Understanding and targeting prostate cancer cell heterogeneity and plasticity. (July 2022)

• Record Type: Journal Article
• Authors: Tang, Dean G.
• Is Part Of: Seminars in cancer biology. Volume 82(2022)
• Page Start: 68
• Page End: 93
• Publication Date: 2022-07
• Subjects: ACD asymmetric cell division -- AD androgen-dependent -- ADT androgen deprivation therapy -- AI androgen-independent -- AP anterior prostate -- AR androgen receptor -- AR-KO AR knockout -- ARSIs AR signaling inhibitors -- AR-Vs AR splice variants -- AVPC aggressive variant prostate cancer -- BCR biochemical recurrence -- BM bone marrow -- BMP bone morphogenic protein -- circRNA circular RNA -- CAF carcinoma associated fibroblasts -- CDSS charcoal and dextran-stripped serum -- CK cytokeratin -- CRPC castration-resistant prostate cancer -- CSCs cancer stem cells -- CTCs circulating tumor cells -- DKO double knockout (i.e., Pten−/l−Rb1-/-) -- DHT 5α-dihydrotestosterone -- DNPC double-negative PCa -- EMT epithelial mesenchymal transition -- Enza enzalutamide -- GR glucocorticoid receptor -- GS Gleason Score -- HGPIN high grade prostate intraepithelial neoplasia -- HPCa human PCa (specimens) -- IF immunofluorescence -- IHC immunohistochemistry -- IL interleukin -- IR irradiated -- ITH intra-tumor heterogeneity -- KO knockout -- LN lymph node -- LP luminal progenitor cells -- mCSPC metastatic castration-sensitive PCa -- mCRPC metastatic castration resistant prostate cancer -- MDV3100 e nzalutamide -- miRNA microRNA -- MSCs mesenchymal stem cells -- NE neuroendocrine -- NEPC neuroendocrine prostate cancer -- NHP normal human prostate -- PCa prostate cancer -- PCSCs prostate cancer stem cells -- PDX patient (tumor) Derived Xenografts -- PIA prostate inflammatory atrophy -- PIN prostate intraepithelial neoplasia -- PSAP-GFP PSA Promoter-driven GFP expressing (lentiviral reporters) -- PSCA prostate stem cell antigen -- PSA prostate specific antigen -- ROS reactive oxygen species -- s.c subcutaneously -- SCCs slow-cycling cells -- scRNA-seq single-cell RNA sequencing -- SNP single nucleotide polymorphism -- SPA supraphysiological androgens -- SPT supraphysiological testosterone -- T testosterone -- TAM tumor-associated macrophages -- TILs tumor-infiltrating lymphocytes -- TF transcription factor -- TMA tissue microarray -- TME tumor microenvironment -- Tregs regulatory T cells -- WM Whole-mount (sections); Cancer cell heterogeneity -- Prostate cancer -- Androgen receptor -- Cancer stem cells -- Cancer cell plasticity; Cancer -- Periodicals; Neoplasms -- Periodicals; Review Literature; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.semcancer.2021.11.001
• Languages: English
• ISSNs: 1044-579X

Abstract

Abstract: Prostate cancer (PCa) is a prevalent malignancy that occurs primarily in old males. Prostate tumors in different patients manifest significant inter-patient heterogeneity with respect to histo-morphological presentations and molecular architecture. An individual patient tumor also harbors genetically distinct clones in which PCa cells display intra-tumor heterogeneity in molecular features and phenotypic marker expression. This inherent PCa cell heterogeneity, e.g., in the expression of androgen receptor (AR), constitutes a barrier to the long-term therapeutic efficacy of AR-targeting therapies. Furthermore, tumor progression as well as therapeutic treatments induce PCa cell plasticity such that AR-positive PCa cells may turn into AR-negative cells and prostate tumors may switch lineage identity from adenocarcinomas to neuroendocrine-like tumors. This induced PCa cell plasticity similarly confers resistance to AR-targeting and other therapies. In this review, I first discuss PCa from the perspective of an abnormal organ development and deregulated cellular differentiation, and discuss the luminal progenitor cells as the likely cells of origin for PCa. I then focus on intrinsic PCa cell heterogeneity in treatment-naïve tumors with the presence of prostate cancer stem cells (PCSCs). I further elaborate on PCa cell plasticity induced by genetic alterations and therapeutic interventions, and present potential strategies to therapeutically tackle PCa cell heterogeneity and plasticity. My discussions will make it clear that, to achieve enduring clinical efficacy, both intrinsic PCa cell heterogeneity and induced PCa cell plasticity need to be targeted with novel combinatorial approaches.