The multifaceted role of extracellular vesicles in prostate cancer-a review

Abstract

Prostate cancer is the second most prominent form of cancer in men and confers the highest mortality after lung cancer. The term “extracellular vesicles” refers to minute endosomal-derived membrane microvesicles and it was demonstrated that extracellular vesicles affect the environment in which tumors originate. Extracellular vesicles’ involvement is also established in the development of drug resistance, angiogenesis, stemness, and radioresistance in various cancers including prostate cancer. Extracellular vesicles influence the general environment, processes, and growth of prostate cancer and can be a potential area that offers a significant lead in prostate cancer therapy. In this review, we have elaborated on the multifaceted role of extracellular vesicles in various processes involved in the development of prostate cancer, and their multitude of applications in the diagnosis and treatment of prostate cancer through the encapsulation of various bioactives.

Keywords

Extracellular vesicles / prostate cancer / stemness / chemoresistance / therapeutic delivery / diagnosis

References

[1] Rawla P.Epidemiology of prostate cancer.World J Oncol2019;10:63-89 PMCID:PMC6497009

[2] Siegel RL,Fuchs HE.Cancer statistics, 2021.CA Cancer J Clin2021;71:7-33

[3] Wang L,He M,Wang Z.Prostate cancer incidence and mortality: global status and temporal trends in 89 countries from 2000 to 2019.Front Public Health2022;10:811044 PMCID:PMC8888523

[4] Chen FZ.Prostate cancer: current treatment and prevention strategies.Iran Red Crescent Med J2013;15:279-84 PMCID:PMC3785898

[5] Nader R,Aragon-Ching JB.Role of chemotherapy in prostate cancer.Asian J Androl2018;20:221-9 PMCID:PMC5952475

[6] Rodríguez SA,Bueno Bravo C.Cryotherapy for primary treatment of prostate cancer: intermediate term results of a prospective study from a single institution.Prostate Cancer2014;2014:571576 PMCID:PMC3945790

[7] Alkhorayef M,Alzimami KS,Fagiri MA.High-intensity focused ultrasound (HIFU) in localized prostate cancer treatment.Pol J Radiol2015;80:131-41 PMCID:PMC4360749

[8] Poon DMC,Ho L,Yu B.Proton therapy for prostate cancer: challenges and opportunities.Cancers2022;14:925 PMCID:PMC8870339

[9] Desai K,Sharifi N.Hormonal therapy for prostate cancer.Endocr Rev2021;42:354-73 PMCID:PMC8152444

[10] Kim EH.Surgical management for prostate cancer.Mo Med2018;115:142-5. PMCID:PMC6139865

[11] Walker CH,Singhal U.Active surveillance for prostate cancer: selection criteria, guidelines, and outcomes.World J Urol2022;40:35-42

[12] Mottet N,Briers E.EAU-EANM-ESTRO-ESUR-SIOG guidelines on prostate cancer-2020 update. Part 1: screening, diagnosis, and local treatment with curative intent.Eur Urol2021;79:243-62

[13] Gomella LG,Lallas C.Hormone therapy in the management of prostate cancer: evidence-based approaches.Ther Adv Urol2010;2:171-81 PMCID:PMC3126080

[14] Laverdière J,Cusan L.Beneficial effect of combination hormonal therapy administered prior and following external beam radiation therapy in localized prostate cancer.Int J Radiat Oncol Biol Phys1997;37:247-52

[15] Recine F.Hormonal therapy and chemotherapy in hormone-naive and castration resistant prostate cancer.Transl Androl Urol2015;4:355-64 PMCID:PMC4708230

[16] Bolla M,Warde P.Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin.N Engl J Med1997;337:295-300

[17] Anderson J,Wirth M.Degarelix versus goserelin (+ antiandrogen flare protection) in the relief of lower urinary tract symptoms secondary to prostate cancer: results from a phase IIIb study (NCT00831233).Urol Int2013;90:321-8

[18] Fizazi K,Fein L.LATITUDE InvestigatorsAbiraterone plus prednisone in metastatic, castration-sensitive prostate cancer.N Engl J Med2017;377:352-60

