frozen LMCA samples to confirm mRNA and protein expression, respectively.

Results: DAB IHC staining showed the expression of PRR, ACE, ATIIR1 and ATIIR2 within all LMCA samples. NanoString analysis and WB confirmed gene and protein expression of these components of the RAS. IF IHC staining demonstrated expression of PRR, ATIIR1 and ATIIR2 by the SOX2⁺ CSCs within the TNs and the OCT4⁺ CSCs within the PTS. ACE was expressed on the endothelium of the microvessels within the PTS.

Conclusion: These finding suggests the CSCs within LMCA maybe a novel therapeutic target by manipulation of the RAS.

Aim: Fibulins and ADAMTSs are two families of extracellular matrix proteins implicated in key functional and pathological processes. The fact that the fibulin-1 and ADAMTS-1 proteins interact raises new questions about the roles of these extracellular matrix proteins in modulating tumor progression. Herein, we described the functional implications of the interaction between fibulin-1 and ADAMTS-1 on the behavior of breast cancer cell lines.

Methods: Fibulin-1 and ADAMTS-1 were exogenously expressed in MCF-7 and MDA-MB-231 cell lines to assay the effect of their interaction in cellular properties.

Results: ADAMTS-1 expression exacerbates tumor effects in terms of proliferation, invasion and mammosphere formation. In contrast, the simultaneous expression of ADAMTS-1 and fibulin-1 impairs these effects. The analysis of the expression of both proteins in human breast cancer tissue arrays provides new insights into the complex roles of fibulin-1 and ADAMTS-1 in this type of tumor.

Conclusion: Our results suggests that the interaction between ADAMTS-1 and fibulin-1 induces a pronounced anti-tumoral effect.

Endocrine therapy is essential for the treatment of patients with estrogen receptor positive (ER+) breast cancer, however, resistance and the development of metastatic disease is common. Understanding how ER+ breast cancer metastasizes is critical since the major cause of death in breast cancer is metastasis to distant organs. Results from many studies suggest dysregulation of the estrogen receptor alpha gene (ESR1) contributes to therapeutic resistance and metastatic biology. This review covers both pre-clinical and clinical evidence on the spectrum of ESR1 alterations including amplification, point mutations, and genomic rearrangement events driving treatment resistance and metastatic potential of ER+ breast cancer. Importantly, we describe how these ESR1 alterations may provide therapeutic opportunities to improve outcomes in patients with lethal, metastatic breast cancer.

Breast cancer is the most significant cause of cancer-related death in women around the world. The vast majority of breast cancer-associated mortality stems from metastasis, which remains an incurable disease state. Metastasis results from evolution of clones that possess the insidious properties required for dissemination and colonization of distant organs. These clonal populations are descended from breast cancer stem cells (CSCs), which are also responsible for their prolonged maintenance and continued evolution. Telomeres impose a lifespan on cells that can be extended when they are actively elongated, as occurs in CSCs. Thus, changes in telomere structure serve to promote the survival of CSCs and subsequent metastatic evolution. The selection of telomere maintenance mechanism (TMM) has important consequences not only for CSC survival and evolution, but also for their coordination of various signaling pathways that choreograph the metastatic cascade. Targeting the telomere maintenance machinery may therefore provide a boon to the treatment of metastatic breast cancer. Here we review the two major TMMs and the roles they play in the development of stem and metastatic breast cancer cells. We also highlight current and future approaches to targeting these mechanisms in clinical settings to alleviate metastatic breast cancers.

Hyponatremia is the most frequent electrolyte disorder encountered in hospitalized patients. Several studies have demonstrated that hyponatremia is a negative prognostic factor in different clinical scenarios. Noteworthy, not only severe and acute hyponatremia has been associated with an increased risk of mortality, but also moderate of even mild chronic hyponatremia may increase the risk of death. This has been demonstrated in different categories of patients, including cancer patients. There is growing evidence that both progression free survival and overall survival are significantly reduced in cancer patients with hyponatremia compared to patients with normonatremia. One important, and still open, question is whether the worse outcome associated with hyponatremia in cancer patients is directly attributable to the electrolyte disorder itself or might be a sign of the severity of the underlying disease. With regard to this point, some basic research studies suggested that low sodium concentration stimulates per se cancer cells proliferation and invasiveness. Recent clinical evidence appears to indicate that the correction of hyponatremia is an independent and favourable prognostic factor in cancer patients. Admittedly, robust confirmatory data from clinical practice are needed, in order to validate the hypothesis that cancer patients may die for hyponatremia and not just with hyponatremia.

Although greater than 90% of breast cancer-related mortality can be attributed to metastases, the molecular mechanisms underpinning the dissemination of primary breast tumor cells and their ability to establish malignant lesions in distant tissues remain incompletely understood. Genomic and transcriptomic analyses identified a class of transcripts called long noncoding RNA (lncRNA), which interact both directly and indirectly with key components of gene regulatory networks to alter cell proliferation, invasion, and metastasis. We identified a pro-metastatic lncRNA BMP/OP-Responsive Gene (BORG) whose aberrant expression promotes metastatic relapse by reactivating proliferative programs in dormant disseminated tumor cells (DTCs). BORG expression is broadly and strongly induced by environmental and chemotherapeutic stresses, a transcriptional response that facilitates the survival of DTCs. Transcriptomic reprogramming in response to BORG resulted in robust signaling via survival and viability pathways, as well as decreased activation of cell death pathways. As such, BORG expression acts as a (1) marker capable of predicting which breast cancer patients are predisposed to develop secondary metastatic lesions; and (2) unique therapeutic target to maximize chemosensitivity of DTCs. Here we review the molecular and cellular factors that contribute to the pathophysiological activities of BORG during its regulation of breast cancer metastasis, chemoresistance, and disease recurrence.

Aim: Volumetric modulated arc therapy (VMAT) has been utilized to plan and treat multiple cranial metastases using a single isocenter due to its ability to provide steep dose gradients around targets as well as low doses to critical structures. VMAT treatment is delivered in a much shorter time compared to using a single isocenter for the treatment of each lesion. However, there is a need to develop methods to reduce the treatment planning time for these cases while also standardizing the plan quality. In this work we demonstrate the use of RapidPlan, which is knowledge-based treatment (KBP) planning software to plan multiple cranial SRS cases.

