Prostate tumor neuroendocrine differentiation via EMT: The road less traveled

doi:10.1016/j.ajur.2018.11.001

Asian Journal of Urology, 2019, 6 (1): 82-90 doi: 10.1016/j.ajur.2018.11.001

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Prostate tumor neuroendocrine differentiation via EMT: The road less traveled

Haley Dicken^a,b,Patrick J. Hensley^a,Natasha Kyprianou^a,b,c,*(

)

a Department of Urology, University of Kentucky College of Medicine, Lexington, KY, USA
b Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA
c Department of Toxicology & Cancer Biology, University of Kentucky College of Medicine, Lexington, KY, USA

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Abstract

The long-standing challenge in the treatment of prostate cancer is to overcome therapeutic resistance during progression to lethal disease. Aberrant transforming-growth factor-β (TGF-β) signaling accelerates prostate tumor progression in a transgenic mouse model via effects on epithelial-mesenchymal transition (EMT), and neuroendocrine differentiation driving tumor progression to castration-resistant prostate cancer (CRPC). Neuroendocrine prostate cancer (NEPC) is highly aggressive exhibiting reactivation of developmental programs associated with EMT induction and stem cell-like characteristics. The androgen receptor (AR) is a critical driver of tumor progression as well as therapeutic response in patients with metastatic CRPC. The signaling interactions between the TGF-β mechanistic network and AR axis impact the EMT phenotypic conversions, and perturbation of epithelial homeostasis via EMT renders a critical venue for epithelial derived tumors to become invasive, acquire the neuroendocrine phenotype, and rapidly metastasize. Combinations of microtubule targeting taxane chemotherapy and androgen/AR targeting therapies have survival benefits in CRPC patients, but therapeutic resistance invariability develops, leading to mortality. Compelling evidence from our group recently demonstrated that chemotherapy (cabazitaxel, second line taxane chemotherapy), or TGF-β receptor signaling targeted therapy, caused reversion of EMT to mesenchymal-epithelial transition and tumor re-differentiation, in in vitro and in vivo prostate cancer models. In this review, we discuss the functional contribution of EMT dynamic changes to the development of the neuroendocrine phenotype—the newly characterized pathological feature of prostate tumors in the context of the tumor microenvironment-navigated cell lineage changes and the role of this neuroendocrine phenotype in metastatic progression and therapeutic resistance.

Key words： Neuroendocrine differentiation Cell polarity Prostate cancer Androgen deprivation therapy Epithelial-mesenchymal transition

Received: 13 June 2018 Available online: 17 November 2018

Corresponding Authors: Natasha Kyprianou E-mail: nkypr2@uky.edu

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Haley Dicken,Patrick J. Hensley,Natasha Kyprianou. Prostate tumor neuroendocrine differentiation via EMT: The road less traveled[J]. Asian Journal of Urology, 2019, 6(1): 82-90.

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http://www.ajurology.com/EN/10.1016/j.ajur.2018.11.001 OR http://www.ajurology.com/EN/Y2019/V6/I1/82

Histopathological characteristics of neuroendocrine prostate cancer. (A) A representative H-E section of a human prostatectomy specimen from a 57-year-old male with PSA 3.4 ng/mL diagnosed with NEPC. Neuroendocrine cells are pathologically small, round epithelial cells that contain irregular nuclei and reduced cytoplasmic granularity; (B) and (C) Images of prostate tumor sections from the TRAMP mouse model tumors at 20 weeks and 34 weeks respectively exhibiting a characteristic progressive spectrum of neuroendocrine differentiation. PSA, prostate-specific antigen; NEPC, neuroendocrine prostate cancer; TRAMP, transgenic mouse of adenocarcinoma of the prostate.

Progression of primary prostate adenocarcinoma to NEPC and EMT-navigated metastatic prostate cancer follows diverse differentiation spectra. Normal epithelial cells may undergo EMT via loss of basoapical polarity and creating a more irregularly shaped, mesenchymal phenotype. Tumor epithelial cells may, upon detaching from the ECM, also transdifferentiate to NEPC as a cellular response to ADT. Another pathway to the neuroendocrine phenotype is differentiation of cell with stem cell-like properties. In addition to the separate lineages, a potential connection and spectrum of differentiation between the two phenotypes within the microenvironment may have significant functional consequences on prostate tumor progression. ADT, androgen deprivation therapy; ECM, extracellular matrix; EMT, epithelial-mesenchymal transition; NEPC, neuroendocrine-prostate cancer; PSA, prostate-specific antigen; AR, androgen receptor; MEK, mitogen-activated protein kinase; AURKA, aurora kinase A; CRPC, castration-resistant prostate cancer.

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