Epithelial-mesenchymal transition (EMT) is a crucial and fundamental mechanism in many cellular processes, beginning with embryogenesis via tissue remodulation and wound healing, and plays a vital role in tumorigenesis and metastasis formation. EMT is a complex process that involves many transcription factors and genes that enable the tumor cell to leave the primary location, invade the basement membrane, and send metastasis to other tissues. Moreover, it may help the tumor avoid the immune system and establish radioresistance and chemoresistance. It may also change the normal microenvironment, thus promoting other key factors for tumor survival, such as hypoxia-induced factor-1 (HIF-1) and promoting neoangiogenesis. In this review, we will focus mainly on the role of EMT in benign prostate disease and especially in the process of establishment of malignant prostate tumors, their invasiveness, and aggressive behavior. We will discuss relevant study methods for EMT evaluation and possible clinical implications. We will also introduce clinical trials conducted according to CONSORT 2010 that try to harness EMT properties in the form of circulating tumor cells to predict aggressive patterns of prostate cancer. This review will provide the most up-to-date information to establish a keen understanding of the cellular and microenvironmental processes for developing novel treatment lines by modifying or blocking the pathways.

Department of Clinical and Molecular Pathology Palacky University University Hospital 779 00 Olomouc Czech Republic

Department of Human Morphology and Pathology Medical Faculty David Tvildiani Medical University Tbilisi 0159 Georgia

Zobrazit více v PubMed

Their J.P. Epithelial-Mesenchymal Transitions in Tumour Progression. Nat. Rev. Cancer. 2002;2:442–454. doi: 10.1038/NRC822. PubMed DOI

Kalluri R., Neilson E.G. Epithelial-Mesenchymal Transition and Its Implications for Fibrosis. J. Clin. Investig. 2003;112:1776–1784. doi: 10.1172/JCI200320530. PubMed DOI PMC

Kalluri R. EMT: When Epithelial Cells Decide to Become Mesenchymal-like Cells. J. Clin. Investig. 2009;119:1417–1419. doi: 10.1172/JCI39675. PubMed DOI PMC

Micalizzi D.S., Farabaugh S.M., Ford H.L. Epithelial-Mesenchymal Transition in Cancer: Parallels between Normal Development and Tumor Progression. J. Mammary Gland. Biol. Neoplasia. 2010;15:117–134. doi: 10.1007/s10911-010-9178-9. PubMed DOI PMC

Marconi G.D., Fonticoli L., Rajan T.S., Pierdomenico S.D., Trubiani O., Pizzicannella J., Diomede F. Epithelial-Mesenchymal Transition (EMT): The Type-2 EMT in Wound Healing, Tissue Regeneration and Organ Fibrosis. Cells. 2021;10:1587. doi: 10.3390/cells10071587. PubMed DOI PMC

Kim D.H., Xing T., Yang Z., Dudek R., Lu Q., Chen Y.H. Epithelial Mesenchymal Transition in Embryonic Development, Tissue Repair and Cancer: A Comprehensive Overview. J. Clin. Med. 2018;7:1. doi: 10.3390/jcm7010001. PubMed DOI PMC

Yin Y., Liu S., Pu L., Luo J., Liu H., Wu W. Nintedanib Prevents TGF-Β2-Induced Epithelial-Mesenchymal Transition in Retinal Pigment Epithelial Cells. Biomed. Pharmacother. 2023;161:114543. doi: 10.1016/j.biopha.2023.114543. PubMed DOI

Salisbury M.L., Conoscenti C.S., Culver D.A., Yow E., Neely M.L., Bender S., Hartmann N., Palmer S.M., Leonard T.B. Antifibrotic Drug Use in Patients with Idiopathic Pulmonary Fibrosis Data from the IPF-PRO Registry. Ann. Am. Thorac. Soc. 2020;17:1413–1423. doi: 10.1513/AnnalsATS.201912-880OC. PubMed DOI PMC

Sethi S., Macoska J., Chen W., Sarkar F.H. Molecular Signature of Epithelial-Mesenchymal Transition (EMT) in Human Prostate Cancer Bone Metastasis. Am. J. Transl. Res. 2011;3:90. PubMed PMC

Vergara D., Merlot B., Lucot J.P., Collinet P., Vinatier D., Fournier I., Salzet M. Epithelial-Mesenchymal Transition in Ovarian Cancer. Cancer Lett. 2010;291:59–66. doi: 10.1016/j.canlet.2009.09.017. PubMed DOI

Bates R.C., Pursell B.M., Mercurio A.M. Epithelial-Mesenchymal Transition and Colorectal Cancer: Gaining Insights into Tumor Progression Using LIM 1863 Cells. Cells Tissues Organs. 2007;185:29–39. doi: 10.1159/000101300. PubMed DOI

Gavert N., Ben-Ze’ev A. Epithelial-Mesenchymal Transition and the Invasive Potential of Tumors. Trends Mol. Med. 2008;14:199–209. doi: 10.1016/j.molmed.2008.03.004. PubMed DOI

Chaves L.P., Melo C.M., Saggioro F.P., Dos Reis R.B., Squire J.A. Epithelial–Mesenchymal Transition Signaling and Prostate Cancer Stem Cells: Emerging Biomarkers and Opportunities for Precision Therapeutics. Genes. 2021;12:1900. doi: 10.3390/genes12121900. PubMed DOI PMC

Ruscetti M., Quach B., Dadashian E.L., Mulholland D.J., Wu H. Tracking and Functional Characterization of Epithelial-Mesenchymal Transition and Mesenchymal Tumor Cells during Prostate Cancer Metastasis. Cancer Res. 2015;75:2749–2759. doi: 10.1158/0008-5472.CAN-14-3476. PubMed DOI PMC