Methods: The 66 patient plans with 125 lesions (range 1-4, median 1) were used to train a model. In addition, the model was validated using 10 cases that were previously treated and chosen randomly. The clinical plans were compared to plans generated by RapidPlan for target coverage and critical organ dose.

Results: Coverage to the target volume, gradient index, conformity index and minimum dose to the target showed no significant difference between the original clinical plan vs. the plan generated by KBP. A comparison of doses to the critical organs namely the brainstem, brain, chiasm, eyes, optic nerves and lenses showed no significant difference. Target dose homogeneity was slightly better with the clinical plan, however this difference was also statistically insignificant.

Conclusion: This work demonstrates that KBP can be trained and efficiently utilized to help not only speed up the planning process but also help standardize the treatment plan quality.

Breast cancer is the second leading cause of cancer-associated death in women in the United States, with more than 90% of those deaths attributed to metastasis. Breast cancer metastasis is incurable and possesses few treatment options and a poor overall prognosis due in part to confounding metastatic attributes, particularly the acquisition of dormancy-associated phenotypes. Dormant disseminated tumor cells can persist for years-to-decades before recurring as highly aggressive, secondary lesions. Dormancy-associated phenotypes are exhibited by breast cancer stem cells (BCSCs), which undergo tumor initiation and unlimited self-renewal. In addition to their specialized abilities to circumvent chemotherapeutic insults, BCSCs also upregulate autophagy during metastatic dormancy as a means to survive in nutrient poor conditions and environmental stress. As such, therapeutic targeting of autophagy is actively being pursued as an attractive strategy to alleviate metastatic disease and the recurrence of dormant BCSCs. Here we review the molecular and cellular features of autophagy, as well as its paradoxical role in both suppressing and promoting mammary tumor development and metastatic progression. Finally, we highlight the clinical challenges associated with therapeutic targeting of autophagy in metastatic breast cancers.

Breast cancer remains the main cause of cancer-related mortality for women world-wide. Main cause of death is the development of therapy-resistant metastases. Relapses occur with a bimodal temporal distribution, with a first peak at 1-2 years after initial therapy and a second peak 2-3 years later. This discontinuous growth kinetics is consistent with the notion that disseminated cancer cells can remain dormant over a prolonged period of time before resuming growth. How cancer cells enter, sustain and exit dormancy, are unanswered questions with relevance to cancer biology, monitoring and therapy. Investigating mechanisms of breast cancer dormancy remains challenging, as in patients the condition is elusive and experimentally there are only a few models that recapitulate the clinical condition. Thus, developing new models to identify clinically relevant mechanisms and candidate therapeutic targets may open new avenues for novel therapies to induce and prolong dormancy. We have observed that cells surviving chemotherapy can enter a state of immunological dormancy. Using this model, we identified IRF-7/Interferon type I/IFNRA as signaling axis essential for this effect. Here we will review concepts and recent developments in cancer metastasis and dormancy with emphasis on breast cancer, and elaborate strategies to exploit them therapeutically.

With more than one million new diseases per year breast cancer is the most common malignancy in women. Metastatic breast cancer remains an incurable disease and the spinal column is most likely affected by metastases. A significantly prolonged patient survival is the consequence of modern oncologic treatment options in the last decade. Surgical treatment of vertebral metastases has become an increasing focus for spine surgeons. With the turn of the millennium it was possible to classify breast cancer into four intrinsic phenotypes with various survival rates. Well known scoring systems help surgeons to evaluate the patient´s prognosis and to choose adequate treatment options. However, tumor entities are differentiated without regard to the molecular subtypes. In this article we describe surgical treatment options in metastatic lesions to the spine with regard to molecular phenotypes of breast cancer malignancy. It is crucial to correctly estimate the expected survival time to plan invasiveness of therapy regarding metastatic spine surgery.

Aim: Lactate can signal through the endogenous lactate receptor, GPR81, which is expressed in some cancers. Lactate metabolism is altered by the metastasis-promoting process of epithelial-mesenchymal transition (EMT). This study examined the expression and function of GPR81 in breast cancer samples, and in receptor-positive epithelial vs. triple-negative post-EMT mesenchymal breast cancer cells.

Methods: GPR81 mRNA expression was examined by breast cancer microarray, and by a Kaplan-Meier survival curve. Using 3-dimensional culture conditions, GPR81 mRNA expression in epithelial and mesenchymal breast cancer cell lines was measured by qRT-PCR. GPR81 siRNA was used to assess the role of GPR81, alone or in conjunction with tamoxifen, in the regulation of MCT1 and MCT4 lactate transporters, intracellular lactate, and cell proliferation and survival.

Results: GPR81 mRNA levels were elevated in receptor-positive breast cancer, relative to non-tumor and triple-negative samples, and correlated with increased survival. GPR81 expression was elevated in the two epithelial breast cancer cell lines vs. the corresponding post-EMT mesenchymal cell lines. GPR81 knock-down in epithelial MCF7 cells caused: 1, selectively lower mRNA and protein expression of the MCT1 transporter, but not MCT2 or MCT4 transporters; 2, lower levels of intracellular lactate; and 3, decreased proliferation and survival in lactate only-containing conditions. GPR81 siRNA plus tamoxifen displayed additive suppressive effects on MCT1 expression and cell viability.

Conclusion: GPR81 promotes the ability of epithelial breast cancer cells to import lactate for energy use. As such, GPR81 represents a potential target for treatment of hormone-positive breast cancer cells, and may be prognostic for higher grade breast cancer.

As a field we have made tremendous strides in treating breast cancer, with a decline in the past 30 years of overall breast cancer mortality. However, this progress is met with little affect once the disease spreads beyond the primary site. With a 5-year survival rate of 22%, 10-year of 13%, for those patients with metastatic breast cancer (mBC), our ability to effectively treat wide spread disease is minimal. A major contributing factor to this ineffectiveness is the complex make-up, or heterogeneity, of the primary site. Within a primary tumor, secreted factors, malignant and pre-malignant epithelial cells, immune cells, stromal fibroblasts and many others all reside alongside each other creating a dynamic environment contributing to metastasis. Furthermore, heterogeneity contributes to our lack of understanding regarding the cells’ remarkable ability to undergo epithelial/non-cancer stem cell (CSC) to mesenchymal/CSC (E-M/CSC) plasticity. The enhanced invasion & motility, tumor-initiating potential, and acquired therapeutic resistance which accompanies E-M/CSC plasticity implicates a significant role in metastasis. While most work trying to understand E-M/CSC plasticity has been done on malignant cells, recent evidence is emerging concerning the ability for pre-malignant cells to undergo E-M/CSC plasticity and contribute to the metastatic process. Here we will discuss the importance of E-M/CSC plasticity within malignant and pre-malignant populations of the tumor. Moreover, we will discuss how one may potentially target these populations, ultimately disrupting the metastatic cascade and increasing patient survival for those with mBC.

