Cellular Plasticity and the Neuroendocrine Phenotype in Prostate Cancer

Overview

Journal Nat Rev Urol

Specialty Urology

Date 2018 Feb 21

PMID 29460922

Citations 210

Authors

Alastair H Davies

Himisha Beltran

Amina Zoubeidi

Affiliations

Soon will be listed here.

Abstract

The success of next-generation androgen receptor (AR) pathway inhibitors, such as abiraterone acetate and enzalutamide, in treating prostate cancer has been hampered by the emergence of drug resistance. This acquired drug resistance is driven, in part, by the ability of prostate cancer cells to change their phenotype to adopt AR-independent pathways for growth and survival. Around one-quarter of resistant prostate tumours comprise cells that have undergone cellular reprogramming to become AR-independent and to acquire a continuum of neuroendocrine characteristics. These highly aggressive and lethal tumours, termed neuroendocrine prostate cancer (NEPC), exhibit reactivation of developmental programmes that are associated with epithelial-mesenchymal plasticity and acquisition of stem-like cell properties. In the past few years, our understanding of the link between lineage plasticity and an emergent NEPC phenotype has considerably increased. This new knowledge can contribute to novel therapeutic modalities that are likely to improve the treatment and clinical management of aggressive prostate cancer.

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References

Wyce A, Degenhardt Y, Bai Y, Le B, Korenchuk S, Crouthame M . Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer. Oncotarget. 2013; 4(12):2419-29. PMC: 3926837. DOI: 10.18632/oncotarget.1572. View

Miyamoto D, Zheng Y, Wittner B, Lee R, Zhu H, Broderick K . RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance. Science. 2015; 349(6254):1351-6. PMC: 4872391. DOI: 10.1126/science.aab0917. View

Li X, Placencio V, Iturregui J, Uwamariya C, Sharif-Afshar A, Koyama T . Prostate tumor progression is mediated by a paracrine TGF-beta/Wnt3a signaling axis. Oncogene. 2008; 27(56):7118-30. PMC: 3222150. DOI: 10.1038/onc.2008.293. View

Lee G, Kwon S, Lee J, Jeon S, Jang K, Choi H . Macrophages induce neuroendocrine differentiation of prostate cancer cells via BMP6-IL6 Loop. Prostate. 2011; 71(14):1525-37. DOI: 10.1002/pros.21369. View

Nieto M . The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu Rev Cell Dev Biol. 2011; 27:347-76. DOI: 10.1146/annurev-cellbio-092910-154036. View

Kim K, Roberts C . Targeting EZH2 in cancer. Nat Med. 2016; 22(2):128-34. PMC: 4918227. DOI: 10.1038/nm.4036. View

Smith P, Keller E . Anti-interleukin-6 monoclonal antibody induces regression of human prostate cancer xenografts in nude mice. Prostate. 2001; 48(1):47-53. DOI: 10.1002/pros.1080. View

Chen C, Welsbie D, Tran C, Baek S, Chen R, Vessella R . Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004; 10(1):33-9. DOI: 10.1038/nm972. View

Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T . Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol. 2007; 26(1):101-6. DOI: 10.1038/nbt1374. View

10.

Huggins C, Hodges C . Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. CA Cancer J Clin. 1972; 22(4):232-40. DOI: 10.3322/canjclin.22.4.232. View

11.

Collins A, Habib F, Maitland N, Neal D . Identification and isolation of human prostate epithelial stem cells based on alpha(2)beta(1)-integrin expression. J Cell Sci. 2001; 114(Pt 21):3865-72. DOI: 10.1242/jcs.114.21.3865. View

12.

Cheng L, Nagabhushan M, Pretlow T, Amini S, Pretlow T . Expression of E-cadherin in primary and metastatic prostate cancer. Am J Pathol. 1996; 148(5):1375-80. PMC: 1861553. View

13.

Dorff T, Goldman B, Pinski J, Mack P, Lara Jr P, Van Veldhuizen Jr P . Clinical and correlative results of SWOG S0354: a phase II trial of CNTO328 (siltuximab), a monoclonal antibody against interleukin-6, in chemotherapy-pretreated patients with castration-resistant prostate cancer. Clin Cancer Res. 2010; 16(11):3028-34. PMC: 2898710. DOI: 10.1158/1078-0432.CCR-09-3122. View

14.

Asangani I, Dommeti V, Wang X, Malik R, Cieslik M, Yang R . Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature. 2014; 510(7504):278-82. PMC: 4075966. DOI: 10.1038/nature13229. View

15.

Lau E, Lo J, Cheng B, Ma M, Lee J, Ng J . Cancer-Associated Fibroblasts Regulate Tumor-Initiating Cell Plasticity in Hepatocellular Carcinoma through c-Met/FRA1/HEY1 Signaling. Cell Rep. 2016; 15(6):1175-89. DOI: 10.1016/j.celrep.2016.04.019. View

16.

Redmer T, Diecke S, Grigoryan T, Quiroga-Negreira A, Birchmeier W, Besser D . E-cadherin is crucial for embryonic stem cell pluripotency and can replace OCT4 during somatic cell reprogramming. EMBO Rep. 2011; 12(7):720-6. PMC: 3128971. DOI: 10.1038/embor.2011.88. View

17.

Vaswani R, Gehling V, Dakin L, Cook A, Nasveschuk C, Duplessis M . Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2,.... J Med Chem. 2016; 59(21):9928-9941. PMC: 5451150. DOI: 10.1021/acs.jmedchem.6b01315. View

18.

Zhang X, Coleman I, Brown L, True L, Kollath L, Lucas J . SRRM4 Expression and the Loss of REST Activity May Promote the Emergence of the Neuroendocrine Phenotype in Castration-Resistant Prostate Cancer. Clin Cancer Res. 2015; 21(20):4698-708. PMC: 4609255. DOI: 10.1158/1078-0432.CCR-15-0157. View

19.

Olumi A, Grossfeld G, Hayward S, Carroll P, Tlsty T, Cunha G . Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 1999; 59(19):5002-11. PMC: 3300837. DOI: 10.1186/bcr138. View

20.

Battula V, Evans K, Hollier B, Shi Y, Marini F, Ayyanan A . Epithelial-mesenchymal transition-derived cells exhibit multilineage differentiation potential similar to mesenchymal stem cells. Stem Cells. 2010; 28(8):1435-45. PMC: 3523728. DOI: 10.1002/stem.467. View