[19] Thakur A,Ghosh A,Banerjee S.Abiraterone acetate in the treatment of prostate cancer.Biomed Pharmacother2018;101:211-8

[20] Beer TM,Rathkopf DE.Enzalutamide in metastatic prostate cancer before chemotherapy.N Engl J Med2014;371:424-33

[21] OH WK.Secondary hormonal therapies in the treatment of prostate cancer.Urology2002;60:87-92; discussion 93

[22] Sartor AO.Progression of metastatic castrate-resistant prostate cancer: impact of therapeutic intervention in the post-docetaxel space.J Hematol Oncol2011;4:18 PMCID:PMC3102641

[23] Karantanos T,Thompson TC.Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches.Oncogene2013;32:5501-11 PMCID:PMC3908870

[24] Dong L,Xue W,Pienta KJ.Metastatic prostate cancer remains incurable, why?.Asian J Urol2019;6:26-41 PMCID:PMC6363601

[25] Johnstone RM.Revisiting the road to the discovery of exosomes.Blood Cells Mol Dis2005;34:214-9

[26] Ha D,Nadithe V.Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges.Acta Pharm Sin B2016;6:287-96 PMCID:PMC4951582

[27] Peng H,Zhao R.Exosome: a significant nano-scale drug delivery carrier.J Mater Chem B2020;8:7591-608

[28] Jiang XC.Exosomes as novel bio-carriers for gene and drug delivery.Int J Pharm2017;521:167-75

[29] H Rashed M,K Helal G.Exosomes: from garbage bins to promising therapeutic targets.Int J Mol Sci2017;18:538 PMCID:PMC5372554

[30] Olejarz W,Chrzanowska A.Exosomes in angiogenesis and anti-angiogenic therapy in cancers.Int J Mol Sci2020;21:5840 PMCID:PMC7461570

[31] Adem B,Melo SA.Decoding the biology of exosomes in metastasis.Trends Cancer2020;6:20-30

[32] Sumrin A,Khan AA.Exosomes as biomarker of cancer.Braz arch biol technol2018;61

[33] Deep G.Hypoxia-induced signaling promotes prostate cancer progression: exosomes role as messenger of hypoxic response in tumor microenvironment.Crit Rev Oncog2015;20:419-34 PMCID:PMC5308872

[34] DeRita RM,Singh A.c-Src, Insulin-like growth factor i receptor, g-protein-coupled receptor kinases and focal adhesion kinase are enriched into prostate cancer cell exosomes.J Cell Biochem2017;118:66-73 PMCID:PMC5552241

[35] Cao Z,Zhao S.Exosome-derived miR-27a produced by PSC-27 cells contributes to prostate cancer chemoresistance through p53.Biochem Biophys Res Commun2019;515:345-51

[36] Logozzi M,Iessi E.Increased PSA expression on prostate cancer exosomes in in vitro condition and in cancer patients.Cancer Lett2017;403:318-29

[37] Tang MKS,Ip PP.Soluble e-cadherin promotes tumor angiogenesis and localizes to exosome surface.Nat Commun2018;9:2270 PMCID:PMC5995921

[38] Li T,Chen L.Exosome circ-0044516 promotes prostate cancer cell proliferation and metastasis as a potential biomarker.J Cell Biochem2020;121:2118-26

[39] Shin S,Jung SH.Urinary exosome microRNA signatures as a noninvasive prognostic biomarker for prostate cancer.NPJ Genom Med2021;6:45 PMCID:PMC8196022

[40] Nilsson J,Nordstrand A.Prostate cancer-derived urine exosomes: a novel approach to biomarkers for prostate cancer.Br J Cancer2009;100:1603-7 PMCID:PMC2696767

[41] Li Q,Shi Y.Exosomal lncAY927529 enhances prostate cancer cell proliferation and invasion through regulating bone microenvironment.Cell Cycle2021;20:2531-46 PMCID:PMC8794529