Aim: Benign prostatic hyperplasia and prostate cancer is an internationally important health problem of the man, particularly in developed countries. The aim of this exploratory study was to evaluate whether significant difference in the levels of Zn and some other trace elements of prostatic fluid exist between the inflamed and malignantly transformed prostate.

Methods: Prostatic fluid levels of Br, Fe, Rb, Sr, and Zn were prospectively evaluated in 52 patients with benign prostatic hyperplasia and 24 patients with prostate cancer. Measurements were performed using ¹⁰⁹Cd radionuclide-induced energy dispersive X-ray fluorescent microanalysis. Prostatic fluid samples were divided into two portions. One was used for cytological study to exclude prostatitis, while the other was intended for trace element analysis.

Results: Mean values ± standard error of means for concentration (mg/L) of trace element in the prostatic fluid of hyperplastic prostate were: Br 2.32 ± 0.30, Fe 11.5 ± 1.8, Rb 1.70 ± 0.23, Sr 1.41 ± 0.26, and Zn 488 ± 42. The contents of Rb and Zn were significantly lower (approximately 3.2 and 7.7 times, respectively) in fluid of cancerous prostate compared with those in fluid of hyperplastic prostate.

Conclusion: There are significant differences in trace element contents in the fluid of hyperplastic and malignantly transformed prostate. The great decrease in levels of Rb and Zn in the fluid of cancerous prostate might demonstrate an involvement of these trace elements in etiology and pathogenesis of malignant prostate tumors. It was supposed that the differences in Rb and Zn levels in prostatic fluid can be used as tumor markers.

Breast cancer usually grows very quickly, becoming insensitive to blood flow in nearby veins; because of that, inside solid tumors it’s possible to find a hypoxic environment, in other words, an environment where oxygen is less available. Another feature of cancer is its angiogenesis rate, because of the high energy demand, new blood vessels must be produced to take nutrients inside the solid tumor mass. Even with normal blood flow bringing the cancer oxygen and nutrients, its cells favor hypoxia, in an event known as Warburg Effect. According to the Warburg Effect, cells, even with normal oxygen rates, prefer to use fermentation instead of the citric acid cycle to produce ATP. For the cancer to operate normally in hypoxia, a transcription factor family is activated, known as hypoxia-induced factors (HIF), composed of a HIF-1β and a HIF-1α subunits. As HIF-1α is expressed during hypoxia, it is a great target for treatments and a breast cancer biomarker. Because of the role of HIF-1α in cancer and the high incidence of breast cancer worlwide, this review was performed in order to bring the most recent results concerning the role HIF-1α can exert in breast cancer development and progression.

The existence of mammary epithelial stem cell (MaSC) populations capable of mediating mammary gland development and homeostasis has been established for over a decade. A combination of lineage tracing and mammary gland transplantation studies has affirmed that MaSCs and their downstream progenitors are organized in a hierarchal manner; however, these techniques have failed to illuminate the complete spectrum of epithelial intermediate populations or their spatial and temporal relationships. The advent of single cell sequencing technology has allowed for characterization of highly heterogeneous tissues at high resolution. In the last two years, the remarkable advances in single cell RNA sequencing technologies have been leveraged to address the heterogeneity of the mammary epithelium. These studies have afforded fresh insights into the transcriptional differentiation hierarchy and its chronology. Importantly, these data have led to a major conceptual shift in which the rigid boundaries separating stem, progenitor, and differentiated epithelial populations have been deconstructed, resulting in a new more fluid and flexible model of epithelial differentiation. The emerging view of the mammary epithelial hierarchy has important implications for mammary development, carcinogenesis, and metastasis, providing novel insights into the underlying cellular states that may promote malignant phenotypes.

Aim: Paxillin is a well-known multidomain scaffold protein that is involved in the regulation of cell-matrix adhesion dynamics, a process required for the tumor cell migration and invasion. Phosphorylation of the serine residue 178 requires c-Jun NH2-terminal kinase (JNK) activation, which occurs downstream of epidermal growth factor receptor (EGFR)-mediated signaling and drives cell migration. In this study, we investigated the significance of paxillin Ser178 phosphorylation in breast cancer progression.

Methods: We employed the rat mammary carcinoma MTLn3 cell line with which we established stabile variants of both wild type and mutant GFP-paxillin constructs. With those, we next performed several in vitro assays including cell proliferation, migration and focal adhesion dynamics. Finally, we monitored the metastatic spread of both cell line variants in an othrotopic mouse model for breast cancer.

Results: Here we show that expression of the phospho-defective mutant paxillinS178A in the metastatic mammary adenocarcinoma MTLn3 cell-line significantly decreased EGF-induced cell migration, which was correlated with impaired focal adhesion dynamics. Moreover, paxillinS178A attenuated lung metastasis formation in an orthotopic In vivo mammary gland tumor/metastasis model, demonstrating the importance of JNK-mediated paxillin phosphorylation in breast cancer progression. Expression of paxillinS178A caused a decrease in EGFR expression, while re-expression of EGFR in MTLn3-paxillinS178A cells fully restored EGF-driven cell motility and focal adhesion dynamics. Furthermore, re-expression of EGFR in MTLn3-paxillinS178A rescued spontaneous metastasis from breast to lung.

Conclusion: Overall our data show an important role for JNK-mediated paxillin Ser178 phosphorylation in the regulation of EGFR expression and thereby, in EGF-driven cell migration and metastasis formation.

