Basal epithelial cells in prostate development, tumorigenesis, and cancer progression

The prostate epithelium is composed of two predominant cell populations: luminal and basal epithelial cells. Luminal cells have a secretory function that supports male fertility while basal cells function in regeneration and maintenance of epithelial tissue. Recent studies in humans and mice have expanded our knowledge of the role and regulation of luminal and basal cells in prostate organogenesis, development, and homeostasis. The insights from healthy prostate biology can inform studies focused on the origins of prostate cancer, progression of the disease, and development of resistance to targeted hormonal therapies. In this review, we discuss a critical role for basal cells in the development and maintenance of healthy prostate tissue. Additionally, we provide evidence supporting a role for basal cells in oncogenesis and therapeutic resistance mechanisms of prostate cancer. Finally, we describe basal cell regulators that may promote lineage plasticity and basal cell identity in prostate cancers that have developed therapeutic resistance. These regulators could serve as therapeutic targets to inhibit or delay resistance and thereby improve outcomes for prostate cancer patients.

[1]  M. Berger,et al.  Chromatin profiles classify castration-resistant prostate cancers suggesting therapeutic targets , 2022, Science.

[2]  Jamie L. Marshall,et al.  Single-nucleus cross-tissue molecular reference maps toward understanding disease gene function , 2022, Science.

[3]  C. Logothetis,et al.  Mesenchymal and stem-like prostate cancer linked to therapy-induced lineage plasticity and metastasis , 2022, Cell reports.

[4]  S. Quake.  The Tabula Sapiens: a multiple organ single cell transcriptomic atlas of humans , 2021, bioRxiv.

[5]  A. Jemal,et al.  Cancer statistics, 2022 , 2022, CA: a cancer journal for clinicians.

[6]  A. D. De Marzo,et al.  SOX2 Mediates Metabolic Reprogramming of Prostate Cancer Cells , 2021, Oncogene.

[7]  Tomasz P. Wypych,et al.  Cellular and functional heterogeneity of the airway epithelium , 2021, Mucosal Immunology.

[8]  C. Roehrborn,et al.  5‐Alpha reductase inhibitors induce a prostate luminal to club cell transition in human benign prostatic hyperplasia , 2021, The Journal of pathology.

[9]  Joshua D Mentzer,et al.  Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer , 2021, Nature Communications.

[10]  M. Gleave,et al.  Prognosis Associated With Luminal and Basal Subtypes of Metastatic Prostate Cancer. , 2021, JAMA oncology.

[11]  J. Welti,et al.  A New Old Target: Androgen Receptor Signaling and Advanced Prostate Cancer. , 2021, Annual review of pharmacology and toxicology.

[12]  L. Xue,et al.  Finding an easy way to harmonize: a review of advances in clinical research and combination strategies of EZH2 inhibitors , 2021, Clinical epigenetics.

[13]  K. Fizazi,et al.  Darolutamide and survival in nonmetastatic, castration-resistant prostate cancer: a patient perspective of the ARAMIS trial. , 2021, Future oncology.

[14]  D. Strand,et al.  Progenitors in prostate development and disease. , 2021, Developmental biology.

[15]  Jiaoti Huang,et al.  Neuroendocrine cells of the prostate: Histology, biological functions, and molecular mechanisms , 2021, Precision clinical medicine.

[16]  Jeffrey M. McManus,et al.  Hormonal Therapy for Prostate Cancer. , 2021, Endocrine reviews.

[17]  B. Vojtesek,et al.  TAp63 and ΔNp63 (p40) in prostate adenocarcinomas: ΔNp63 associates with a basal-like cancer stem cell population but not with metastasis , 2020, Virchows Archiv.

[18]  F. Saad,et al.  Apalutamide and Overall Survival in Prostate Cancer. , 2020, European urology.

[19]  Simran K. Sandhu,et al.  Urethral luminal epithelia are castration‐insensitive cells of the proximal prostate , 2020, The Prostate.

[20]  Michael D. Nyquist,et al.  Combined TP53 and RB1 Loss Promotes Prostate Cancer Resistance to a Spectrum of Therapeutics and Confers Vulnerability to Replication Stress. , 2020, Cell reports.