Li J., Yao H., Huang J., Li C., Zhang Y., Xu R., Wang Z., Long Z., Tang J., Wang L. METTL3 Promotes Prostatic Hyperplasia by Regulating PTEN Expression in an M6A-YTHDF2-Dependent Manner. Cell Death Dis. 2022;13:723. doi: 10.1038/s41419-022-05162-4. PubMed DOI PMC

Weilbaecher K.N., Guise T.A., McCauley L.K. Cancer to Bone: A Fatal Attraction. Nat. Rev. Cancer. 2011;11:411. doi: 10.1038/nrc3055. PubMed DOI PMC

Lu T., Lin W.J., Izumi K., Wang X., Xu D., Fang L.Y., Li L., Jiang Q., Jin J., Chang C. Targeting Androgen Receptor to Suppress Macrophage-Induced EMT and Benign Prostatic Hyperplasia (BPH) Development. Mol. Endocrinol. 2012;26:1707–1715. doi: 10.1210/me.2012-1079. PubMed DOI PMC

Zavadil J., Böttinger E.P. TGF-Beta and Epithelial-to-Mesenchymal Transitions. Oncogene. 2005;24:5764–5774. doi: 10.1038/sj.onc.1208927. PubMed DOI

Mathias R.A., Simpson R.J. Towards Understanding Epithelial–Mesenchymal Transition: A Proteomics Perspective. Biochim. Biophys. Acta BBA Proteins Proteom. 2009;1794:1325–1331. doi: 10.1016/j.bbapap.2009.05.001. PubMed DOI

Stemmer V., De Craene B., Berx G., Behrens J. Snail Promotes Wnt Target Gene Expression and Interacts with Beta-Catenin. Oncogene. 2008;27:5075–5080. doi: 10.1038/onc.2008.140. PubMed DOI

Klymkowsky M.W. β-Catenin and Its Regulatory Network. Hum. Pathol. 2005;36:225–227. doi: 10.1016/j.humpath.2005.02.002. PubMed DOI

Vignjevic D., Montagnac G. Reorganisation of the Dendritic Actin Network during Cancer Cell Migration and Invasion. Semin. Cancer Biol. 2008;18:12–22. doi: 10.1016/j.semcancer.2007.08.001. PubMed DOI

Hay E.D. An Overview of Epithelio-Mesenchymal Transformation. Acta Anat. 1995;154:8–20. doi: 10.1159/000147748. PubMed DOI

Buck E., Eyzaguirre A., Barr S., Thompson S., Sennello R., Young D., Iwata K.K., Gibson N.W., Cagnoni P., Haley J.D. Loss of Homotypic Cell Adhesion by Epithelial-Mesenchymal Transition or Mutation Limits Sensitivity to Epidermal Growth Factor Receptor Inhibition. Mol. Cancer Ther. 2007;6:532–541. doi: 10.1158/1535-7163.MCT-06-0462. PubMed DOI

Kurrey N.K., Jalgaonkar S.P., Joglekar A.V., Ghanate A.D., Chaskar P.D., Doiphode R.Y., Bapat S.A. Snail and Slug Mediate Radioresistance and Chemoresistance by Antagonizing P53-Mediated Apoptosis and Acquiring a Stem-like Phenotype in Ovarian Cancer Cells. Stem Cells. 2009;27:2059–2068. doi: 10.1002/stem.154. PubMed DOI

Kharaishvili G., Bouchal J. Ph.D. Thesis. Palacky University; Olomouc, Czech Republic: 2011. Extracellular Matrix Proteins and Epithelial Cell Plasticity in Progression of Breast and Prostate Cancer.

Janda E., Lehmann K., Killisch I., Jechlinger M., Herzig M., Downward J., Beug H., Grünert S. Ras and TGFβ Cooperatively Regulate Epithelial Cell Plasticity and Metastasis: Dissection of Ras Signaling Pathways. J. Cell Biol. 2002;156:299–313. doi: 10.1083/jcb.200109037. PubMed DOI PMC

Jenndahl L.E., Isakson P., Baeckström D. C-ErbB2-Induced Epithelial-Mesenchymal Transition in Mammary Epithelial Cells Is Suppressed by Cell-Cell Contact and Initiated Prior to E-Cadherin Downregulation. Int. J. Oncol. 2005;27:439–448. doi: 10.3892/ijo.27.2.439. PubMed DOI

Kupferman M.E., Jiffar T., El-Naggar A., Yilmaz T., Zhou G., Xie T., Feng L., Wang J., Holsinger F.C., Yu D., et al. TrkB Induces EMT and Has a Key Role in Invasion of Head and Neck Squamous Cell Carcinoma. Oncogene. 2010;29:2047. doi: 10.1038/onc.2009.486. PubMed DOI PMC

Smit M.A., Geiger T.R., Song J.-Y., Gitelman I., Peeper D.S. A Twist-Snail Axis Critical for TrkB-Induced Epithelial-Mesenchymal Transition-like Transformation, Anoikis Resistance, and Metastasis. Mol. Cell Biol. 2009;29:3722–3737. doi: 10.1128/MCB.01164-08. PubMed DOI PMC

Smit M.A., Peeper D.S. Epithelial-Mesenchymal Transition and Senescence: Two Cancer-Related Processes Are Crossing Paths. Aging. 2010;2:735. doi: 10.18632/aging.100209. PubMed DOI PMC

Stoker M., Perryman M. An Epithelial Scatter Factor Released by Embryo Fibroblasts. J. Cell Sci. 1985;77:209–223. doi: 10.1242/jcs.77.1.209. PubMed DOI

