Prostate cancer is the second leading cause of noncutaneous cancer deaths in men in the United States. With approximately 1 in 6 men diagnosed during their lifetime, there were an estimated 190 000 new diagnoses made in the United States in 2010 (Merkle and Hoffmann, 2011
). Several treatments have proved efficient in the treatment of localized disease, including radical prostatectomy, radiotherapy, and hormone therapy (androgen ablation or castration). Unfortunately, no treatment is currently available for the management of metastatic prostate cancer (Hill and Kyprianou, 2002
), which is clinically significant as cancer metastasis is the leading cause of cancer-related deaths (Hsu et al, 2011
). Moreover, the shift from androgen-sensitive prostate tumors (treated with hormone therapy) to castration-resistant prostate cancer (CRPC) presents an increasingly complex target for optimizing the therapeutic efficacy of antitumor modalities. Efforts to establish suitable animal models to physiologically mimic the tumor microenvironment have met with varying degrees of success because of obstacles in genetic manipulation.
The use of mammalian models to study tumorigenesis requires the physiological relevance to human disease. The challenge specifically relating to prostate cancer stems from the heterogeneity of prostate tumors. In vitro studies utilizing immortalized human prostate cancer cell lines such as DU-145, PC-3, and LNCaP (reviewed in Sobel and Sadar, 2005
) have been successful in characterizing intracellular mechanisms involved in various stages of tumor progression, but lack in a systemic sense the complex paracrine signaling of the tumor microenvironment. Prostate cancer does not stem from a single focus of cells; rather it tends to develop multifocally in nearly 60%–90% of patients (Andreoiu and Cheng, 2010
). Prostate cancer progresses from prostatic intraepithelial neoplasia (PIN) to confined androgen-dependent carcinogenic cells to andro-gen-independent metastatic cells, no longer under endogenous control of the cell cycle or programmed cell death mechanisms (Ibrahim et al, 2010
; Sakamoto and Kyprianou, 2010
). The ability of prostate cancer to metastasize to the bone and influence hematopoietic lineages is seen in greater than 80% of prostate cancer– related deaths (Ibrahim et al, 2010
) and must be accounted for in an efficient in vivo model. The vast heterogeneity of prostate tumorigenesis at the pathological and molecular levels has exhausted efforts to establish mammalian models that mimic the onset, behavior, and progression of metastasis and CRPC.
Mammalian genome manipulation has been exploited to ectopically model human prostate cancer onset, progression, and metastasis in a highly reproducible and tissue-specific manner. Mario Capecchi received the 2007 Nobel Prize in Medicine for his development of gene-specific modification in mice using embryonic stem cells (Thomas and Capecchi, 1987
). More sophisticated techniques have resulted from technological advances, including transgene expression, conditional knockouts, inducible mutations, and xenograft transplantation. These have added temporal and spatial regulation to gene targeting. The use of traditional gene targeting to knock out tumor suppressor genes has been successful in recapitulating many characteristics of prostate cancer. Transgenic expression of oncogenes can functionally stimulate prostatic stromal cell hyperplasia, effectively modeling human benign prostatic hyperplasia (BPH). In other models, genetic manipulation causes epithelial proliferation as an effective model of human PIN (Kasper, 2005
). Both BPH and PIN are inflammatory precursors to prostate cancer and are targets for early diagnosis and intervention in the progression of the disease.
In 1971, Dr Alfred Knudson’s groundbreaking discovery of the retinoblastoma gene led to a revolutionary concept that cancer development correlates with DNA mutation frequency. A mutation in a tumor suppressor gene during early embryogenesis is propagated to the progeny during cell division, eventually creating a mosaic array of somatic expression of the particular mutation. Loss of heterozygosity (LOH) mutations in the remaining functional allele render progeny with no functional gene expression, which becomes phenotypically manifested in tumorigenesis (Knudson, 1985
). In certain cases, simply mutating 1 allele can result in an insufficient expression of protein required for proper function, a phenomenon known as haploinsufficiency. At least 25 genes have been identified whereby haploinsufficient expression leads to tumor development, including mutations in Pten
and the DNA repair enzyme Nbn
). Each of these tumor suppressor genes has potential value in the development of knockout models to study human carcinogenesis. Diverse efforts have focused on breeding a variety of null alleles to both Pten
mutants. Compound mutants expressing mutations in the cyclin-dependent kinase inhibitor p27kip1
or its substrate Cdkn1b
have been shown to enhance carcinogenesis via an increased proliferative index (Di Cristofano et al, 2001
; Gao et al, 2004
This review discusses the current use of mouse models to study prostate cancer progression to advanced metastatic disease (summarized in the ), including the limitations posed by each, efforts directed at circumventing such limitations, and the translational significance of interrogation of molecular pathways toward construction of clinically relevant in vivo models of prostate cancer for therapeutic targeting and biomarker validation.
Current well-characterized mouse models for prostate cancer