[21]  J. Brooks,et al.  Trop2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1 , 2020, Proceedings of the National Academy of Sciences.

[22]  Guochao Liao,et al.  LSD1/KDM1A inhibitors in clinical trials: advances and prospects , 2019, Journal of Hematology & Oncology.

[23]  Chunxiao Wu,et al.  SOX2 has dual functions as a regulator in the progression of neuroendocrine prostate cancer , 2019, Laboratory Investigation.

[24]  F. D. de Sauvage,et al.  The great escape: tumour cell plasticity in resistance to targeted therapy , 2019, Nature Reviews Drug Discovery.

[25]  Myles A Brown,et al.  Transcriptional Regulation in Prostate Cancer. , 2018, Cold Spring Harbor perspectives in medicine.

[26]  Venkat S. Malladi,et al.  A Cellular Anatomy of the Normal Adult Human Prostate and Prostatic Urethra , 2018, bioRxiv.

[27]  M. Gleave,et al.  Androgen deprivation promotes neuroendocrine differentiation and angiogenesis through CREB-EZH2-TSP1 pathway in prostate cancers , 2018, Nature Communications.

[28]  O. Franco,et al.  Development of the human prostate. , 2018, Differentiation; research in biological diversity.

[29]  Aviv Regev,et al.  A revised airway epithelial hierarchy includes CFTR-expressing ionocytes , 2018, Nature.

[30]  A. D. De Marzo,et al.  ETS2 is a prostate basal cell marker and is highly expressed in prostate cancers aberrantly expressing p63 , 2018, The Prostate.

[31]  Menggang Yu,et al.  Associations of Luminal and Basal Subtyping of Prostate Cancer With Prognosis and Response to Androgen Deprivation Therapy , 2017, JAMA oncology.

[32]  Laura C. Greaves,et al.  Multipotent Basal Stem Cells, Maintained in Localized Proximal Niches, Support Directed Long-Ranging Epithelial Flows in Human Prostates , 2017, Cell reports.

[33]  M. Shen,et al.  Prostate organogenesis: tissue induction, hormonal regulation and cell type specification , 2017, Development.

[34]  J. Martı́n-Caballero,et al.  ΔNp63α promotes adhesion of metastatic prostate cancer cells to the bone through regulation of CD82 , 2017, Oncogene.

[35]  T. Cai,et al.  Dissecting cell-type-specific roles of androgen receptor in prostate homeostasis and regeneration through lineage tracing , 2017, Nature Communications.

[36]  M. Rubin,et al.  SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer , 2017, Science.

[37]  Kaitlyn M. Gayvert,et al.  N-Myc Induces an EZH2-Mediated Transcriptional Program Driving Neuroendocrine Prostate Cancer. , 2016, Cancer cell.

[38]  M. Shen,et al.  Basal Progenitors Contribute to Repair of the Prostate Epithelium Following Induced Luminal Anoikis , 2016, Stem cell reports.

[39]  Jiaoti Huang,et al.  Prostate epithelial cell of origin determines cancer differentiation state in an organoid transformation assay , 2016, Proceedings of the National Academy of Sciences.

[40]  Yue Lu,et al.  Stem cell and neurogenic gene-expression profiles link prostate basal cells to aggressive prostate cancer , 2016, Nature Communications.

[41]  Liang Cheng,et al.  Basal cell carcinoma of the prostate is an aggressive tumor with frequent loss of PTEN expression and overexpression of EGFR. , 2015, Human pathology.

[42]  D. Goldenberg,et al.  Sacituzumab Govitecan (IMMU-132), an Anti-Trop-2/SN-38 Antibody-Drug Conjugate: Characterization and Efficacy in Pancreatic, Gastric, and Other Cancers. , 2015, Bioconjugate chemistry.

[43]  M. Gleave,et al.  Inhibition of the HER2-YB1-AR axis with Lapatinib synergistically enhances Enzalutamide anti-tumor efficacy in castration resistant prostate cancer , 2015, Oncotarget.

[44]  A. Sangoi,et al.  Prostate Adenocarcinomas Aberrantly Expressing p63 Are Molecularly Distinct from Usual-Type Prostatic Adenocarcinomas , 2014, Modern Pathology.