Grant C.M., Kyprianou N. Epithelial Mesenchymal Transition (EMT) in Prostate Growth and Tumor Progression. Transl. Androl. Urol. 2013;2:202–211. doi: 10.3978/J.ISSN.2223-4683.2013.09.04. PubMed DOI PMC

Lemster A.L., Sievers E., Pasternack H., Lazar-Karsten P., Klümper N., Sailer V., Offermann A., Brägelmann J., Perner S., Kirfel J. Histone Demethylase KDM5C Drives Prostate Cancer Progression by Promoting EMT. Cancers. 2022;14:1894. doi: 10.3390/cancers14081894. PubMed DOI PMC

Wu J., Ji H., Li T., Guo H., Xu H., Zhu J., Tian J., Gao M., Wang X., Zhang A. Targeting the Prostate Tumor Microenvironment by Plant-Derived Natural Products. Cell. Signal. 2024;115:111011. doi: 10.1016/j.cellsig.2023.111011. PubMed DOI

Yang J., Mani S.A., Donaher J.L., Ramaswamy S., Itzykson R.A., Come C., Savagner P., Gitelman I., Richardson A., Weinberg R.A. Twist, a Master Regulator of Morphogenesis, Plays an Essential Role in Tumor Metastasis. Cell. 2004;117:927–939. doi: 10.1016/j.cell.2004.06.006. PubMed DOI

Dave N., Guaita-Esteruelas S., Gutarra S., Frias À., Beltran M., Peiró S., De Herreros A.G. Functional Cooperation between Snail1 and Twist in the Regulation of ZEB1 Expression during Epithelial to Mesenchymal Transition. J. Biol. Chem. 2011;286:12024–12032. doi: 10.1074/jbc.M110.168625. PubMed DOI PMC

Li Q., Chen C., Kapadia A., Zhou Q., Harper M.K., Schaack J., LaBarbera D.V. 3D Models of Epithelial-Mesenchymal Transition in Breast Cancer Metastasis: High-Throughput Screening Assay Development, Validation, and Pilot Screen. J. Biomol. Screen. 2011;16:141–154. doi: 10.1177/1087057110392995. PubMed DOI

Otsuki S., Inokuchi M., Enjoji M., Ishikawa T., Takagi Y., Kato K., Yamada H., Kojima K., Sugihara K. Vimentin Expression Is Associated with Decreased Survival in Gastric Cancer. Oncol. Rep. 2011;25:1235–1242. doi: 10.3892/OR.2011.1185. PubMed DOI

Abdelrahman A.E., Arafa S.A., Ahmed R.A. Prognostic Value of Twist-1, E-Cadherin and EZH2 in Prostate Cancer: An Immunohistochemical Study. Turk. Patoloji Derg. 2017;1:198–210. doi: 10.5146/tjpath.2016.01392. PubMed DOI

Børretzen A., Gravdal K., Haukaas S.A., Mannelqvist M., Beisland C., Akslen L.A., Halvorsen O.J. The Epithelial–Mesenchymal Transition Regulators Twist, Slug, and Snail Are Associated with Aggressive Tumour Features and Poor Outcome in Prostate Cancer Patients. J. Pathol. Clin. Res. 2021;7:253–270. doi: 10.1002/cjp2.202. PubMed DOI PMC

Jin L., Zhou Y., Chen G., Dai G., Fu K., Yang D., Zhu J. EZH2-TROAP Pathway Promotes Prostate Cancer Progression Via TWIST Signals. Front. Oncol. 2021;10:592239. doi: 10.3389/fonc.2020.592239. PubMed DOI PMC

Nishioka R., Itoh S., Gui T., Gai Z., Oikawa K., Kawai M., Tani M., Yamaue H., Muragaki Y. SNAIL Induces Epithelial-to-Mesenchymal Transition in a Human Pancreatic Cancer Cell Line (BxPC3) and Promotes Distant Metastasis and Invasiveness in Vivo. Exp. Mol. Pathol. 2010;89:149–157. doi: 10.1016/j.yexmp.2010.05.008. PubMed DOI

Blanco M.J., Moreno-Bueno G., Sarrio D., Locascio A., Cano A., Palacios J., Nieto M.A. Correlation of Snail Expression with Histological Grade and Lymph Node Status in Breast Carcinomas. Oncogene. 2002;21:3241–3246. doi: 10.1038/sj.onc.1205416. PubMed DOI

Casas E., Kim J., Bendesky A., Ohno-Machado L., Wolfe C.J., Yang J. Snail2 Is an Essential Mediator of Twist1-Induced Epithelial-Mesenchymal Transition and Metastasis. Cancer Res. 2011;71:245. doi: 10.1158/0008-5472.CAN-10-2330. PubMed DOI PMC

Yu Q., Zhang K., Wang X., Liu X., Zhang Z. Expression of Transcription Factors Snail, Slug, and Twist in Human Bladder Carcinoma. J. Exp. Clin. Cancer Res. 2010;29:1–9. doi: 10.1186/1756-9966-29-119. PubMed DOI PMC

Xu S., Zhou Y., Biekemitoufu H., Wang H., Li C., Zhang W., Ma Y. Expression of Twist, Slug and Snail in Esophageal Squamous Cell Carcinoma and Their Prognostic Significance. Oncol. Lett. 2021;21:184. doi: 10.3892/ol.2021.12445. PubMed DOI PMC

Bhat-Nakshatri P., Appaiah H., Ballas C., Pick-Franke P., Goulet R., Badve S., Srour E.F., Nakshatri H. SLUG/SNAI2 and Tumor Necrosis Factor Generate Breast Cells with CD44+/CD24− Phenotype. BMC Cancer. 2010;10:411. doi: 10.1186/1471-2407-10-411. PubMed DOI PMC

