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Genetics and Biology of Prostate Cancer

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Genetics and Biology of Prostate Cancer Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Genetics and biology of prostate cancer Guocan Wang,1,3 Di Zhao,2,3 Denise J. Spring,2 and Ronald A. DePinho2 1Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; 2Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA Despite the high long-term survival in localized prostate Prostate anatomy cancer, metastatic prostate cancer remains largely incur- The human and mouse prostates exhibit anatomic differ- able even after intensive multimodal therapy. The lethal- ences as well as cellular similarities (Fig. 1A). On the basis ity of advanced disease is driven by the lack of therapeutic of transcriptome profiles, the dorsolateral prostate in mice regimens capable of generating durable responses in the equates to the peripheral zone of the human prostate (Ber- setting of extreme tumor heterogeneity on the genetic quin et al. 2005), where ∼60%–75% of human prostate can- and cell biological levels. Here, we review available pros- cers arise (McNeal et al. 1988; Haffner et al. 2009). On the tate cancer model systems, the prostate cancer genome at- cellular level, both human and mouse prostates contain a las, cellular and functional heterogeneity in the tumor pseudostratified epithelium with three types of terminally microenvironment, tumor-intrinsic and tumor-extrinsic differentiated epithelial cells: luminal, basal, and neuroen- mechanisms underlying therapeutic resistance, and tech- docrine (van Leenders and Schalken 2003; Shen and Abate- nological advances focused on disease detection and Shen 2010). Although the cell of origin for prostate cancer management. These advances, along with an improved remains an area of active investigation (Lee and Shen 2015; understanding of the adaptive responses to conventional Strand and Goldstein 2015), luminal (Wang et al. 2009, cancer therapies, anti-androgen therapy, and immuno- 2013; Choi et al. 2012; Yoo et al. 2016) or basal (Lawson therapy, are catalyzing development of more effective et al. 2007, 2010; Goldstein et al. 2010; Choi et al. 2012; therapeutic strategies for advanced disease. In particular, Wang et al. 2013, 2014) phenotypes areobserved in prostate knowledge of the heterotypic interactions between and cancer (Fig. 1B). Various model systems and techniques coevolution of cancer and host cells in the tumor microen- (e.g., flow cytometry sorting, ex vivo three-dimensional vironment has illuminated novel therapeutic com- [3D] culture of prostate spheres, genetic lineage tracing, binations with a strong potential for more durable etc.) have documented the tumorigenic potential of both therapeutic responses and eventual cures for advanced stem/progenitor and differentiated cells. The biological disease. Improved disease management will also benefit and clinical relevance of the cell of origin is not clear: from artificial intelligence-based expert decision support One study concluded that luminal cell-derived prostate tu- systems for proper standard of care, prognostic determi- mors are more aggressive and that a luminal cell signature nant biomarkers to minimize overtreatment of localized carries a worse prognosis than basal cell-derived prostate disease, and new standards of care accelerated by next- cancer (Wang et al. 2013), whereas another study proposed generation adaptive clinical trials. that prostate cancers with a basal stem cell signature cor- relate with a more aggressive prostate cancer subtype (Smith et al. 2015). Larger prospective studies of these sig- The normal and neoplastic prostate natures are needed to determine their significance as prog- Prostate cancer is the most common noncutaneous can- nostic biomarkers. The prostate epithelium’sothercell cer in men worldwide, with an estimated 1,600,000 cases types, such as fibroblasts, smooth muscle cells, endothelial and 366,000 deaths annually (Torre et al. 2015). Despite cells, immune cells, autonomic nerve fibers, and associated recent progress, prostate cancer remains a significant ganglia, can influence the biology and clinical behavior of medical problem for the men affected, with overtreatment the prostate (see below; Barron and Rowley 2012). of inherently benign disease and inadequate therapies for metastatic prostate cancer. This review focuses on the Prostate neoplasia current state of knowledge and summarizes opportunities to curb the morbidity and mortality of prostate cancer. Malignant transformation of the prostate follows a multistep process, initiating as prostatic intraepithelial [Keywords: prostate cancer; therapy resistance; tumor