[42] Corcoran C,O'Brien K.Docetaxel-resistance in prostate cancer: evaluating associated phenotypic changes and potential for resistance transfer via exosomes.PLoS One2012;7:e50999 PMCID:PMC3519481

[43] Mostafazadeh M,Kahroba H,Haiaty S.Potential roles and prognostic significance of exosomes in cancer drug resistance.Cell Biosci2021;11:1 PMCID:PMC7789218

[44] Ramteke A,Agarwal C.Exosomes secreted under hypoxia enhance invasiveness and stemness of prostate cancer cells by targeting adherens junction molecules.Mol Carcinog2015;54:554-65 PMCID:PMC4706761

[45] Gibbons N,Coffey R,Fitzpatrick J.Heat-shock proteins inhibit induction of prostate cancer cell apoptosis.Prostate2000;45:58-65

[46] Teng Y,Mei Y,Cowell JK.HSP90 and HSP70 proteins are essential for stabilization and activation of WASF3 metastasis-promoting protein.J Biol Chem2012;287:10051-9 PMCID:PMC3323057

[47] Ariotti N,Okano S.An inverted CAV1 (caveolin 1) topology defines novel autophagy-dependent exosome secretion from prostate cancer cells.Autophagy2021;17:2200-16 PMCID:PMC8496722

[48] Karam JA,Roehrborn CG,Karakiewicz PI.Caveolin-1 overexpression is associated with aggressive prostate cancer recurrence.Prostate2007;67:614-22

[49] Gaballa R,Mahmoud MO.Exosomes-mediated transfer of itga2 promotes migration and invasion of prostate cancer cells by inducing epithelial-mesenchymal transition.Cancers2020;12:2300 PMCID:PMC7466113

[50] Westendorf JJ.Type I collagen receptor ({alpha}2{beta}1) signaling promotes the growth of human prostate cancer cells within the bone: Hall CL, Dai J, van Golen KL, Keller ET, Long MW, Departments of Urology and Internal Medicine, University of Michigan, MI.Urol Oncol-Semin Ori2007;25:179-80

[51] Tan SH,Chen Y.Prognostic features of Annexin A2 expression in prostate cancer.Pathology2021;53:205-13 PMCID:PMC7855416

[52] Shiozawa Y,Jung Y.Annexin II/annexin II receptor axis regulates adhesion, migration, homing, and growth of prostate cancer.J Cell Biochem2008;105:370-80 PMCID:PMC3614912

[53] Inokuchi J,Yee DS.Annexin A2 positively contributes to the malignant phenotype and secretion of IL-6 in DU145 prostate cancer cells.Int J Cancer2009;124:68-74

[54] Wei J,Wu M.Overexpression of vimentin contributes to prostate cancer invasion and metastasis via src regulation.Anticancer Res2008;28:327-34

[55] Li T,Sha J,Huang Y.MicroRNA-21 directly targets MARCKS and promotes apoptosis resistance and invasion in prostate cancer cells.Biochem Biophys Res Commun2009;383:280-5

[56] Ribas J.The transcriptional regulation of miR-21, its multiple transcripts, and their implication in prostate cancer.Cell Cycle2010;9:923-9 PMCID:PMC3462654

[57] Zhou F,Han D.TMPRSS2-ERG activates NO-cGMP signaling in prostate cancer cells.Oncogene2019;38:4397-411 PMCID:PMC6542710

[58] Galardi S,Giorda E.MiR-221 and MiR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27Kip1.J Biol Chem2007;282:23716-24

[59] Zhang D,Li H.Long ncRNA MALAT1 promotes cell proliferation, migration, and invasion in prostate cancer via sponging miR-145.Transl Androl Urol2021;10:2307-19 PMCID:PMC8261405

[60] Li T,Gao Y.Long noncoding RNA HOTAIR regulates the invasion and metastasis of prostate cancer by targeting hepaCAM.Br J Cancer2021;124:247-58 PMCID:PMC7782544

[61] Mushtaq M,Darekar S.Cell stemness is maintained upon concurrent expression of RB and the mitochondrial ribosomal protein S18-2.Proc Natl Acad Sci U S A2020;117:15673-83 PMCID:PMC7355020

