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.

In epithelial tissues, the lineage relationship between normal progenitor cells and cell type(s) of origin for cancer has been poorly understood. Here we show that a known regulator of prostate epithelial differentiation, the homeobox gene Nkx3.1, marks a stem cell population that functions during prostate regeneration. Genetic lineage-marking demonstrates that rare luminal cells which express Nkx3.1 in the absence of testicular androgens (castration-resistant Nkx3.1-expressing cells, CARNs) are bipotential and can self-renew in vivo, while single-cell transplantation assays show that CARNs can reconstitute prostate ducts in renal grafts. Functional assays of Nkx3.1 mutant mice in serial prostate regeneration assays suggest that Nkx3.1 is required for stem cell maintenance. Finally, targeted deletion of the Pten tumor suppressor gene in CARNs results in rapid formation of carcinoma following androgen-mediated regeneration. These observations indicate that CARNs represent a novel luminal stem cell population that is an efficient target for oncogenic transformation in prostate cancer.

In aging men, the prostate gland becomes hyperproliferative and displays a propensity toward carcinoma. Although this hyperproliferative process has been proposed to represent an inappropriate reactivation of an embryonic differentiation program, the regulatory genes responsible for normal prostate development and function are largely undefined. Here we show that the murine Nkx3.1 homeobox gene is the earliest known marker of prostate epithelium during embryogenesis and is subsequently expressed at all stages of prostate differentiation in vivo as well as in tissue recombinants. A null mutation for Nkx3.1 obtained by targeted gene disruption results in defects in prostate ductal morphogenesis and secretory protein production. Notably, Nkx3.1 mutant mice display prostatic epithelial hyperplasia and dysplasia that increases in severity with age. This epithelial hyperplasia and dysplasia also occurs in heterozygous mice, indicating haploinsufficiency for this phenotype. Because human NKX3.1 is known to map to a prostate cancer hot spot, we propose that NKX3.1 is a prostate-specific tumor suppressor gene and that loss of a single allele may predispose to prostate carcinogenesis. The Nkx3.1 mutant mice provide a unique animal model for examining the relationship between normal prostate differentiation and early stages of prostate carcinogenesis.

Bladder cancer is the fifth most prevalent cancer in the U.S., yet is understudied, and few laboratory models exist that reflect the biology of the human disease. Here, we describe a biobank of patient-derived organoid lines that recapitulates the histopathological and molecular diversity of human bladder cancer. Organoid lines can be established efficiently from patient biopsies acquired before and after disease recurrence and are interconvertible with orthotopic xenografts. Notably, organoid lines often retain parental tumor heterogeneity and exhibit a spectrum of genomic changes that are consistent with tumor evolution in culture. Analyses of drug response using bladder tumor organoids show partial correlations with mutational profiles, as well as changes associated with treatment resistance, and specific responses can be validated using xenografts in vivo. Our studies indicate that patient-derived bladder tumor organoids represent a faithful model system for studying tumor evolution and treatment response in the context of precision cancer medicine.

Prostate cancer afflicts one man in nine over the age of 65 and represents the most frequently diagnosed cancer in American men (Coffey 1993). Early detection through serum testing for prostate specific antigen (PSA) and improved procedures for surgical intervention and radiation therapy have significantly reduced the number of fatalities; however, there is still no effective cure for men with advanced disease. Therefore, much research has been dedicated to identifying prognostic markers that distinguish indolent versus aggressive forms of prostate cancer. In contrast, significantly less research has been devoted to understanding the molecular mechanisms that underlie normal prostate growth and development or cancer initiation and progression.In this review, we address recent progress toward the central objectives of understanding parameters of normal versus abnormal prostatic development and of elucidating a molecular pathway for prostate cancer progression. We focus on key regulatory molecules that have been implicated by analysis of patterns of allelic loss in human prostate cancers and/or by reverse genetic approaches in the mouse.