microenvironment] © 2018 Wang et al. This article is distributed exclusively by Cold Spring 3These authors contributed equally to this work. Harbor Laboratory Press for the first six months after the full-issue publi- Corresponding authors: [email protected], gwang6@mdanderson cation date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After .org six months, it is available under a Creative Commons License (Attribu- Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.315739. tion-NonCommercial 4.0 International), as described at http://creative- 118. commons.org/licenses/by-nc/4.0/. GENES & DEVELOPMENT 32:1105–1140 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/18; www.genesdev.org 1105 Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Wang et al. Figure 1. The normal and neoplastic pros- tate. (A) Comparison of human and mousse normal prostates. Anatomically, the human A prostate contains three zones: (1) the periph- eral zone, where ∼60%–75% of prostate can- cers arise (McNeal et al. 1988; Haffner et al. 2009); the central zone; and (3) the transition zone (McNeal 1969, 1981, 1988). In contrast, the mouse prostate consists of the following distinct lobes: the anterior prostate (AP), the ventral prostate (VP), and the dorsolateral prostate (DLP) (Cunha et al. 1987). The lumi- B nal cells produce secretory proteins and are defined by expression of cytokeratin 8 (CK8) and CK18 and androgen receptor (AR). The basal cells are nestled between the basal lamina and luminal cells and ex- press high levels of CK5 and p63 and very low levels of AR. Neuroendocrine cells, a small population of endocrine–paracrine cells located on the basal cell layer, express neuroendocrine markers such as synapto- physin and chromogranin A and do not ex- press AR. (B) Prostate cancer cell of origin. Studies have demonstrated that both lumi- nal cells and basal cells can serve as the cell of origin for prostate cancer; however, it remains unknown whether neuroendocrine cells can be transformed to generate prostate cancer. Overexpression of oncogenes such as constitutively active myristoylated AKT1 (myr- AKT1) transforms normal human prostate epithelial cells into prostate cancer cells, which display prostate adenocarcinoma and squamous cell carcinoma phenotypes. In addition, N-Myc and myrAKT1 in normal prostate epithelial cells resulted in the formation of prostate ad- enocarcinoma and NEPC (neuroendocrine prostate cancer). Conditional inactivation of tumor suppressor genes Pten, Smad4, and Trp53 in both basal cells and luminal cells (ARR2PB-Cre), in basal cells (CK14-CreER), and in luminal cells (CK8-CreER) resulted the formation of prostate adenocarcinoma. Interestingly, inactivation of Pten, Rb1, and Trp53 resulted in the formation of NEPC. Castration in mice bearing Pten/Rb1-deficient prostate adenocarcinoma or abiraterone treatment of Pten/Trp53-deficient prostate adenocarcinoma resulted in the formation of NEPC. neoplasia (PIN) followed by localized prostate cancer and entiation of AR+ adenocarcinoma into AR-low and AR− then advanced prostate adenocarcinoma with local inva- tumors (Fig. 1B; Hu et al. 2015; Zou et al. 2017). sion, culminating in metastatic prostate cancer (Fig. 2; Shen and Abate-Shen 2010). The Gleason grading system, Metastatic prostate cancer which was originally defined by Donald Gleason (Gleason and Mellinger 1974) based on histological patterns of pros- Metastatic disease is the leading cause of prostate cancer- tate adenocarcinoma, has been refined over the years and associated deaths. Lymph nodes adjacent to the primary is the most widely used grading system defining prostate tumors are often the first site of metastases (Datta et al. cancer aggressiveness (Epstein et al. 2005, 2016). A central 2010), followed by metastases to the liver, lungs, and feature of prostate cancer is its hormone responsiveness, bones (Fig. 2). Human prostate cancer bone metastases first recognized by Huggins and Hodges (1941), who re- most often present as osteoblastic lesions with mixed ported that castration led to tumor regression in prostate osteolytic features, which cause severe pain, hypercalce- cancer patients. Androgen deprivation therapy (ADT) us- mia, and frequent fractures. ing agents that block the androgen pathway is now the Extensive effort has focused on understanding the biol- standard of care for prostate cancer. Resistance to ADT ogy of bone metastasis, with the goal of illuminating more can develop, resulting in primary castration-resistant effective treatment options for this lethal disease. Epithe- prostate cancer (CRPC) or metastatic CRPC (mCRPC). lial–mesenchymal transition (EMT) has been proposed to − In recent years, androgen receptor
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