[62] Aponte PM.Stemness in cancer: stem cells, cancer stem cells, and their microenvironment.Stem Cells Int2017;2017:5619472 PMCID:PMC5394399

[63] Chaffer CL,Scheel C.Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state.Proc Natl Acad Sci U S A2011;108:7950-5 PMCID:PMC3093533

[64] Li P,Xu L.Hypoxia enhances stemness of cancer stem cells in glioblastoma: an in vitro study.Int J Med Sci2013;10:399-407 PMCID:PMC3590599

[65] Song YJ,Guo XL.Autophagy contributes to the survival of CD133+ liver cancer stem cells in the hypoxic and nutrient-deprived tumor microenvironment.Cancer Lett2013;339:70-81

[66] Rao GH,Li BW.Establishment of a human colorectal cancer cell line P6C with stem cell properties and resistance to chemotherapeutic drugs.Acta Pharmacol Sin2013;34:793-804 PMCID:PMC3674520

[67] Chen W,Haiech J,Zeniou M.Cancer stem cell quiescence and plasticity as major challenges in cancer therapy.Stem Cells Int2016;2016:1740936 PMCID:PMC4932171

[68] Mei W,Kapoor A,Zhao K.The contributions of prostate cancer stem cells in prostate cancer initiation and metastasis.Cancers2019;11:434 PMCID:PMC6521153

[69] Harris KS.Prostate cancer stem cell markers drive progression, therapeutic resistance, and bone metastasis.Stem Cells Int2017;2017:8629234 PMCID:PMC5485361

[70] Li Y,Li D.Exosome carrying PSGR promotes stemness and epithelial-mesenchymal transition of low aggressive prostate cancer cells.Life Sci2021;264:118638

[71] Abd Elmageed ZY,Thomas R.Neoplastic reprogramming of patient-derived adipose stem cells by prostate cancer cell-associated exosomes.Stem Cells2014;32:983-97 PMCID:PMC4184251

[72] Cho JA,Lim EH.Exosomes from breast cancer cells can convert adipose tissue-derived mesenchymal stem cells into myofibroblast-like cells.Int J Oncol2012;40:130-8

[73] Gu J,Shen L.Gastric cancer exosomes trigger differentiation of umbilical cord derived mesenchymal stem cells to carcinoma-associated fibroblasts through TGF-β/Smad pathway.PLoS One2012;7:e52465 PMCID:PMC3527492

[74] Bhagirath D,Tabatabai ZL.BRN4 Is a novel driver of neuroendocrine differentiation in castration-resistant prostate cancer and is selectively released in extracellular vesicles with BRN2.Clin Cancer Res2019;25:6532-45 PMCID:PMC6825556

[75] Zhang A,Sun H.Tumor heterogeneity reshapes the tumor microenvironment to influence drug resistance.Int J Biol Sci2022;18:3019-33 PMCID:PMC9066118

[76] Zhu Y,Xu L.p21-activated kinase 1 determines stem-like phenotype and sunitinib resistance via NF-κB/IL-6 activation in renal cell carcinoma.Cell Death Dis2015;6:e1637 PMCID:PMC4669810

[77] Coco S,Alama A.Afatinib resistance in non-small cell lung cancer involves the PI3K/AKT and MAPK/ERK signalling pathways and epithelial-to-mesenchymal transition.Target Oncol2015;10:393-404

[78] Spetz J,Rudqvist N.Hedgehog inhibitor sonidegib potentiates¹⁷⁷ Lu-octreotate therapy of GOT1 human small intestine neuroendocrine tumors in nude mice.BMC Cancer2017;17:528 PMCID:PMC5549301

[79] Margariti N,Bottini A.“Overcoming breast cancer drug resistance with mTOR inhibitors”. Could it be a myth or a real possibility in the short-term future?.Breast Cancer Res Treat2011;128:599-606

[80] Kharaziha P,Rutishauser D.Molecular profiling of prostate cancer derived exosomes may reveal a predictive signature for response to docetaxel.Oncotarget2015;6:21740-54 PMCID:PMC4673300

