Article Data

  • Views 1477
  • Dowloads 225


Open Access Special Issue

Mechanisms of castration resistant prostate cancer formation and progression through neuroendocrine differentiation

  • Xueping Ma1
  • Xu Jiang1
  • Xuezhen Yang1

1Department of Urology, the Second Affiliated Hospital of Bengbu Medical College, 233020 Bengbu, Anhui, China

DOI: 10.31083/jomh.2021.040 Vol.17,Issue 4,September 2021 pp.17-21

Submitted: 02 March 2021 Accepted: 22 March 2021

Published: 30 September 2021

*Corresponding Author(s): Xuezhen Yang E-mail:

PDF (91.54 kB)


Normal prostate tissues consist mainly of epithelial cells, including secretory epithelial cells, basal cells, and neuroendocrine cells, and of mesenchymal cells, including smooth muscle cells and fibroblasts. The mechanisms leading to castration resistant prostate cancer (CRPC) are complex and diverse, but most involve neuroendocrine differentiation. In fact, during the development of prostate cancer, some of the tumor cells transform into neuroendocrine-like cells. This transition is a main underlying mechanism of CRPC formation.


Prostate cancer; Neuroendocrine differentiation; Castration resistance prostate cancer

Cite and Share

Xueping Ma,Xu Jiang,Xuezhen Yang. Mechanisms of castration resistant prostate cancer formation and progression through neuroendocrine differentiation. Journal of Men's Health. 2021. 17(4);17-21.


[1] US Preventive Services Task Force, Grossman DC, Curry SJ, Owens DK, Bibbins-Domingo K, Caughey AB, et al. Screening for prostate cancer: US preventive services task force recommendation statement. The Journal of the American Medical Association. 2018; 319: 1901–1913.

[2] Zhang Y, Zheng D, Zhou T, Song H, Hulsurkar M, Su N, et al. Androgen deprivation promotes neuroendocrine differentiation and angiogenesis through CREB-EZH2-TSP1 pathway in prostate cancers. Nature Communications. 2018; 9: 4080.

[3] Ather MH, Abbas F. Prognostic significance of neuroendocrine differentiation in prostate cancer. European Urology. 2000; 38: 535–542.

[4] Beltran H, Prandi D, Mosquera JM, Benelli M, Puca L, Cyrta J, et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nature Medicine. 2016; 22: 298–305.

[5] Yang X, Chen MW, Terry S, Vacherot F, Chopin DK, Bemis DL, et al. A human- and male-specific protocadherin that acts through the wnt signaling pathway to induce neuroendocrine transdifferentiation of prostate cancer cells. Cancer Research. 2005; 65: 5263–5271.

[6] Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015; 161: 1215–1228.

[7] Tan H, Sood A, Rahimi HA, Wang W, Gupta N, Hicks J, et al. Rb loss is characteristic of prostatic small cell neuroendocrine carcinoma. Clinical Cancer Research. 2014; 20: 890–903.

[8] Ham WS, Cho NH, Kim WT, Ju HJ, Lee JS, Choi YD. Pathological effects of prostate cancer correlate with neuroendocrine differentia-tion and PTEN expression after bicalutamide monotherapy. Journal of Urology. 2009; 182: 1378–1384.

[9] Berman-Booty LD, Knudsen KE. Models of neuroendocrine prostate cancer. Endocrine-Related Cancer. 2015; 22: R33–R49.

[10] Zou M, Toivanen R, Mitrofanova A, Floch N, Hayati S, Sun Y, et al. Transdifferentiation as a mechanism of treatment resistance in a mouse model of castration-resistant prostate cancer. Cancer Discovery. 2017; 7: 736–749.

[11] Li Y, Donmez N, Sahinalp C, Xie N, Wang Y, Xue H, et al. SRRM4 drives neuroendocrine transdifferentiation of prostate ade-nocarcinoma under androgen receptor pathway inhibition. European Urology. 2018; 71: 68–78.

[12] Schwab M, Varmus HE, Bishop JM, Grzeschik KH, Naylor SL, Sakaguchi AY, et al. Chromosome localization in normal human cells and neuroblastomas of a gene related to c-myc. Nature. 1984; 308: 288–291.