In oncology, liquid biopsy is applied to detect with high efficiency clinically relevant analytes, such as tumor cells, cell-free nucleic acids, and exosomes in peripheral blood and other body fluids of cancer patients. Liquid biopsy is considered one of the most advanced non-invasive diagnostic systems useful, in the next future, for enabling personalized treatments in precision medicine. Medical actions include, but are not limited to, early diagnosis, staging, prognosis, anticipation (lead time) and prediction of therapy responses, as well as follow up. Experimental system for validation of the proposed liquid biopsy approaches is highly needed. In this review article we will discuss the establishment of xenotransplanted mouse model systems for the validation of liquid biopsy protocols aimed to identify changes in the miRNA plasma content. Human colon cancer HT-29 and LoVo cells have been xenotransplanted and miR-221-3p and miR-222-3p have been comparatively analyzed in cultured HT-29 and LoVo cells, xenotransplants and plasma samples.

Small-cell lung cancer (SCLC) has a high propensity to metastasize into the brain. Radiotherapy plays a major role in the treatment of brain metastases (BM) from SCLC. Whole-brain radiotherapy (WBRT) is the standard treatment of BM from SCLC. However, the neurocognitive toxicity and modest efficacy of this approach have led to the increased use of stereotactic radiosurgery. We have no strong evidence for the use of different forms of radiation (WBRT vs. radiosurgery) in SCLC, because BM from this primary tumor were excluded from clinical trials. In this review, the use of radiation in form of WBRT or radiosurgery is discussed in distinct clinical indications: as a primary treatment and at relapse; without prior use of prophylactic cranial irradiation (PCI); and after PCI. Combinations of radiotherapy with chemotherapy are discussed as BM in SCLC occur rarely as a sole event.

Brain metastasis are the most common intracranial malignancy in the adult population. Their incidence has increased dramatically over the last 20 years, as a result of the increasing number of cases stemming from lung and breast cancer together with the higher cancer survival rates due to diagnostic and therapeutic advances. More than 40% of cancer patients develop brain metastases during the course of their disease: specifically, they appear in 50% of patients with lung cancer, more than 25% of patients with breast cancer, and 20% of patients with melanoma. Diagnosis is made using different imaging approaches, such as computed tomography and magnetic resonance imaging, accompanied by clinical manifestations and a history of malignancy supporting the diagnosis of a brain metastasis. Current treatment options should be oriented to the patient’s current performance, the number of intracranial and extracranial lesions, and related factors. Although surgical resection and whole-brain radiotherapy have been standard treatments for many years, numerous treatment modalities have become more easily available and accepted worldwide, producing more favorable and reliable results. Among these is stereotactic radiosurgery, and the latest clinical trials support this treatment.

A large and incremental number of non-coding RNAs, including microRNAs (miRNAs) have been recently demonstrated to play a very important role in human pathologies, including cancer. Therefore, microRNAs have been proposed as therapeutic targets and molecules exhibiting anti-miRNA activity or mimicking functional miRNAs have been developed. Among biomolecules proposed in anti-miRNA therapy, peptide nucleic acids (PNAs) are appealing, in consideration of their stability and efficacy in recognizing RNA targets. PNAs against tumor associated miRNAs have proven to be efficient in inducing anti-tumor effects both in vitro and in vivo. For instance, PNAs targeting miR-155-5p are able to induce apoptosis in glioma cell lines and to enhance the sensitivity to temozolomide (TMZ) in TMZ resistant glioma cells. In vivo, PNAs anti-miR-21 were found to exhibit anti-tumor effects associated with improved survival when administered to animals with intracranial gliomas.

Cancer cells often have an increased amount of glycans, such as sialic acid (SA), on the cell surface, which normally play an important role in cell growth, proliferation and differentiation. In this study, SA expression is determined by fluorescent nanoprobes, molecularly imprinted polymers, SA-MIPs. The nanoprobes are synthesized with an imprinting approach to produce tailor-made fluorescent core-shell particles with high affinity for cell surface SA. Inflammation and cytokine production are well known tumor promoters, modulating the cellular microenvironment, including an aberrant cell surface glycan pattern. The recombinant cytokines IL-4, IL-6, IL-8 and a cocktail of cytokines collected from stimulated T leukemia Jurkat cells were used to induce in vitro inflammation in two cell lines, and thereafter analyzed with the use of SA-MIPs and flow cytometry. One of the cell lines showed a different binding pattern of SA-MIPs after treatment with recombinant cytokines and the cytokine cocktail. This study shows that SA-MIPs can be an important tool in the investigation of overexpressed glycans in the tumor microenvironment.

Aim: Exon 18 expression of NCAM has been recognized as a biomarker for small cell lung cancer (SCLC). To use this finding for an improved diagnosis of SCLC and personalized treatment of patients, techniques to identify and quantitate E18, the exon 18 encoded protein moiety of NCAM, are needed. We developed three monoclonal antibodies for this purpose.

Methods: The his-tagged E18 antigen was expressed in E. coli and, after purification, used to immunize mice. Hybridoma’s were isolated by standard procedures and tested for their reaction with E18.

Results: Three monoclonal antibodies, MUM-1, MUM-4 and MUM-6 were obtained. They reacted with E18 in western blots, with SCLC cell line NCI-H82, but not with unrelated his-tagged proteins. Only permeabilized NCI-H82 cells stained with the antibodies, confirming the intracellular position of E18. Next an enzyme-linked immunosorbent assay was developed using the earlier isolated monoclonal antibody MUMi-21B2, coated on the surface of microtiter wells as capture antibody and biotinylated MUM-6 as second antibody. Using streptavidin conjugated to horse radish peroxidase a linear dose response curve to his-tagged E18 antigen was obtained between 0 and 5 µg/mL with a sensitivity of at least 0.5 µg/mL or 50 ng/well.

Conclusion: Four monoclonal antibodies are available to be used in assays for the identification and quantification of SCLC biomarker E18. This will enable the development of liquid biopsies to follow the tumor load in patients.