[45]  E. Cuppen,et al.  Identification of Multipotent Luminal Progenitor Cells in Human Prostate Organoid Cultures , 2014, Cell.

[46]  P. Chambon,et al.  Luminal cells are favored as the cell of origin for prostate cancer. , 2014, Cell reports.

[47]  W. Bushman,et al.  Prostate progenitor cells proliferate in response to castration. , 2014, Stem cell research.

[48]  Yan Geng,et al.  p63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia , 2013, Proceedings of the National Academy of Sciences.

[49]  Junn-Liang Chang,et al.  Conditionally ablated Pten in prostate basal cells promotes basal-to-luminal differentiation and causes invasive prostate cancer in mice. , 2013, The American journal of pathology.

[50]  R. Cardiff,et al.  Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell of origin model for prostate cancer heterogeneity , 2013, Nature Cell Biology.

[51]  Kyle J. Kiriluk,et al.  Sox2 Is an Androgen Receptor-Repressed Gene That Promotes Castration-Resistant Prostate Cancer , 2013, PloS one.

[52]  C. Blanpain,et al.  Multipotent and unipotent progenitors contribute to prostate postnatal development , 2012, Nature Cell Biology.

[53]  M. Ittmann,et al.  Adult murine prostate basal and luminal cells are self-sustained lineages that can both serve as targets for prostate cancer initiation. , 2012, Cancer cell.

[54]  P. Chambon,et al.  Regenerated luminal epithelial cells are derived from preexisting luminal epithelial cells in adult mouse prostate. , 2011, Molecular endocrinology.

[55]  Jiaoti Huang,et al.  Identification of a Cell of Origin for Human Prostate Cancer , 2010, Science.

[56]  T. Enver,et al.  Forcing cells to change lineages , 2009, Nature.

[57]  M. Shen,et al.  A luminal epithelial stem cell that is a cell of origin for prostate cancer , 2009, Nature.

[58]  G. Prins,et al.  Molecular signaling pathways that regulate prostate gland development. , 2008, Differentiation; research in biological diversity.

[59]  E. Gelmann,et al.  R E V Ie W a Rt I C L E , 2022 .

[60]  H. F. Carvalho,et al.  Dynamics of the Epithelium During Canalization of the Rat Ventral Prostate , 2007, Anatomical record.

[61]  J. Epstein,et al.  Basal Cell Carcinoma of the Prostate: A Clinicopathologic Study of 29 Cases , 2007, The American journal of surgical pathology.

[62]  Megan F. Cole,et al.  Control of Developmental Regulators by Polycomb in Human Embryonic Stem Cells , 2006, Cell.

[63]  A. Mills,et al.  Role of p63 and basal cells in the prostate , 2004, Development.

[64]  T. Sun,et al.  Proximal location of mouse prostate epithelial stem cells , 2002, The Journal of cell biology.

[65]  R. Cardiff,et al.  Cooperativity of Nkx3.1 and Pten loss of function in a mouse model of prostate carcinogenesis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[66]  Christian A. Rees,et al.  Molecular portraits of human breast tumours , 2000, Nature.

[67]  J. Schalken,et al.  Demonstration of Intermediate Cells during Human Prostate Epithelial Differentiation In Situ and In Vitro Using Triple-Staining Confocal Scanning Microscopy , 2000, Laboratory Investigation.

[68]  R. Matusik,et al.  Prostate cancer in a transgenic mouse. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[69]  J. Epstein,et al.  The Utility of Basal Cell—Specific Anti‐Cytokeratin Antibody (34βE12) in the Diagnosis of Prostate Cancer: A Review of 228 Cases , 1995, The American journal of surgical pathology.

[70]  J. McNeal,et al.  Normal histology of the prostate. , 1988, The American journal of surgical pathology.

[71]  G. Cunha,et al.  Whole-mount autoradiography study of DNA synthetic activity during postnatal development and androgen-induced regeneration in the mouse prostate. , 1986, Biology of reproduction.

[72]  G. Pointis,et al.  Regulation of testosterone synthesis in the fetal mouse testis. , 1979, Journal of steroid biochemistry.