[13] Rickman DS, Schulte JH, Eilers M. The expanding world of N-MYC-driven tumors. Cancer Discovery. 2019; 8: 150–163.

[14] Beltran H, Rickman DS, Park K, Chae SS, Sboner A, MacDonald TY, et al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discovery. 2011; 1: 487–495.

[15] Lee JK, Phillips JW, Smith BA, Park JW, Stoyanova T, McCaffrey EF, et al. N-Myc drives neuroendocrine prostate cancer initiated from human prostate epithelial cells. Cancer Cell. 2016; 29: 536–547.

[16] Dardenne E, Beltran H, Benelli M, Gayvert K, Berger A, Puca L, et al. N-Myc induces an EZH2-mediated transcriptional program driving neuroendocrine prostate cancer. Cancer Cell. 2016; 30: 563–577.

[17] Gupta S, Li J, Kemeny G, Bitting RL, Beaver J, Somarelli JA, et al. Whole genomic copy number alterations in circulating tumor cells from men with abiraterone or enzalutamide-resistant metastatic castration-resistant prostate cancer. Clinical Cancer Research. 2017; 23: 1346–1357.

[18] Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun X, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 2005; 310: 644–648.

[19] Carver BS, Tran J, Chen Z, Carracedo-Perez A, Alimonti A, Nardella C, et al. ETS rearrangements and prostate cancer initiation. Nature. 2009; 457: E1–E1.

[20] Volante M, Tota D, Giorcelli J, Bollito E, Napoli F, Vatrano S, et al. Androgen deprivation modulates gene expression profile along prostate cancer progression. Human Pathology. 2016; 56: 81–88.

[21] Mounir Z, Lin F, Lin VG, Korn JM, Yu Y, Valdez R, et al. TM-PRSS2:ERG blocks neuroendocrine and luminal cell differentiation to maintain prostate cancer proliferation. Oncogene. 2015; 34: 3815–3825.

[22] Jung S, Shin S, Kim MS, Baek I, Lee JY, Lee SH, et al. Genetic progression of high grade prostatic intraepithelial neoplasia to prostate cancer. European Urology. 2016; 69: 823–830.

[23] Park JW, Lee JK, Witte ON, Huang J. FOXA2 is a sensitive and specific marker for small cell neuroendocrine carcinoma of the prostate. Modern Pathology. 2017; 30: 1262–1272.

[24] Mirosevich J, Gao N, Gupta A, Shappell SB, Jove R, Matusik RJ. Expression and role of Foxa proteins in prostate cancer. the Prostate. 2006; 66: 1013–1028.

[25] Qi J, Nakayama K, Cardiff RD, Borowsky AD, Kaul K, Williams R, et al. Siah2-dependent concerted activity of HIF and FoxA2 regulates formation of neuroendocrine phenotype and neuroendocrine prostate tumors. Cancer Cell. 2010; 18: 23–38.

[26] Gupta A, Yu X, Case T, Paul M, Shen MM, Kaestner KH, et al. Mash1 expression is induced in neuroendocrine prostate cancer upon the loss of Foxa2. Prostate. 2013; 73: 582–589.

[27] Kallio HML, Hieta R, Latonen L, Brofeldt A, Annala M, Kivinummi K, et al. Constitutively active androgen receptor splice variants AR-V3, AR-V7 and AR-V9 are co-expressed in castration-resistant prostate cancer metastases. British Journal of Cancer. 2018; 119: 347–356.

[28] Magani F, Peacock SO, Rice MA, Martinez MJ, Greene AM, Magani PS, et al. Targeting AR variant-coactivator interactions to exploit prostate cancer vulnerabilities. Molecular Cancer Research. 2017; 15: 1469–1480.

[29] Lapuk AV, Wu C, Wyatt AW, McPherson A, McConeghy BJ, Brahmbhatt S, et al. From sequence to molecular pathology, and a mechanism driving the neuroendocrine phenotype in prostate cancer. Journal of Pathology. 2012; 227: 286–297.