Chua H.L., Bhat-Nakshatri P., Clare S.E., Morimiya A., Badve S., Nakshatri H. NF-ΚB Represses E-Cadherin Expression and Enhances Epithelial to Mesenchymal Transition of Mammary Epithelial Cells: Potential Involvement of ZEB-1 and ZEB-2. Oncogene. 2007;26:711–724. doi: 10.1038/sj.onc.1209808. PubMed DOI

Katoh M., Katoh M. Identification and Characterization of Human SNAIL3 (SNAI3) Gene in Silico. Int. J. Mol. Med. 2003;11:383–388. doi: 10.3892/ijmm.11.3.383. PubMed DOI

Smith B.N., Odero-Marah V.A. The Role of Snail in Prostate Cancer. Cell Adhes. Migr. 2012;6:433–441. doi: 10.4161/cam.21687. PubMed DOI PMC

Vandewalle C., Van Roy F., Berx G. The Role of the ZEB Family of Transcription Factors in Development and Disease. Cell. Mol. Life Sci. 2009;66:773–787. doi: 10.1007/s00018-008-8465-8. PubMed DOI PMC

Vega S., Morales A.V., Ocaña O.H., Valdés F., Fabregat I., Nieto M.A. Snail Blocks the Cell Cycle and Confers Resistance to Cell Death. Genes. Dev. 2004;18:1131–1143. doi: 10.1101/gad.294104. PubMed DOI PMC

Eger A., Aigner K., Sonderegger S., Dampier B., Oehler S., Schreiber M., Berx G., Cano A., Beug H., Foisner R. DeltaEF1 Is a Transcriptional Repressor of E-Cadherin and Regulates Epithelial Plasticity in Breast Cancer Cells. Oncogene. 2005;24:2375–2385. doi: 10.1038/sj.onc.1208429. PubMed DOI

Kajita M., McClinic K.N., Wade P.A. Aberrant Expression of the Transcription Factors Snail and Slug Alters the Response to Genotoxic Stress. Mol. Cell Biol. 2004;24:7559. doi: 10.1128/MCB.24.17.7559-7566.2004. PubMed DOI PMC

Hugo H.J., Kokkinos M.I., Blick T., Ackland M.L., Thompson E.W., Newgreen D.F. Defining the E-Cadherin Repressor Interactome in Epithelial-Mesenchymal Transition: The PMC42 Model as a Case Study. Cells Tissues Organs. 2010;193:23–40. doi: 10.1159/000320174. PubMed DOI

Hanrahan K., O’Neill A., Prencipe M., Bugler J., Murphy L., Fabre A., Puhr M., Culig Z., Murphy K., Watson R.W. The Role of Epithelial-Mesenchymal Transition Drivers ZEB1 and ZEB2 in Mediating Docetaxel-Resistant Prostate Cancer. Mol. Oncol. 2017;11:251–265. doi: 10.1002/1878-0261.12030. PubMed DOI PMC

Zavadil J., Narasimhan M., Blumenberg M., Schneider R.J. Transforming Growth Factor-β and MicroRNA:MRNA Regulatory Networks in Epithelial Plasticity. Cells Tissues Organs. 2007;185:157–161. doi: 10.1159/000101316. PubMed DOI

Gregory P.A., Bert A.G., Paterson E.L., Barry S.C., Tsykin A., Farshid G., Vadas M.A., Khew-Goodall Y., Goodall G.J. The MiR-200 Family and MiR-205 Regulate Epithelial to Mesenchymal Transition by Targeting ZEB1 and SIP1. Nat. Cell Biol. 2008;10:593–601. doi: 10.1038/ncb1722. PubMed DOI

Sossey-Alaoui K., Bialkowska K., Plow E.F. The MiR200 Family of MicroRNAs Regulates WAVE3-Dependent Cancer Cell Invasion. J. Biol. Chem. 2009;284:33019–33029. doi: 10.1074/jbc.M109.034553. PubMed DOI PMC

Sharma N., Baruah M.M. The MicroRNA Signatures: Aberrantly Expressed MiRNAs in Prostate Cancer. Clin. Transl. Oncol. 2019;21:126–144. doi: 10.1007/s12094-018-1910-8. PubMed DOI

Fabris L., Ceder Y., Chinnaiyan A.M., Jenster G.W., Sorensen K.D., Tomlins S., Visakorpi T., Calin G.A. The Potential of MicroRNAs as Prostate Cancer Biomarkers. Eur. Urol. 2016;70:312–322. doi: 10.1016/j.eururo.2015.12.054. PubMed DOI PMC

Sekhon K., Bucay N., Majid S., Dahiya R., Saini S. MicroRNAs and Epithelial-Mesenchymal Transition in Prostate Cancer. Oncotarget. 2016;7:67597–67611. doi: 10.18632/oncotarget.11708. PubMed DOI PMC

Dubey A., Prajapati K.S., Swamy M., Pachauri V. Heat Shock Proteins: A Therapeutic Target Worth to Consider. Vet. World. 2015;8:46. doi: 10.14202/vetworld.2015.46-51. PubMed DOI PMC

Fu X., Liu J., Yan X., DiSanto M.E., Zhang X. Heat Shock Protein 70 and 90 Family in Prostate Cancer. Life. 2022;12:1489. doi: 10.3390/life12101489. PubMed DOI PMC

Seclì L., Fusella F., Avalle L., Brancaccio M. The Dark-Side of the Outside: How Extracellular Heat Shock Proteins Promote Cancer. Cell. Mol. Life Sci. 2021;78:4069–4083. doi: 10.1007/s00018-021-03764-3. PubMed DOI PMC