[81] Quaglia F,Daaboul GG.Small extracellular vesicles modulated by αVβ3 integrin induce neuroendocrine differentiation in recipient cancer cells.J Extracell Vesicles2020;9:1761072 PMCID:PMC7448905

[82] Quaglia M,Guglielmetti G,Castellano G.Extracellular vesicles as mediators of cellular crosstalk between immune system and kidney graft.Front Immunol2020;11:74 PMCID:PMC7057849

[83] Saari H,Viitala T,Siljander P.Microvesicle- and exosome-mediated drug delivery enhances the cytotoxicity of Paclitaxel in autologous prostate cancer cells.J Control Release2015;220:727-37

[84] Shan G,Zhou D.Cancer-associated fibroblast-secreted exosomal miR-423-5p promotes chemotherapy resistance in prostate cancer by targeting GREM2 through the TGF-β signaling pathway.Exp Mol Med2020;52:1809-22 PMCID:PMC8080786

[85] Kato T,Kawakami K,Ehara H.CD44v8-10 mRNA contained in serum exosomes as a diagnostic marker for docetaxel resistance in prostate cancer patients.Heliyon2020;6:e04138 PMCID:PMC7334415

[86] Peak TC,Praharaj PP.Syntaxin 6-mediated exosome secretion regulates enzalutamide resistance in prostate cancer.Mol Carcinog2020;59:62-72 PMCID:PMC6916724

[87] Ni J,Malouf D,Graham P.Exosomes in cancer radioresistance.Front Oncol2019;9:869 PMCID:PMC6742697

[88] Hurwitz MD,Nagaraja GM,Manola J.Radiation therapy induces circulating serum Hsp72 in patients with prostate cancer.Radiother Oncol2010;95:350-8 PMCID:PMC2883632

[89] Kumar D,Shankar S.Biomolecular characterization of exosomes released from cancer stem cells: Possible implications for biomarker and treatment of cancer.Oncotarget2015;6:3280-91 PMCID:PMC4413653

[90] Li L,Su L,He XS.The role of autophagy in cancer radiotherapy.Curr Mol Pharmacol2020;13:31-40

[91] Malla B,Vassella E,Dal Pra A.Exosomes and exosomal micrornas in prostate cancer radiation therapy.Int J Radiat Oncol Biol Phys2017;98:982-95

[92] Bai S,Wang M.Tumor-derived exosomes modulate primary site tumor metastasis.Front Cell Dev Biol2022;10:752818 PMCID:PMC8924426

[93] Whiteside TL.Tumor-derived exosomes and their role in cancer progression.Adv Clin Chem2016;74:-41 PMCID:PMC5382933

[94] Liu Y.Characteristics and significance of the pre-metastatic niche.Cancer Cell2016;30:668-81

[95] van Zijl F,Mikulits W.Initial steps of metastasis: cell invasion and endothelial transmigration.Mutat Res2011;728:23-34 PMCID:PMC4028085

[96] Doglioni G,Fendt SM.Interactions in the (Pre)metastatic Niche Support Metastasis Formation.Front Oncol2019;9:219 PMCID:PMC6491570

[97] Huang W,Moyano J V,Orend G.Interference of tenascin-C with syndecan-4 binding to fibronectin blocks cell adhesion and stimulates tumor cell proliferation.Cancer Res2001;61:8586-94

[98] Høye AM.Structural ECM components in the premetastatic and metastatic niche.Am J Physiol Cell Physiol2016;310:C955-67

[99] Peinado H,Matei IR.Pre-metastatic niches: organ-specific homes for metastases.Nat Rev Cancer2017;17:302-17

[100] Henrich SE,Plebanek MP.Prostate cancer extracellular vesicles mediate intercellular communication with bone marrow cells and promote metastasis in a cholesterol-dependent manner.J Extracell Vesicles2020;10:e12042 PMCID:PMC7775568