Estrogen disrupting chemicals are environmental compounds which mimic, antagonize or interfere in the action of physiological estrogens. They occur naturally (plant phytoestrogens) but the majority are man-made compounds, which, through their use in agricultural, industrial and consumer products, have become widely present in human tissues including breast tissue. Since exposure to estrogen is a risk factor for breast cancer, estrogen disrupting chemicals may also contribute to breast cancer development. This review discusses evidence implicating estrogen disrupting chemicals in increasing migratory and invasive activity of breast epithelial cells, in epithelial-to-mesenchymal transition, and in growth of breast tumours at metastatic sites as well as the primary site. Mechanisms may be through the ability of such chemicals to bind to estrogen receptors, but unlike for proliferation, effects on cell migration and invasion are not limited to estrogen receptor-mediated mechanisms. Furthermore, whilst effects on proliferation can be measured within hours/days of adding an estrogen disrupting chemical to estrogen-responsive breast cancer cells, effects on cell migration occur after longer times (weeks). Most studies have focused on individual chemicals, but there is now a need to consider the environmentally relevant effects of long-term, low-dose exposure to complex mixtures of estrogen disrupting chemicals on mechanisms of metastasis.

Syndrome of inappropriate antidiuresis (SIAD) is a common paraneoplastic syndrome commonly associated with thoracic malignancies, gastrointestinal cancers and kidney tumors. It is defined as hyponatremia in euvolemic patients, often due to abnormal secretion of antidiuretic hormone by tumor cells. Tolvaptan, a vasopressin-2-receptor antagonist, is currently recommended for patients affected by SIAD with mild or moderate symptoms. Among patients with prostatic cancer, SIAD represents a rare condition but it is frequently associated with poorly differentiated adenocarcinoma or pure small-cell carcinoma histotype. We report a case of SIAD appeared at disease progression in a 60-year-old male patient with acinar adenocarcinoma with neuroendocrine differentiation together with a literature review.

Cancer cachexia is a debilitating syndrome mainly characterized by muscle and fat wasting, leading to the progressive loss of body weight and complicating the management of cancer patient. In particular, the loss of muscle weight is a negative prognostic factor, being associated with chemotherapy toxicity and reduced survival. Increased inflammation and protein dysmetabolism are some of the impairments that lead to muscle wasting in cancer patients. Together with these alterations, tumor growth and chemotherapy administration may affect mitochondrial function, impinging on the muscle energy metabolism. Indeed, therapeutic approaches poised to correct both hypercatabolism and mitochondrial alterations could be effective in preventing cancer-induced muscle wasting. Among the non-pharmacological approaches, exercise training is one of the best modulator of muscle physiology able to impinge on both protein and energy metabolism. However, the wasting phenotype that characterizes cancer patients could be not compatible with physical training, prompting the development of different strategies to improve muscle metabolism. The aim of this mini-review is to discuss both the beneficial effects and the limitations of exercise training in cancer cachexia and the adoption of drugs able to modulate exercise-induced pathways.

Aim: There is increasing appreciation of the role of the renin-angiotensin system (RAS) in carcinogenesis with recent evidence showing expression of the RAS by cancer stem cells (CSCs) in different types of cancer. We have recently demonstrated the presence of three CSC subpopulations within metastatic melanoma (MM) to the brain: a Melan-A⁺ subpopulation and a Melan-A^- subpopulation within the tumor that express OCT4, SALL4, SOX2 and NANOG; and a pSTAT3⁺ subpopulation localized to the CD34⁺ endothelium of microvessels within the tumor. In this study we investigated the expression and localization of components of the RAS in relation to these CSCs in MM to the brain.

Methods: 3, 3-diaminobenzidine immunohistochemical (IHC) staining of components of the RAS: pro-renin receptor (PRR), angiotensin converting enzyme (ACE), angiotensin II receptor 1 (ATIIR1) and angiotensin II receptor 2 (ATIIR2) was performed on the same ten samples of MM to the brain included in our previous study. Immunofluorescence IHC staining of these components of the RAS was performed with embryonic stem cell markers OCT4 and NANOG, and endothelial marker CD34, on two of the samples of MM to the brain from the original cohort of ten patients. Western blotting (n = 5) and NanoString mRNA analysis (n = 4) were performed on samples of MM to the brain to confirm protein and mRNA expression of these components of the RAS, respectively.

Results: DAB IHC staining showed the presence of PRR, ACE, ATIIR1 and ATIIR2 in all ten samples of MM to the brain. IF IHC staining showed that the CSC subpopulations in MM to the brain expressed PRR, ATIIR1 and ATIIR2; and a CSC subpopulation on the endothelium of the microvessels expressed ACE. Western blotting and NanoString mRNA analysis confirmed protein and mRNA expression of these components of the RAS, respectively.

Conclusion: CSCs in MM to the brain expressed components of the RAS. Targeting the CSCs using modulators of the RAS may be a novel therapeutic approach for treating this aggressive cancer.

Aim: Hypersensitivity reactions to carboplatin are not an infrequent adverse event in ovarian cancer patients. However, reintroduction of platinum-containing schedules is the standard of care in platinum-sensitive recurrent ovarian cancer. Rapid desensitization is a procedure for gradual reintroduction of drug. It allows a safe administration of medications that are beneficial for the management of patients after certain types of hypersensitivity reactions. It is indicated in cases in which there are no reasonable therapeutic alternatives.

Methods: We performed a descriptive retrospective study of high-grade ovarian cancer patients with known carboplatin hypersensitivity reactions that were treated with a 13-steps rapid desensitization protocol with 3 different solutions and infusion rates. The procedure followed a mathematic model (gradual increases with a relationship between doses following a geometric series) which is called logarithmic rapid desensitization protocol (LRDP). The aim was to describe the safety of the LRDP in terms of number and severity of infusion reactions and the effectiveness in the rate of cycles completely administered.

Results: Four different patients diagnosed with recurrent platinum-sensitive ovarian cancer with a previous infusion reaction were included. LRDP was administered in 19 different cycles. LRDP was administered safety in all 19 cycles, only 2 patients had a mild cutaneous reaction in 4 different cycles during LRDP (21.05%). The foreseen dose of carboplatin was fully administered in all cycles.

Conclusion: LRDP with carboplatin is a feasible and safe protocol in patients with previous infusion reaction to carboplatin. The protocol might allow a safe administration of drugs, that are beneficial for the management of patients, after certain types of hypersensitivity reactions, and it is indicated in cases in which there are no reasonable therapeutic alternatives.