Jiang B., Liang P., Deng G., Tu Z., Liu M., Xiao X. Increased Stability of Bcl-2 in HSP70-Mediated Protection against Apoptosis Induced by Oxidative Stress. Cell Stress. Chaperones. 2011;16:143. doi: 10.1007/s12192-010-0226-6. PubMed DOI PMC

Cultrara C.N., Kozuch S.D., Ramasundaram P., Heller C.J., Shah S., Beck A.E., Sabatino D., Zilberberg J. GRP78 Modulates Cell Adhesion Markers in Prostate Cancer and Multiple Myeloma Cell Lines. BMC Cancer. 2018;18:1263. doi: 10.1186/s12885-018-5178-8. PubMed DOI PMC

Teng Y., Ngoka L., Mei Y., Lesoon L., Cowell J.K. HSP90 and HSP70 Proteins Are Essential for Stabilization and Activation of WASF3 Metastasis-Promoting Protein. J. Biol. Chem. 2012;287:10051. doi: 10.1074/jbc.M111.335000. PubMed DOI PMC

Hance M.W., Dole K., Gopal U., Bohonowych J.E., Jezierska-Drutel A., Neumann C.A., Liu H., Garraway I.P., Isaacs J.S. Secreted Hsp90 Is a Novel Regulator of the Epithelial to Mesenchymal Transition (EMT) in Prostate Cancer. J. Biol. Chem. 2012;287:37732–37744. doi: 10.1074/jbc.M112.389015. PubMed DOI PMC

Chatterjee S., Burns T.F. Targeting Heat Shock Proteins in Cancer: A Promising Therapeutic Approach. Int. J. Mol. Sci. 2017;18:1978. doi: 10.3390/ijms18091978. PubMed DOI PMC

Nolan K.D., Franco O.E., Hance M.W., Hayward S.W., Isaacs J.S. Tumor-Secreted Hsp90 Subverts Polycomb Function to Drive Prostate Tumor Growth and Invasion. J. Biol. Chem. 2015;290:8271–8282. doi: 10.1074/jbc.M115.637496. PubMed DOI PMC

Coulter J.B., Easwaran H. Combining EZH2 and HDAC Inhibitors to Target Castration-Resistant Prostate Cancers. PLoS Biol. 2023;21:e3002081. doi: 10.1371/journal.pbio.3002081. PubMed DOI PMC

Liu Y.J., Du J., Li J., Tan X.P., Zhang Q. CTHRC1, a Novel Gene with Multiple Functions in Physiology, Disease and Solid Tumors (Review) Oncol. Lett. 2023;25:266. doi: 10.3892/ol.2023.13852. PubMed DOI PMC

Zhou Q., Xiong W., Zhou X., Gao R.S., Lin Q.F., Liu H.Y., Li J.N., Tian X.F. CTHRC1 and PD-1/PD-L1 Expression Predicts Tumor Recurrence in Prostate Cancer. Mol. Med. Rep. 2019;20:4244. doi: 10.3892/mmr.2019.10690. PubMed DOI PMC

Ma Z., Chao F., Wang S., Song Z., Zhuo Z., Zhang J., Xu G., Chen G. CTHRC1 Affects Malignant Tumor Cell Behavior and Is Regulated by MiR-30e-5p in Human Prostate Cancer. Biochem. Biophys. Res. Commun. 2020;525:418–424. doi: 10.1016/j.bbrc.2020.02.098. PubMed DOI

Wang Z., An J., Zhu D., Chen H., Lin A., Kang J., Liu W., Kang X. Periostin: An Emerging Activator of Multiple Signaling Pathways. J. Cell Commun. Signal. 2022;16:515. doi: 10.1007/s12079-022-00674-2. PubMed DOI PMC

Tian Y., Choi C.H., Li Q.K., Rahmatpanah F.B., Chen X., Kim S.R., Veltri R., Chia D., Zhang Z., Mercola D., et al. Overexpression of Periostin in Stroma Positively Associated with Aggressive Prostate Cancer. PLoS ONE. 2015;10:e0130333. doi: 10.1371/JOURNAL.PONE.0121502. PubMed DOI PMC

Hu Q., Tong S., Zhao X., Ding W., Gou Y., Xu K., Sun C., Xia G. Periostin Mediates TGF-β-Induced Epithelial Mesenchymal Transition in Prostate Cancer Cells. Cell. Physiol. Biochem. 2015;36:799–809. doi: 10.1159/000430139. PubMed DOI

Liao Y., Huang J., Liu P., Zhang C., Liu J., Xia M., Shang C., Ooi S., Chen Y., Qin S., et al. Downregulation of LNMAS Orchestrates Partial EMT and Immune Escape from Macrophage Phagocytosis to Promote Lymph Node Metastasis of Cervical Cancer. Oncogene. 2022;41:1931–1943. doi: 10.1038/s41388-022-02202-3. PubMed DOI PMC

Wang L., Li S., Luo H., Lu Q., Yu S. PCSK9 Promotes the Progression and Metastasis of Colon Cancer Cells through Regulation of EMT and PI3K/AKT Signaling in Tumor Cells and Phenotypic Polarization of Macrophages. J. Exp. Clin. Cancer Res. 2022;41:303. doi: 10.1186/s13046-022-02477-0. PubMed DOI PMC

Fang S., Yarmolinsky J., Gill D., Bull C.J., Perks C.M., Smith G.D., Gaunt T.R., Richardson T.G. Association between Genetically Proxied PCSK9 Inhibition and Prostate Cancer Risk: A Mendelian Randomisation Study. PLoS Med. 2023;20:e1003988. doi: 10.1371/journal.pmed.1003988. PubMed DOI PMC