[101] Xiao D,Kmetz D.Melanoma cell-derived exosomes promote epithelial-mesenchymal transition in primary melanocytes through paracrine/autocrine signaling in the tumor microenvironment.Cancer Lett2016;376:318-27 PMCID:PMC4869527

[102] Hao Y,Ten Dijke P.TGF-β-mediated epithelial-mesenchymal transition and cancer metastasis.Int J Mol Sci2019;20:2767 PMCID:PMC6600375

[103] Webber J,Mason MD,Clayton A.Cancer exosomes trigger fibroblast to myofibroblast differentiation.Cancer Res2010;70:9621-30

[104] Chowdhury R,Gurney M,Tabi Z.Cancer exosomes trigger mesenchymal stem cell differentiation into pro-angiogenic and pro-invasive myofibroblasts.Oncotarget2015;6:715-31 PMCID:PMC4359250

[105] McAtee CO,Elowsky C.Prostate tumor cell exosomes containing hyaluronidase Hyal1 stimulate prostate stromal cell motility by engagement of FAK-mediated integrin signaling.Matrix Biol2019;78-9:165-79 PMCID:PMC6230312

[106] Josson S,Gururajan M.microRNAs and prostate cancer.Adv Exp Med Biol2015;889:105-18. PMCID:PMC4736547

[107] Fedele C,Zerlanko BJ,Languino LR.The αvβ6 integrin is transferred intercellularly via exosomes.J Biol Chem2015;290:4545-51 PMCID:PMC4335196

[108] Krishn SR,Quaglia F.The αvβ6 integrin in cancer cell-derived small extracellular vesicles enhances angiogenesis.J Extracell Vesicles2020;9:1763594 PMCID:PMC7301698

[109] Bijnsdorp IV,Lavaei M,van Moorselaar RJ.Exosomal ITGA3 interferes with non-cancerous prostate cell functions and is increased in urine exosomes of metastatic prostate cancer patients.J Extracell Vesicles2013;2:22097 PMCID:PMC3873120

[110] Honeywell DR,Zhao H,Addison CL.miR-105 inhibits prostate tumour growth by suppressing CDK6 levels.PLoS One2013;8:e70515 PMCID:PMC3737265

[111] Read J,Al Saleh HA.Nuclear transportation of exogenous epidermal growth factor receptor and androgen receptor via extracellular vesicles.Eur J Cancer2017;70:62-74

[112] Maolake A,Natsagdorj A.Tumor necrosis factor-α induces prostate cancer cell migration in lymphatic metastasis through CCR7 upregulation.Cancer Sci2018;109:1524-31 PMCID:PMC5980342

[113] Dilsiz N.Role of exosomes and exosomal microRNAs in cancer.Future Sci OA2020;6:FSO465 PMCID:PMC7117563

[114] Thakur BK,Becker A.Double-stranded DNA in exosomes: a novel biomarker in cancer detection.Cell Res2014;24:766-9 PMCID:PMC4042169

[115] Martin TA,Sanders AJ,Jiang WG. Cancer Invasion and Metastasis: molecular and cellular perspective. Austin (TX): Landes Bioscience; p. 2000-2013. Available from: https://www.ncbi.nlm.nih.gov/books/NBK164700/. [Last accessed on 25 July 2023]

[116] O'Malley G,Houston AM.Mesenchymal stromal cells (MSCs) and colorectal cancer: a troublesome twosome for the anti-tumour immune response?.Oncotarget2016;7:60752-74 PMCID:PMC5312417

[117] Tian W,Li B.Potential role of exosomes in cancer metastasis.Biomed Res Int2019;2019:4649705 PMCID:PMC6634128

[118] Shi A,Qiu X.TGF-β loaded exosome enhances ischemic wound healing in vitro and in vivo.Theranostics2021;11:6616-31 PMCID:PMC8120220

[119] Zhang M,Han MK,Merlin D.Oral administration of ginger-derived nanolipids loaded with siRNA as a novel approach for efficient siRNA drug delivery to treat ulcerative colitis.Nanomedicine2017;12:1927-43 PMCID:PMC5827822