Excess adiposity, a worldwide-growing pathological condition, is now recognized as a main risk factor for most chronic diseases including colorectal cancer (CRC). Obese subjects show an increased cancer incidence with obesity representing an important indicator of survival, prognosis, recurrence and response to therapy. A low-grade chronic inflammation of metabolically active tissues including the adipose tissue (AT), defined as meta-inflammation, is a main feature of obesity. Fatty acids (FA), the main AT components, are important modulators of inflammation, and the type of FA stored in AT critically affects tissue functions. Their profile within AT mirrors FA dietary intake but also depends on a metabolic control. Obesity, changes in the habitual diet, weight loss or pathological conditions like CRC influence FA profile of AT pointing to these molecules as important actors in AT dysfunction and meta-inflammation, that characterize metabolic diseases and may favor cancer development. Worth of note, diet is receiving growing attention as a main determinant in cancer prevention due to its capacity to modulate immune response and inflammation. Alterations in the balance between different families of FA may contribute to generate a pro-inflammatory profile with deleterious effects on metabolic and immune homeostasis at both local and systemic levels. This review focuses on FA as regulators of human AT inflammation discussing the role of obesity-, diet-, and weight loss-associated changes in FA profile in this process. The relevance of FA composition of AT in linking diet, obesity and CRC will be also reviewed.

Cancer exacts a heavy socioeconomic cost. Earlier detection and treatment are likely to mitigate this cost. Unfortunately, conventional tissue biopsy, the gold standard in cancer diagnosis cannot fulfill the goal of earlier detection. While liquid biopsy is a promising alternative to tissue biopsy, it has its challenges and limitations. A major challenge is the isolation of bona fide lipid membrane vesicles from biological fluids. In this review, we presented a new perspective of isolating different types of extracellular vesicles (EVs) by their affinity for membrane lipid binding ligands for liquid biopsy. EVs are lipid membrane particles naturally released by almost all cells and are found in almost all biological fluids suitable for liquid biopsy. They carry materials from the secreting cells that could affect the biology of the recipient cells and could thus inform on the state and progress of the disease. However, isolating bona fide EVs is a technical challenge as biological fluids have a complex composition and contain particles or aggregates that are physically similar to EVs. Here we review the use of membrane lipid-binding ligands to isolate different bona fide EV subtypes, and to circumvent the problem of co-isolating physically similar non-EV complexes in current EV isolation protocols. We will discuss the advantages of this technique and its potential for accelerated biomarker discovery and validation through examples of pre-clinical studies. We propose that isolating EV subtypes is a technically viable and robust strategy to overcome the current bottleneck of isolating EVs for liquid biopsy.

Patients with glioblastoma (GBM), a malignant brain tumor, exhibit a mean survival of less than 1.5 years. Despite treatment, the disease eventually develops resistance, resulting in disease relapse. Autophagy is a process of degradation and clearance that is activated to maintain cellular homeostasis. Its roles in cancer disease course and the treatment response, however, are controversial. In GBM, accumulating evidence has indicated that autophagy can protect cells, especially those with stemness features, causing the development of cell resistance. In this review, we discuss the impact of the cell reaction to currently active treatments, including temozolomide, radiation, tumor treating fields, bevacizumab (Avastin), etoposide (VP-16), cisplatin (CDDP), and carmustine (BCNU). Most of these induce the up-regulation of autophagy through signaling pathways of DNA damage response, reactive oxygen species, hypoxia, retinoblastoma, AMP-activated protein kinase, AKT/mTOR and MST4 kinase affecting cell fate by altering cell metabolism, cell death, and DNA repair. Treatment-related autophagy may be modulated by combining autophagy inhibitors such as chloroquine or antioxidants to prevent the development of resistance, thus improving cancer treatment.

Liquid biopsy consists in a simple blood sampling that allows to analyze cell free DNA (cfDNA), containing specific genomic clues released by the tumor into the bloodstream. In this review, we shall focus on the analysis of cfDNA in lymphoma and, in particular, on its application in the genotyping and monitoring of two common types of B-cell lymphoma, i.e., diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL). From a diagnostic standpoint and based upon the current international guidelines, lymphoma diagnosis has so far relied on the analysis of the tissue biopsy. From a molecular viewpoint, though, the tissue biopsy does not reflect the entire molecular heterogeneity of lymphomas. In fact, in an individual patient, lymph nodes at different anatomical sites, as well as different areas of the same lymph node, may show different genetic profiles. Consequently, molecular analysis of genomic DNA extracted from a single lymph node biopsy may not recapitulate the whole mutational landscape of the disease. Liquid biopsy may overcome this hurdle, since cfDNA is released by all tumoral cells and can reveal the entire molecular complexity of lymphomas. From a translational perspective, liquid biopsy may also be used to evaluate clonal evolution, response to therapy and minimal residual disease. Consistently, in DLBCL as well in cHL, the drop of the mutational burden during the treatment course provides complementary information to conventional imaging techniques. The integration of liquid biopsy with imaging techniques may prove useful for a better prediction of patients’ outcome and for a better treatment tailoring.

Cachexia affects the majority of patients with advanced cancer. It leads to poor surgical and oncological outcomes, and negatively affects quality of life. It has long been reported that components of the host immune system, including pro-inflammatory cytokines such as IL-1α, IL-6, TNF-α and INF-γ, participate in the syndrome of cachexia. Yet therapeutic targeting of these pro-inflammatory factors has not yielded meaningful improvements in cachexia management. More recently, the impact of immune cells in the tumour mass (tumour-associated macrophages) and host circulation (myeloid suppressor cells) has garnered much interest with regards to their role in immune tolerance in cancer. However, their role in the generation of systemic inflammation and cancer cachexia is underexplored and outstanding questions remain. This review summarises the key mediators and targets of immune dysfunction in cancer cachexia. Here we describe the host response including skeletal muscle wasting; highlight the current knowledge gap areas; and report the results of previously trialled immunotherapies. A greater understanding of complex interaction between the tumour, immune system and peripheral tissues in the genesis and maintenance of cancer cachexia is a key step in n identifying future therapeutic targets.