Gan S.S., Ye J.Q., Wang L., Qu F.J., Chu C.M., Tian Y.J., Yang W., Cui X.G. Inhibition of PCSK9 Protects against Radiation-Induced Damage of Prostate Cancer Cells. OncoTargets Ther. 2017;10:2139. doi: 10.2147/OTT.S129413. PubMed DOI PMC

Sun L., Ding H., Jia Y., Shi M., Guo D., Yang P., Wang Y., Liu F., Zhang Y., Zhu Z. Associations of Genetically Proxied Inhibition of HMG-CoA Reductase, NPC1L1, and PCSK9 with Breast Cancer and Prostate Cancer. Breast Cancer Res. 2022;24:12. doi: 10.1186/s13058-022-01508-0. PubMed DOI PMC

Stopsack K.H., Gerke T.A., Andrén O., Andersson S.O., Giovannucci E.L., Mucci L.A., Rider J.R. Cholesterol Uptake and Regulation in High-Grade and Lethal Prostate Cancers. Carcinogenesis. 2017;38:806–811. doi: 10.1093/carcin/bgx058. PubMed DOI PMC

Datar I., Schalper K.A. Epithelial–Mesenchymal Transition and Immune Evasion during Lung Cancer Progression: The Chicken or the Egg? Clin. Cancer Res. 2016;22:3422. doi: 10.1158/1078-0432.CCR-16-0336. PubMed DOI PMC

Messex J.K., Liou G.Y. Impact of Immune Cells in the Tumor Microenvironment of Prostate Cancer Metastasis. Life. 2023;13:333. doi: 10.3390/life13020333. PubMed DOI PMC

Rice A.J., Cortes E., Lachowski D., Cheung B.C.H., Karim S.A., Morton J.P., Del Río Hernández A. Matrix Stiffness Induces Epithelial–Mesenchymal Transition and Promotes Chemoresistance in Pancreatic Cancer Cells. Oncogenesis. 2017;6:e352. doi: 10.1038/oncsis.2017.54. PubMed DOI PMC

Kharaishvili G., Simkova D., Bouchalova K., Gachechiladze M., Narsia N., Bouchal J. The Role of Cancer-Associated Fibroblasts, Solid Stress and Other Microenvironmental Factors in Tumor Progression and Therapy Resistance. Cancer Cell Int. 2014;14:41. doi: 10.1186/1475-2867-14-41. PubMed DOI PMC

Liu J., Shen J.X., Wu H.T., Li X.L., Wen X.F., Du C.W., Zhang G.J. Collagen 1A1 (COL1A1) Promotes Metastasis of Breast Cancer and Is a Potential Therapeutic Target. Discov. Med. 2018;25:211–223. PubMed

Hanley C.J., Noble F., Ward M., Bullock M., Drifka C., Mellone M., Manousopoulou A., Johnston H.E., Hayden A., Thirdborough S., et al. A Subset of Myofibroblastic Cancer-Associated Fibroblasts Regulate Collagen Fiber Elongation, Which Is Prognostic in Multiple Cancers. Oncotarget. 2015;7:6159–6174. doi: 10.18632/oncotarget.6740. PubMed DOI PMC

Levental K.R., Yu H., Kass L., Lakins J.N., Egeblad M., Erler J.T., Fong S.F.T., Csiszar K., Giaccia A., Weninger W., et al. Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling. Cell. 2009;139:891–906. doi: 10.1016/j.cell.2009.10.027. PubMed DOI PMC

Kryza T., Silva L.M., Bock N., Fuhrman-Luck R.A., Stephens C.R., Gao J., Samaratunga H., Lawrence M.G., Hooper J.D., Dong Y., et al. Kallikrein-Related Peptidase 4 Induces Cancer-Associated Fibroblast Features in Prostate-Derived Stromal Cells. Mol. Oncol. 2017;11:1307–1329. doi: 10.1002/1878-0261.12075. PubMed DOI PMC

Wright K., Ly T., Kriet M., Czirok A., Thomas S.M. Cancer-Associated Fibroblasts: Master Tumor Microenvironment Modifiers. Cancers. 2023;15:1899. doi: 10.3390/cancers15061899. PubMed DOI PMC

Taddei M.L., Giannoni E., Comito G., Chiarugi P. Microenvironment and Tumor Cell Plasticity: An Easy Way Out. Cancer Lett. 2013;341:80–96. doi: 10.1016/j.canlet.2013.01.042. PubMed DOI

Giannoni E., Bianchini F., Masieri L., Serni S., Torre E., Calorini L., Chiarugi P. Reciprocal Activation of Prostate Cancer Cells and Cancer-Associated Fibroblasts Stimulates Epithelial-Mesenchymal Transition and Cancer Stemness. Cancer Res. 2010;70:6945–6956. doi: 10.1158/0008-5472.CAN-10-0785. PubMed DOI

Chen Q., Yang D., Zong H., Zhu L., Wang L., Wang X., Zhu X., Song X., Wang J. Growth-Induced Stress Enhances Epithelial-Mesenchymal Transition Induced by IL-6 in Clear Cell Renal Cell Carcinoma via the Akt/GSK-3β/β-Catenin Signaling Pathway. Oncogenesis. 2017;6:e375. doi: 10.1038/oncsis.2017.74. PubMed DOI PMC

Tse J.M., Cheng G., Tyrrell J.A., Wilcox-Adelman S.A., Boucher Y., Jain R.K., Munn L.L. Mechanical Compression Drives Cancer Cells toward Invasive Phenotype. Proc. Natl. Acad. Sci. USA. 2012;109:911–916. doi: 10.1073/pnas.1118910109. PubMed DOI PMC