[120] Barillari G.The impact of matrix metalloproteinase-9 on the sequential steps of the metastatic process.Int J Mol Sci2020;21:4526 PMCID:PMC7350258

[121] Gao Z,Li J,Fan T.Emerging role of exosomes in liquid biopsy for monitoring prostate cancer invasion and metastasis.Front Cell Dev Biol2021;9:679527 PMCID:PMC8129505

[122] Lorenc T,Michalczewska I,Kubiak-Tomaszewska G.Exosomes in prostate cancer diagnosis, prognosis and therapy.Int J Mol Sci2020;21:2118 PMCID:PMC7139716

[123] Ahearn TU,Pettersson A.Transdisciplinary prostate cancer partnership (topcap)expression of IGF/insulin receptor in prostate cancer tissue and progression to lethal disease.Carcinogenesis2018;39:1431-7 PMCID:PMC6314328

[124] Mancarella C,Calatrava A.Insulin-like growth factor 1 receptor affects the survival of primary prostate cancer patients depending on TMPRSS2-ERG status.BMC Cancer2017;17:367 PMCID:PMC5445474

[125] Figel S.Focal adhesion kinase controls prostate cancer progression via intrinsic kinase and scaffolding functions.Anticancer Agents Med Chem2011;11:607-16

[126] Varkaris A,Araujo JC,Corn PG.Src signaling pathways in prostate cancer.Cancer Metastasis Rev2014;33:595-606 PMCID:PMC4640186

[127] Khodabakhsh F,Eisavand MR.Crosstalk between MUC1 and VEGF in angiogenesis and metastasis: a review highlighting roles of the MUC1 with an emphasis on metastatic and angiogenic signaling. Cancer Cell Int 2021;21:200. PMCID:PMC8033681

[128] Tang X,Shi S.Bisphosphonates suppress insulin-like growth factor 1-induced angiogenesis via the HIF-1alpha/VEGF signaling pathways in human breast cancer cells.Int J Cancer2010;126:90-103 PMCID:PMC2784023

[129] Wu X,Liang Q.Recent progress on FAK inhibitors with dual targeting capabilities for cancer treatment.Biomed Pharmacother2022;151:113116

[130] Zhang X,Shi H,Qian H.Exosomes in cancer: small particle, big player.J Hematol Oncol2015;8:83 PMCID:PMC4496882

[131] Kahlert C.Exosomes in tumor microenvironment influence cancer progression and metastasis.J Mol Med2013;91:431-7 PMCID:PMC4073669

[132] Crow J,Banskota S,Schmitt S.Exosomes as mediators of platinum resistance in ovarian cancer.Oncotarget2017;8:11917-36 PMCID:PMC5355315

[133] Jones E,Kyprianou N.Targeting TGF-beta in prostate cancer: therapeutic possibilities during tumor progression.Expert Opin Ther Targets2009;13:227-34

[134] Massagué J.TGFβ signalling in context.Nat Rev Mol Cell Biol2012;13:616-30 PMCID:PMC4027049

[135] Gaglani S,Lundon DJ,Dogra N.Exosomes as a next-generation diagnostic and therapeutic tool in prostate cancer.Int J Mol Sci2021;22:10131 PMCID:PMC8465219

[136] Salciccia S,Laganà A.Biomarkers in prostate cancer diagnosis: from current knowledge to the role of metabolomics and exosomes.Int J Mol Sci2021;22:4367 PMCID:PMC8122596

[137] Khan S,Valenzuela MM.Plasma-derived exosomal survivin, a plausible biomarker for early detection of prostate cancer.PLoS One2012;7:e46737 PMCID:PMC3473028

[138] Pucci M,Reclusa P.Exosomes in semen: opportunities as a new tool in prostate cancer diagnosis.Transl Cancer Res2017;6:S1331-8

[139] Duijvesz D,Bangma CH.Exosomes as biomarker treasure chests for prostate cancer.Eur Urol2011;59:823-31

[140] Samsonov R,Burdakov V.Lectin-induced agglutination method of urinary exosomes isolation followed by mi-RNA analysis: application for prostate cancer diagnostic.Prostate2016;76:68-79