While we made great strides in the early detection of a handful of cancers, many other cancers are still detected at fairly later stages, thus hindering the deployment of effective surgical or therapeutic intervention to change their dismal clinical outcomes. The arduous journey of cancer cells from the primary tumor to colonize distant secondary organs or tissues begins with their ability to activate or deactivate various cellular processes at will, including the autophagy machinery. In this review, we discuss how circulatory cancer cells from primary tumors could selectively mobilize different subsets of microRNAs (miRNAs) to enable autophagic recycling of nutrients during their search for secondary sites to colonize and to disable such cell survival programs once they have successfully established at distant organs or tissues. We also discuss how this new miRNA-autophagy-metastasis axis can be targeted by the emerging RNA Medicine toolkit.

Multiple myeloma (MM) is a plasma cell cancer characterized by sustained endoplasmic reticulum (ER) stress and unfolded protein response activation in the setting of high rates of immunoglobulin synthesis. Consequently, MM cells rely heavily on protein quality control pathways for survival as evidenced by the clinical efficacy of proteasome inhibitors (PI). Autophagy is an intracellular self-digestion mechanism that plays a role in the ER protein quality control process. Unsurprisingly then, basal levels of autophagy were recently found to confer a survival and drug-resistance benefit to MM cells. However, excessive induction of autophagy in MM cells leads to autophagic cell death, highlighting the double-edged nature of autophagy modulation in MM. This review provides an overview of the role that autophagy plays in MM pathogenesis, survival, and drug-resistance. We highlight the potential utility of therapeutically targeting autophagy in MM, focusing on preclinical data of autophagic modulators in combination with alkylators, anthracyclines, PI, and immunomodulatory drugs.

Hyponatremia is the most frequently encountered electrolyte disorder in cancer patients and is usually multifactorial in its origin. In this review, we discuss the predisposing factors, pathophysiology, clinical symptomatology, and currently available diagnostic and therapeutic options for the management of hyponatremia. In addition to paraneoplastic syndromes, concurrent chemotherapy and comorbidities predispose oncology patients to the risk of hyponatremia. Initial symptoms and signs can be subtle and the prompt evaluation and initiation of treatment is of paramount importance to prevent neurocognitive and other complications. The syndrome of inappropriate antidiuresis (SIAD) is the most common cause of hyponatremia, and the use of serum and urine parameters that distinguish SIAD from other etiologies is discussed. Individualized treatment is preferred depending on the underlying cause and severity of hyponatremia. The treatment of hyponatremia is reviewed and the importance of avoiding rapid overcorrection of the sodium level to reduce the risk of osmotic demyelination syndrome is emphasized. Vasopressin receptor antagonists (vaptans) offer a direct approach to the management of euvolemic and hypervolemic hyponatremia, but the indications for their use and long-term safety need to be clarified. The treatment of hyponatremia is likely to reduce complications and improve survival in cancer patients.

As with many types of cancer, immunotherapy is changing the management of squamous cell carcinoma of the head and neck (HNSCC). In a locally advanced or metastatic setting, treatment options have long been curtailed, but this paradigm is currently changing. Checkpoint inhibitors were the first to be validated in second-line treatment with PD-1 and PD-L1 inhibitors and these treatments are available in USA for first-line use. In addition, many studies are underway to use its molecules earlier in the care or try to increase their effectiveness with associations. The issues of patient selection that would benefit the most from immunotherapy and the evaluation of the response to these treatments are not completely solved. The goal is here to update the possibilities of current treatment by immunotherapy in HNSCC as well as on various development pathways in progress.

Persistent high-risk human papillomavirus (HR-HPV) infection is associated with anogenital and head & neck squamous epithelial (HNSCC) tumors, which altogether cause about 550,000 new cases every year. Several evidences suggest that the microbiota could have a role on the inflammatory, epithelial mesenchymal transition and tumorigenesis processes promoted by HR-HPV infection, yet the mechanisms involved remain to be clarified. In this review we report the state of the art on this topic and on the most promising in vitro developed models for studying the host-pathogen interactions. Using MEDLINE, several terms were searched and combined to select the most pertinent papers. The investigation was limited to the international indexed articles published in PubMed in the last 10 years. This review reports the latest knowledge in the field of the microbial-associated anogenital tumors and HNSCC. In addition, we also discuss the in vitro epithelial culture systems that reproduce the pathophysiological features of the tumoral microenvironment and the in vivo response to microbial agents, thus representing a useful tool for analyzing at cellular and molecular levels the role played by infective agents in tumorigenesis.

Cell-to-cell communication guarantees homeostasis in a multi-cellular organism. Cancer-to-microenvironment communication sustains malignant growth and dissemination. Whereas the accumulation of mutations is at the origin of malignant cell transformation and neoplasia onset, the interaction between cancer and the surrounding stroma, specifically immune cells, influences the balance between tumour regression and tumour progression. To study how the interaction between cancer and stromal cells is disadvantageous or beneficial for tumour progression, the use of a transparent in vivo model bears important research potentials. Zebrafish has been increasingly used as animal model to study tumour biology. The use of transparent zebrafish embryos, with fluorescent endothelial and immune cells, allows the visualization of cell-to-cell interaction, among host cells themselves and between zebrafish stroma and implanted human cancer cells. Here, we summarise our findings on the role of CXCR4 signalling in tumour progression, considering its signature both on cell autonomous and host dependent mechanisms. Finally, we address the translational impact of targeting CXCR4 signalling in cancer and the tumour microenvironment for the treatment of metastatic cancer.

Conventionally, in the pharmacokinetic/pharmacodynamic analysis of small molecule compounds such as cytotoxic anticancer drugs, polymorphism analysis of genes related to absorption, distribution, metabolism, and excretion has been performed in addition to the analyses of blood concentrations of drugs. Such pharmacogenetic factors play an important role in predicting therapeutic effects and adverse events and in the proper use of drugs. With the recent launch of immune checkpoint inhibitors (ICIs) and the rapid development of antibody-drug conjugates (ADCs) currently underway, there is no doubt that antibody drugs, which are large molecule compounds, will become key drugs in anticancer drug treatment. However, the pharmacokinetic and pharmacodynamic analysis of antibody drugs is still not sufficient, and further elucidation of factors and mechanisms affecting their dynamics in the human body is necessary. Moreover, the pharmacogenomic factors of antibody drugs have not yet been fully studied. There are many factors that should be clarified, such as factors that regulate the host immune response in ICI therapy and the effects of ATP-binding cassette transporter and cytochrome P450 on the payload of ADCs. This review provides an outline of antibody drugs in cancer treatment and summarizes the pharmacogenomic factors of antibody drugs known to date.