Brown M.S., Muller K.E., Pattabiraman D.R. Quantifying the Epithelial-to-Mesenchymal Transition (EMT) from Bench to Bedside. Cancers. 2022;14:1138. doi: 10.3390/cancers14051138. PubMed DOI PMC

Mickova A., Kharaishvili G., Kurfurstova D., Gachechiladze M., Kral M., Vacek O., Pokryvkova B., Mistrik M., Soucek K., Bouchal J. Skp2 and Slug Are Coexpressed in Aggressive Prostate Cancer and Inhibited by Neddylation Blockade. Int. J. Mol. Sci. 2021;22:2844. doi: 10.3390/ijms22062844. PubMed DOI PMC

Leggett S.E., Sim J.Y., Rubins J.E., Neronha Z.J., Williams E.K., Wong I.Y. Morphological Single Cell Profiling of the Epithelial-Mesenchymal Transition. Integr. Biol. 2016;8:1133–1144. doi: 10.1039/C6IB00139D. PubMed DOI PMC

Meyer-Schaller N., Cardner M., Diepenbruck M., Saxena M., Tiede S., Lüönd F., Ivanek R., Beerenwinkel N., Christofori G. A Hierarchical Regulatory Landscape during the Multiple Stages of EMT. Dev. Cell. 2019;48:539–553.e6. doi: 10.1016/j.devcel.2018.12.023. PubMed DOI

Zhong W., Sun T. Editorial: Epithelial-Mesenchymal Transition (EMT) as a Therapeutic Target in Cancer, Volume II. Front. Oncol. 2023;13:1218855. doi: 10.3389/fonc.2023.1218855. PubMed DOI PMC

Qiao P., Tian Z. Atractylenolide I Inhibits EMT and Enhances the Antitumor Effect of Cabozantinib in Prostate Cancer via Targeting Hsp27. Front. Oncol. 2023;12:1084884. doi: 10.3389/fonc.2022.1084884. PubMed DOI PMC

Baritaki S., Huerta-Yepez S., Sahakyan A., Karagiannides I., Bakirtzi K., Jazirehi A.R., Bonavida B., Kugel J.F. Mechanisms of Nitric Oxide-Mediated Inhibition of EMT in Cancer: Inhibition of the Metastasis-Inducer Snail and Induction of the Metastasis-Suppressor RKIP. Cell Cycle. 2010;9:4931. doi: 10.4161/cc.9.24.14229. PubMed DOI PMC

Fischer K.R., Durrans A., Lee S., Sheng J., Li F., Wong S.T.C., Choi H., El Rayes T., Ryu S., Troeger J., et al. Epithelial-to-Mesenchymal Transition Is Not Required for Lung Metastasis but Contributes to Chemoresistance. Nature. 2015;527:472–476. doi: 10.1038/nature15748. PubMed DOI PMC

Castellón E.A., Indo S., Contreras H.R. Cancer Stemness/Epithelial-Mesenchymal Transition Axis Influences Metastasis and Castration Resistance in Prostate Cancer: Potential Therapeutic Target. Int. J. Mol. Sci. 2022;23:14917. doi: 10.3390/ijms232314917. PubMed DOI PMC

Slabáková E., Pernicová Z., Slavíčková E., Staršíchová A., Kozubík A., Souček K. TGF-Β1-Induced EMT of Non-Transformed Prostate Hyperplasia Cells Is Characterized by Early Induction of SNAI2/Slug. Prostate. 2011;71:1332–1343. doi: 10.1002/pros.21350. PubMed DOI

Gogola S., Rejzer M., Bahmad H.F., Abou-Kheir W., Omarzai Y., Poppiti R. Epithelial-to-Mesenchymal Transition-Related Markers in Prostate Cancer: From Bench to Bedside. Cancers. 2023;15:2309. doi: 10.3390/cancers15082309. PubMed DOI PMC

Allan A. Influence of EMT on CTCs and Disease Progression in Prostate Cancer. ClinicalTrials.gov Identifier: NTC04021394. [(accessed on 17 September 2023)]; Available online: https://clinicaltrials.gov/study/NCT04021394.

De Giorgi U. CTC, Free DNA, Stem Cells and EMT-Related Antigens as Biomarkers of Activity of Cabazitaxel in CRPC. ClinicalTrials.gov Identifier: NCT03381326. [(accessed on 17 September 2023)]; Available online: https://clinicaltrials.gov/study/NCT03381326.

Koinis F., Zafeiriou Z., Messaritakis I., Katsaounis P., Koumarianou A., Kontopodis E., Chantzara E., Aidarinis C., Lazarou A., Christodoulopoulos G., et al. Prognostic Role of Circulating Tumor Cells in Patients with Metastatic Castration-Resistant Prostate Cancer Receiving Cabazitaxel: A Prospective Biomarker Study. Cancers. 2023;15:4511. doi: 10.3390/cancers15184511. PubMed DOI PMC

Ramesh V., Brabletz T., Ceppi P. Targeting EMT in Cancer with Repurposed Metabolic Inhibitors. Trends Cancer. 2020;6:942–950. doi: 10.1016/j.trecan.2020.06.005. PubMed DOI

Caro-Maldonado A., Camacho L., Zabala-Letona A., Torrano V., Fernández-Ruiz S., Zamacola-Bascaran K., Arreal L., Valcárcel-Jiménez L., Martín-Martín N., Flores J.M., et al. Low-Dose Statin Treatment Increases Prostate Cancer Aggressiveness. Oncotarget. 2017;9:1494–1504. doi: 10.18632/oncotarget.22217. PubMed DOI PMC