[141] Gabriel K,Austin R.Regulation of the tumor suppressor PTEN through exosomes: a diagnostic potential for prostate cancer.PLoS One2013;8:e70047 PMCID:PMC3723640

[142] Logozzi M,Di Raimo R.Plasmatic exosome number and size distinguish prostate cancer patients from healthy individuals: a prospective clinical study.Front Oncol2021;11:727317 PMCID:PMC8564386

[143] Logozzi M,Capasso C.Plasmatic exosomes from prostate cancer patients show increased carbonic anhydrase IX expression and activity and low pH.J Enzyme Inhib Med Chem2020;35:280-8 PMCID:PMC6896418

[144] Li P,Han W.Ultrasensitive and reversible nanoplatform of urinary exosomes for prostate cancer diagnosis.ACS Sens2019;4:1433-41

[145] Cho S,Rhee WJ.Simultaneous multiplexed detection of exosomal microRNAs and surface proteins for prostate cancer diagnosis.Biosens Bioelectron2019;146:111749

[146] Li Q,Ling L.Rapid and specific detection nanoplatform of serum exosomes for prostate cancer diagnosis.Mikrochim Acta2021;188:283

[147] Wang Y,Shi H.Microfluidic raman biochip detection of exosomes: a promising tool for prostate cancer diagnosis.Lab Chip2020;20:4632-7

[148] Andaloussi S, Lakhal S, Mäger I, Wood MJ. Exosomes for targeted siRNA delivery across biological barriers.Adv Drug Deliv Rev2013;65:391-7

[149] Gutierrez-Millan C,Lanao JM.Advances in exosomes-based drug delivery systems.Macromol Biosci2021;21:e2000269

[150] Limoni SK,Moazzeni SM,Salimi F.Engineered exosomes for targeted transfer of siRNA to HER2 positive breast cancer cells.Appl Biochem Biotechnol2019;187:352-64

[151] Lin D,Liu R.iRGD-modified exosomes effectively deliver CPT1A siRNA to colon cancer cells, reversing oxaliplatin resistance by regulating fatty acid oxidation.Mol Oncol2021;15:3430-46 PMCID:PMC8637580

[152] Zhang Q,Ning T.Exosome-delivered c-met siRNA could reverse chemoresistance to cisplatin in gastric cancer.Int J Nanomedicine2020;15:2323-35 PMCID:PMC7133545

[153] Han Q,Li F.Targeted inhibition of SIRT6 via engineered exosomes impairs tumorigenesis and metastasis in prostate cancer.Theranostics2021;11:6526-41 PMCID:PMC8120217

[154] Krishn SR,Naranjo NM.Small extracellular vesicle-mediated ITGB6 siRNA delivery downregulates the αVβ6 integrin and inhibits adhesion and migration of recipient prostate cancer cells.Cancer Biol Ther2022;23:173-85 PMCID:PMC8865252

[155] Zhupanyn P,Büch T.Extracellular vesicle (ECV)-modified polyethylenimine (PEI) complexes for enhanced siRNA delivery in vitro and in vivo.J Control Release2020;319:63-76

[156] Kar R,Mukherjee S.Exosome-based smart drug delivery tool for cancer theranostics.ACS Biomater Sci Eng2023;9:577-94 PMCID:PMC9930096

[157] Pan S,Huang M.Urinary exosomes-based engineered nanovectors for homologously targeted chemo-chemodynamic prostate cancer therapy via abrogating EGFR/AKT/NF-kB/IkB signaling.Biomaterials2021;275:120946

[158] Tian J,Zhang W.Exosomes derived from nanocomplex-loaded macrophages for targeted delivery of docetaxel and siPLK1 against castrate-resistance prostate cancer.Res Sq2020;Perprint:

[159] Beeraka NM,Sadhu SP.The role of exosomes in stemness and neurodegenerative diseases-chemoresistant-cancer therapeutics and phytochemicals.Int J Mol Sci2020;21:6818 PMCID:PMC7555629