Molecular genetics of prostate cancer: new prospects for old challenges

Abstract

Despite much recent progress, prostate cancer continues to represent a major cause of cancer-related mortality and morbidity in men. Since early studies on the role of the androgen receptor that led to the advent of androgen deprivation therapy in the 1940s, there has long been intensive interest in the basic mechanisms underlying prostate cancer initiation and progression, as well as the potential to target these processes for therapeutic intervention. Here, we present an overview of major themes in prostate cancer research, focusing on current knowledge of principal events in cancer initiation and progression. We discuss recent advances, including new insights into the mechanisms of castration resistance, identification of stem cells and tumor-initiating cells, and development of mouse models for preclinical evaluation of novel therapuetics. Overall, we highlight the tremendous research progress made in recent years, and underscore the challenges that lie ahead.

Figure 1.

Progression pathway for human prostate cancer. Stages of progression are shown, together with molecular processes and genes/pathways that are likely to be significant at each stage. Adapted from Abate-Shen and Shen (2000).

Figure 2.

Histopathology of human and mouse prostate cancer. (A–D) Hematoxylin-eosin-stained sections of human prostate. (A) Benign normal tissue, with representative basal (bas) and luminal (lum) cells indicated. (B) PIN; arrows indicate regions of hyperplastic epithelium. (C) Well-differentiated adenocarcinoma. (D) Poorly differentiated adenocarcinoma. (E–H) Hematoxylin-eosin-stained sections of anterior prostate from genetically engineered mouse models. (E) Normal tissue, with characteristic papillary tufting (arrowheads). (F) High-grade PIN. (G) Prostate carcinoma. (H) Prostate carcinoma with an invasive phenotype. We thank Dr. Robert Cardiff and Alexander Borowsky (School of Medicine, University of California at Davis) for providing images of human prostate specimens.

Figure 3.

Role of AR in castration-resistant prostate cancer. (A) AR maintains homeostasis of both epithelial and stromal tissues in the normal prostate. (B) Following androgen ablation, stromal cells produce paracrine proapoptotic signals that act on neighboring epithelial cells, promoting regression of normal prostate. (C–F) Castration resistance can occur through a variety of molecular mechanisms, including AR amplification (C); gain-of-function mutation of AR mutation (D); ligand-independent AR activation by up-regulation of other signaling pathways, such as the Akt/mTOR and Erk MAPK pathways (E); or endogenous biosynthesis of androgens by tumor cells (F). Adapted from Shen and Abate-Shen (2007); © 2007 American Association for Cancer Research.

Figure 4.

Lineage hierarchy in the prostate epithelium and the cell of origin for prostate cancer. Two possible lineage relationships for the adult prostate epithelium are shown, together with the potential roles of Lin⁻Sca-1⁺CD49f⁺ cells (LSCs) and CARNs. Different cell types of origin in the lineage hierarchy might then generate distinct tumor subtypes following oncogenic transformation (red arrows). (A) In this model, LSCs correspond to stem cells, and CARNs correspond to a luminal progenitor that acquires stem cell properties in the context of prostate regeneration (green arrows), thus corresponding to a facultative stem cell. (B) An alternative model is that LSCs and CARNs correspond to independent stem cells that maintain basal and luminal populations, respectively. Adapted from X Wang et al. (2009); © 2009 Nature.