In alignment with the World Health Organization’s strategy to eliminate cervical cancer, substantial progress has been made in the treatment of this malignancy. Cervical cancer, largely driven by human papillomavirus (HPV) infection, is considered preventable and manageable because of its well-established etiology. Advancements in precision screening technologies, such as DNA methylation triage, HPV integration detection, liquid biopsies, and artificial intelligence-assisted diagnostics, have augmented traditional screening methods such as HPV nucleic acid testing and cytology. Therapeutic strategies aimed at eradicating HPV and reversing precancerous lesions have been refined as pivotal measures for disease prevention. The controversy surrounding surgery for early-stage cervical cancer revolves around identifying optimal candidates for minimally invasive and conservative procedures without compromising oncological outcomes. Recent clinical trials have yielded promising results for the development of systemic therapies for advanced cervical cancer. Immunotherapies, such as immune checkpoint inhibitors (ICIs), antibody-drug conjugates (ADCs), and targeted therapy have demonstrated significant effectiveness, marking a substantial advancement in cervical cancer management. Various combination therapies have been validated, and ongoing trials aim to enhance outcomes through the development of novel drugs and optimized combination regimens. The prospect of eradicating cervical cancer as the first malignancy to be eliminated is now within reach. In this review, we provide a comprehensive overview of the latest scientific insights, with a particular focus on precision managements for various stages of cervical disease, and explore future research directions in cervical cancer.
Background: Recurrence and metastasis remain significant challenges in lung adenocarcinoma (LUAD) after radical resection. The mechanisms behind the recurrence and metastasis of LUAD remain elusive, and deregulated cellular metabolism is suspected to play a significant role. This study explores the metabolic and epigenetic regulation mediated by nicotinamide N-methyl transferase (NNMT) in LUAD.
Methods: Untargeted metabolomic analyses were performed to detect metabolism irregularities. Single-cell RNA sequencing (RNA-seq) databases and multiplex immunofluorescence analysis were used to identify the location of NNMT within the tumor microenvironment. The biological functions of NNMT were investigated both in vitro and in vivo, with RNA-seq and chromatin immunoprecipitation-PCR providing insights into underlying mechanisms. Finally, single-cell RNA-seq data and immunohistochemistry of primary tumors were analyzed to validate the main findings.
Results: Untargeted metabolomic analyses revealed metabolic aberrations in amino acids, organic acids, lipids, and nicotinamide pathways, which are linked to metastasis of non-small cell lung cancer. NNMT is a key enzyme in nicotinamide metabolism, and we found the bulk tissue mRNA level of NNMT gene was inversely associated with LUAD metastasis. NNMT was proved to be predominantly expressed in cancer-associated fibroblasts (CAFs) within the stromal regions of LUAD, and a low stromal NNMT expression was identified as a predictor of poor disease-free survival following radical resection of LUAD. The isolation and primary culture of CAFs from LUAD enabled in vitro and in vivo experiments, which confirmed that NNMT negatively regulated the metastasis-promoting properties of CAFs in LUAD. Mechanistically, the downregulation of NNMT led to an increase in intracellular methyl groups by reducing the activity of the methionine cycle, resulting in heightened methylation at H3K4me3. This alteration triggered the upregulation of genes involved in extracellular matrix remodeling in CAFs, including those encoding collagens, integrins, laminins, and matrix metalloproteinases, thereby facilitating cancer cell invasion and metastasis. Reanalysis of single-cell RNA-seq data and immunohistochemistry assays of primary LUAD tissues substantiated NNMT’s negative regulation of these genes in CAFs.
Conclusions: This study provides novel insights into the metabolic and epigenetic regulatory functions of NNMT in CAFs, expanding the current understanding of LUAD metastasis regulation and suggesting potential avenues for future research and therapeutic development.
Background: The interaction between the metastatic microenvironment and tumor cells plays an important role in metastatic tumor formation. Platelets play pivotal roles in hematogenous cancer metastasis through tumor cell-platelet interaction in blood vessels. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy distinguished by its notable tendency to metastasize to the liver. However, the role of platelet in the liver metastatic niche of PDAC remains elusive. This study aimed to elucidate the role of platelets and their interactions with tumor cells in the liver metastatic niche of PDAC.
Methods: An mCherry niche-labeling system was established to identify cells in the liver metastatic niche of PDAC. Platelet depletion in a liver metastasis mouse model was used to observe the function of platelets in PDAC liver metastasis. Gain-of-function and loss-of-function of erythropoietin-producing hepatocellular receptor B1 (Ephb1), tumor cell-platelet adhesion, recombinant protein, and tryptophan hydroxylase 1 (Tph1)-knockout mice were used to study the crosstalk between platelets and tumor cells in the liver metastatic niche.
Results: The mCherry metastatic niche-labeling system revealed the presence of activated platelets in the liver metastatic niche of PDAC patients. Platelet depletion decreased liver metastatic tumor growth in mice. Mechanistically, tumor cell-expressed EPHB1 and platelet-expressed Ephrin B1 (EFNB1) mediated contact-dependent activation of platelets via reverse signaling-mediated AKT signaling activation, and in turn, activated platelet-released 5-HT, further enhancing tumor growth.
Conclusion: We revealed the crosstalk between platelets and tumor cells in the liver metastatic niche of PDAC. Reciprocal tumor-platelet interaction mediated by the EPHB1-EFNB1 reverse signaling promoted metastatic PDAC outgrowth via 5-HT in the liver. Interfering the tumor-platelet interaction by targeting the EPHB1-EFNB1 axis may represent a promising therapeutic intervention for PDAC liver metastasis.
Background: Cancer remains a major cause of mortality and a significant economic burden in China. Exploring the disparities in cancer patterns and control strategies between China and developed countries may offer valuable insights for policy formulation and enhance cancer management efforts. This study examined the incidence, mortality, and disability-adjusted life year (DALY) burden of cancer in China, and compared these metrics with those observed in the United States (US) and the United Kingdom (UK).
Methods: Data on cancer incidence, mortality, and DALYs for China, the US, and the UK were sourced from the GLOBOCAN 2022 online database and the Global Burden of Disease 2021 study (GBD 2021). We utilized Joinpoint regression models to analyze trends in cancer incidence and mortality across these countries, calculating annual percent changes (APCs) and determining the optimal joinpoints.
Results: In 2022, China recorded around 4,824,703 new cancer cases and 2,574,176 cancer-related deaths, contributing to 71,037,170 DALYs. China exhibited a lower cancer incidence rate compared to the US and the UK. Although cancer-related mortality in China is slightly lower than that in the UK, it is significantly higher than that in the US. Additionally, China experienced significantly higher DALY rates compared to both the US and UK. The cancer landscape in China was also undergoing significant changes, with a rapid rise in the incidence and burden of lung, colorectal, breast, cervical, and prostate cancers. Meanwhile, the incidence and burden of stomach cancer continued to decline. Although the incidence of liver and esophageal cancers was decreasing, the burden of liver cancer was increasing, while the burden of esophageal cancer remained largely unchanged.
Conclusions: The cancer profile of China is shifting from that of a developing country to one more typical of a developed country. The ongoing population aging and the rise in unhealthy lifestyles are expected to further escalate the cancer burden in China. Consequently, it is crucial for Chinese authorities to revise the national cancer control program, drawing on successful strategies from developed countries, while also accounting for the regional diversity in cancer types across China.