[30] Zhu Y, Liu C, Cui Y, Nadiminty N, Lou W, Gao AC. Interleukin-6 induces neuroendocrine differentiation (NED) through suppression of re-1 silencing transcription factor (REST). Prostate. 2014; 74: 1086–1094.

[31] Liang H, Studach L, Hullinger RL, Xie J, Andrisani OM. Down-regulation of re-1 silencing transcription factor (REST) in advanced prostate cancer by hypoxia-induced miR-106b 25. Experimental Cell Research. 2014; 320: 188–199.

[32] Quesnel-Vallières M, Irimia M, Cordes SP, Blencowe BJ. Essential roles for the splicing regulator nSR100/SRRM4 during nervous system development. Genes & Development. 2015; 29: 746–759.

[33] Zhang X, Coleman IM, Brown LG, True LD, Kollath L, Lucas JM, et al. SRRM4 expression and the loss of REST activity may promote the emergence of the neuroendocrine phenotype in castration-resistant prostate cancer. Clinical Cancer Research. 2015; 21: 4698–4708.

[34] Calcinotto A, Spataro C, Zagato E, Di Mitri D, Gil V, Crespo M, et al. IL-23 secreted by myeloid cells drives castration-resistant prostate cancer. Nature. 2018; 559: 363–369.

[35] Siegall CB, Schwab G, Nordan RP, FitzGerald DJ, Pastan I. Expression of the interleukin 6 receptor and interleukin 6 in prostate carcinoma cells. Cancer Research. 1990; 50: 7786–7788.

[36] Wang Q, Horiatis D, Pinski J. Interleukin-6 inhibits the growth of prostate cancer xenografts in mice by the process of neuroendocrine differentiation. International Journal of Cancer. 2004; 111: 508–513.

[37] Wang C, Peng G, Huang H, Liu F, Kong D, Dong K, et al. Blocking the feedback loop between neuroendocrine differentiation and macrophages improves the therapeutic effects of enzalutamide (MDV3100) on prostate cancer. Clinical Cancer Research. 2018; 24: 708–723.

[38] Ge D, Gao AC, Zhang Q, Liu S, Xue Y, You Z. LNCaP prostate cancer cells with autocrine interleukin-6 expression are resistant to IL-6-induced neuroendocrine differentiation due to increased expression of suppressors of cytokine signaling. Prostate. 2012; 72: 1306–1316.

Abstracted / indexed in

Science Citation Index Expanded Created as SCI in 1964, Science Citation Index Expanded now indexes over 9,200 of the world’s most impactful journals across 178 scientific disciplines. More than 53 million records and 1.18 billion cited references date back from 1900 to present.

Social Sciences Citation Index Social Sciences Citation Index contains over 3,400 journals across 58 social sciences disciplines, as well as selected items from 3,500 of the world’s leading scientific and technical journals. More than 9.37 million records and 122 million cited references date back from 1900 to present.

Current Contents - Social & Behavioral Sciences Current Contents - Social & Behavioral Sciences provides easy access to complete tables of contents, abstracts, bibliographic information and all other significant items in recently published issues from over 1,000 leading journals in the social and behavioral sciences.

Current Contents - Clinical Medicine Current Contents - Clinical Medicine provides easy access to complete tables of contents, abstracts, bibliographic information and all other significant items in recently published issues from over 1,000 leading journals in clinical medicine.

SCOPUS Scopus is Elsevier's abstract and citation database launched in 2004. Scopus covers nearly 36,377 titles (22,794 active titles and 13,583 Inactive titles) from approximately 11,678 publishers, of which 34,346 are peer-reviewed journals in top-level subject fields: life sciences, social sciences, physical sciences and health sciences.

DOAJ DOAJ is a community-curated online directory that indexes and provides access to high quality, open access, peer-reviewed journals.

CrossRef Crossref makes research outputs easy to find, cite, link, assess, and reuse. Crossref committed to open scholarly infrastructure and collaboration, this is now announcing a very deliberate path.

Portico Portico is a community-supported preservation archive that safeguards access to e-journals, e-books, and digital collections. Our unique, trusted process ensures that the content we preserve will remain accessible and usable for researchers, scholars, and students in the future.

Submission Turnaround Time