Small E.J., Meyer M., Marshall M.E., Reyno L.M., Meyers F.J., Natale R.B., Lenehan P.F., Chen L., Slichenmyer W.J., Eisenberger M. Suramin Therapy for Patients with Symptomatic Hormone-Refractory Prostate Cancer: Results of a Randomized Phase III Trial Comparing Suramin plus Hydrocortisone to Placebo plus Hydrocortisone. J. Clin. Oncol. 2000;18:1440–1450. doi: 10.1200/JCO.2000.18.7.1440. PubMed DOI

Garcia-Schürmann J.M., Schulze H., Haupt G., Pastor J., Senge T. Suramin Treatment in Hormone- and Chemotherapy-Refractory Prostate Cancer. Urology. 1999;53:535–541. doi: 10.1016/S0090-4295(98)00544-5. PubMed DOI

Ganju A., Yallapu M.M., Khan S., Behrman S.W., Chauhan S.C., Jaggi M. Nanoways to Overcome Docetaxel Resistance in Prostate Cancer. Drug Resist. Updates. 2014;17:13–23. doi: 10.1016/j.drup.2014.04.001. PubMed DOI PMC

Kim J., Wu L., Zhao J.C., Jin H.J., Yu J. TMPRSS2-ERG Gene Fusions Induce Prostate Tumorigenesis by Modulating MicroRNA MiR-200c. Oncogene. 2014;33:5183–5192. doi: 10.1038/onc.2013.461. PubMed DOI PMC

Slovin S., Hussain S., Saad F., Garcia J., Picus J., Ferraldeschi R., Crespo M., Flohr P., Riisnaes R., Lin C., et al. Pharmacodynamic and Clinical Results from a Phase I/II Study of the Hsp90 Inhibitor Onalespib in Combination with Abiraterone Acetate in Prostate Cancer. Clin. Cancer Res. 2019;25:4624–4633. doi: 10.1158/1078-0432.CCR-18-3212. PubMed DOI PMC

Goetz M.P., Toft D.O., Ames M.M., Erlichman C. The Hsp90 Chaperone Complex as a Novel Target for Cancer Therapy. Ann. Oncol. 2003;14:1169–1176. doi: 10.1093/annonc/mdg316. PubMed DOI

Chen L., Li J., Farah E., Sarkar S., Ahmad N., Gupta S., Larner J., Liu X. Cotargeting HSP90 and Its Client Proteins for Treatment of Prostate Cancer. Mol. Cancer Ther. 2016;15:2107–2118. doi: 10.1158/1535-7163.MCT-16-0241. PubMed DOI PMC

Thakur M.K., Heilbrun L.K., Sheng S., Stein M., Liu G., Antonarakis E.S., Vaishampayan U., Dzinic S.H., Li X., Freeman S., et al. A Phase II Trial of Ganetespib, a Heat Shock Protein 90 Hsp90) Inhibitor, in Patients with Docetaxel-Pretreated Metastatic Castrate-Resistant Prostate Cancer (CRPC)-a Prostate Cancer Clinical Trials Consortium (PCCTC) Study. Investig. New Drugs. 2016;34:112–118. doi: 10.1007/s10637-015-0307-6. PubMed DOI PMC

Baker C., Retzik-Stahr C., Singh V., Plomondon R., Anderson V., Rasouli N. Should Metformin Remain the First-Line Therapy for Treatment of Type 2 Diabetes? Ther. Adv. Endocrinol. Metab. 2021;12:2042018820980225. doi: 10.1177/2042018820980225. PubMed DOI PMC

Wang M., Liu X., Chen Z., Chen H., Tan Y. Metformin Suppressed Tumor Necrosis Factor-α-Induced Epithelial- Mesenchymal Transition in Prostate Cancer by Inactivating the NF-ΚB Signaling Pathway. Transl. Cancer Res. 2020;9:6086–6095. doi: 10.21037/tcr-20-1186. PubMed DOI PMC

Tong D., Liu Q., Liu G., Xu J., Lan W., Jiang Y., Xiao H., Zhang D., Jiang J. Metformin inhibits castration-induced EMT in prostate cancer by repressing COX2/PGE2/STAT3 axis. Cancer Lett. 2017;389:23–32. doi: 10.1016/j.canlet.2016.12.031. PubMed DOI

Li S.H., Ryu J.H., Park S.E., Cho Y.S., Park J.W., Lee W.J., Chun Y.S. Vitamin C Supplementation Prevents Testosterone-Induced Hyperplasia of Rat Prostate by down-Regulating HIF-1alpha. J. Nutr. Biochem. 2010;21:801–808. doi: 10.1016/j.jnutbio.2009.06.004. PubMed DOI

Gasmi A., Roubaud G., Dariane C., Barret E., Beauval J.B., Brureau L., Créhange G., Fiard G., Fromont G., Gauthé M., et al. Overview of the Development and Use of Akt Inhibitors in Prostate Cancer. J. Clin. Med. 2021;11:160. doi: 10.3390/jcm11010160. PubMed DOI PMC

Shore N., Mellado B., Shah S., Hauke R., Costin D., Adra N., Cullberg M., Teruel C.F., Morris T. A Phase I Study of Capivasertib in Combination With Abiraterone Acetate in Patients With Metastatic Castration-Resistant Prostate Cancer. Clin. Genitourin. Cancer. 2023;21:278–285. doi: 10.1016/j.clgc.2022.11.017. PubMed DOI

Flaig T.W., Gustafson D.L., Su L.J., Zirrolli J.A., Crighton F., Harrison G.S., Pierson A.S., Agarwal R., Glodé L.M. A Phase I and Pharmacokinetic Study of Silybin-Phytosome in Prostate Cancer Patients. Investig. New Drugs. 2007;25:139–146. doi: 10.1007/s10637-006-9019-2. PubMed DOI