Unresectable recurrent or metastatic head and neck cancer is an incurable disease with survival of approximately 12 months. Head and neck tumors exhibit numerous derangements in the tumor microenvironment that aid in immune evasion and may serve as targets for future therapies. Pembrolizumab is now approved as a first line therapy. Despite the promise of currently approved immunotherapies there continues to be low response rates and additional strategies are needed. Here, alterations in the immune microenvironment and current therapeutic strategies are reviewed with a focus on novel immunologic approaches.

Aim: Colorectal cancer (CRC) is the third leading cancer-related cause of death due to its propensity to metastasize. Epithelial-mesenchymal transition (EMT) is a multistep process important for invasion and metastasis of CRC. Krüppel-like factor 4 (KLF4) is a zinc finger transcription factor highly expressed in differentiated cells of the intestinal epithelium. KLF4 has been shown to play a tumor suppressor role during CRC tumorigenesis - its loss accelerates development and progression of cancer. The present study examined the relationship between KLF4 and markers of EMT in CRC.

Methods: Immunofluorescence staining for KLF4 and EMT markers was performed on archived patient samples after colorectal cancer resection and on colonic tissues of mice with colitis-associated cancer.

Results: We found that KLF4 expression is lost in tumor sections obtained from CRC patients and in those of mouse colon following azoxymethane and dextran sodium sulfate (AOM/DSS) treatment when compared to their respective normal appearing mucosa. Importantly, in CRC patient tumor sections, we observed a negative correlation between KLF4 levels and mesenchymal markers including TWIST, β-catenin, claudin-1, N-cadherin, and vimentin. Similarly, in tumor tissues from AOM/DSS-treated mice, KLF4 levels were negatively correlated with mesenchymal markers including SNAI2, β-catenin, and vimentin and positively correlated with the epithelial marker E-cadherin.

Conclusion: These findings suggest that the loss of KLF4 expression is a potentially significant indicator of EMT in CRC.

The histone chaperone facilitates chromatin transcription (FACT) plays important roles in essentially every chromatin-associated process and is an important indirect target of the curaxin class of anti-cancer drugs. Curaxins are aromatic compounds that intercalate into DNA and can trap FACT in bulk chromatin, thus interfering with its distribution and its functions in cancer cells. Recent studies have provided mechanistic insight into how FACT and curaxins cooperate to promote unfolding of nucleosomes and chromatin fibers, resulting in genome-wide disruption of contact chromatin domain boundaries, perturbation of higher-order chromatin organization, and global dysregulation of gene expression. Here, we discuss the implications of these insights for cancer biology.

Electrolyte disorders are very common complications in cancer patients. They might be associated to a worsening outcome, influencing quality of life, possibility to receive anticancer drugs, and conditioning survival. In fact, they might provoke important morbidity, with dysfunction of multiple organs and rarely causing life-threatening conditions. Moreover, recent studies showed that they might worsen cancer patients’ outcome, while a prompt correction seems to have a positive impact. Furthermore, there is evidence of a correlation between electrolyte alterations and poorer performance status, delays in therapy commencement and continuation, and negative treatment outcomes. These alterations usually involve sodium, potassium, calcium, and magnesium serum levels. Several causes might contribute to electrolyte disorders in cancer patients: cancer effects, such as paraneoplastic syndrome of inappropriate antidiuresis and tumor lysis syndrome; anti-cancer therapies; and other concomitant clinical conditions or treatments. However, the origin of the electrolyte disorder is often multifactorial, thus identifying and correcting the causes is not always feasible. Furthermore, they are often not recognized or not considered in clinical practice, worsening these alterations and patient condition. An improvement of knowledge about the physiological mechanisms underlying electrolyte disorders is necessary to strengthen their identification and set up a prompt, adequate, and effective treatment. The aim of this systematic review is to provide an analysis of the pathophysiological mechanisms of electrolyte abnormalities in cancer patients to facilitate their identification, management, and therapy to improve patient outcome.

Breast and prostate cancer are the leading causes of death in females and males, respectively. Triple negative breast cancer (TNBC) does not express the estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2, resulting in limited treatment options. Androgen deprivation therapy is the standard care for prostate cancer patients; however, metastasis and recurrence are seen in androgen-independent prostate cancer. Both prostate and breast cancer show higher resistance after recurrence and metastasis, which increases the difficulty of treatment. Natural killer (NK) cells play a critical role during innate immunity and tumor recognition and elimination. NK cell function is determined by a delicate balance of inhibitory signals and activation signals received through cell surface receptors. Lectin-like transcript 1 (LLT1, CLEC2D, OCIL) is a ligand of NK cell inhibitory receptor NKRP1A (CD161). Several studies have that reported higher expression of LLT1 is associated with the development of various tumors. Our studies revealed that TNBC and prostate cancer cells express higher levels of LLT1. In the presence of a monoclonal antibody against LLT1, NK cell-mediated killing of TNBC and prostate cancer cells were greatly enhanced. This review highlights the potential that using monoclonal antibodies to block LLT1 - NKRP1A interactions could be an effective immunotherapeutic approach to treat triple negative breast cancer and prostate cancer.

The most widely used chemotherapeutic combinations in locally advanced (LA) or metastatic pancreatic ductal adenocarcinoma (PDAC) are Nab-Paclitaxel-Gemcitabine (Nab-PCT-GEM) and Fluorouracil, Folinic acid, Oxaliplatin, and irinotecan (FOLFIRINOX). Chemo-resistance, typical of PDAC, appears to be due to the negative influence of stroma population cells, namely regulatory T cells (Treg) and myeloid-derived suppressor cells, macrophages with inhibitory effects on the antitumor activity of the innate and adaptive immune systems, and resistance to cancer treatment. Among other factors that may influence immune surveillance, constant physical activity appears to reduce the risk of cancer-related mortality and cardiovascular risk. However, this does not seem to increase the survival of patients with PDAC. The exception is our young inoperable patient. For LA head PDAC, he was treated with seven cycles of Nab-PCT-GEM and RT 50 Gy/15 fractions combined to biweekly GEM and salvage FOLFIRINOX. The five-year surviving patient travelled 15,000 km on foot and continues inexorably his "walking therapy".