Progress toward understanding the biology of prostate cancer has been slow due to the few animal research models available to study the spectrum of this uniquely human disease. To develop an animal model for prostate cancer, several lines of transgenic mice were generated by using the prostate-specific rat probasin promoter to drive expression of the simian virus 40 large tumor antigencoding region. Mice expressing high levels of the transgene display progressive forms of prostatic disease that histologically resemble human prostate cancer, ranging from mild intraepithelial hyperplasia to large multinodular malignant neoplasia. Prostate tumors have been detected specirically in the prostate as early as 10 weeks ofage. Immunohistochemical analysis of tumor tissue has demonstrated that dorsolateral prostate-specific secretory proteins were confined to welldifferentiated ductal epithelial cells adjacent to, or within, the poorly differentiated tumor mass. Prostate tumors in the mice also display elevated levels of nuclear p53 and a decreased heterogeneous pattern of androgen-receptor expression, as observed in advanced human prostate cancer. The establishment of breeding lines of transgenic mice that reproducibly develop prostate cancer provides an animal model system to study the molecular basis of transformation of normal prostatic cells and the factors influencing the progression to metastatic prostate cancer.Prostate cancer will likely claim the lives of 35,000 men in the United States this year alone, and some 200,000 more men will be diagnosed with the disease (1). However, progress toward understanding the biology of prostate cancer and the development of new therapies for this disease has been slowed, in part, by the need for in vivo model systems that adequately reproduce the spectrum of benign, latent, aggressive, and metastatic forms of the human disease.Prostate cancer is a disease quite unique to man. Although naturally occurring prostatic disease has been reported in some canine (2) and rodent (3-5) species, these animals have not provided the appropriate models to adequately study the molecular mechanisms related to the early development and progression of human prostate cancer. To this end, we initiated a research program to establish a transgenic animal model for prostate cancer by using a prostate-specific transgene expression system that has been developed in our laboratories based on the regulatory elements of the rat probasin (rPB)-encoding gene.The rPB gene encodes an androgen-and zinc-regulated protein specific to the dorsolateral epithelium (6-8). Isolation of the rPB gene has facilitated identification of cis-acting androgen-response regions within the 5' flanking region (9). More recently, the ability of the prostate-specific rPB gene promoter to target heterologous genes specifically to the prostate in transgenic mice has been demonstrated (10). InThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "adver...

Complete inactivation of the PTEN tumor suppressor gene is extremely common in advanced cancer, including prostate cancer (CaP). However, one PTEN allele is already lost in the vast majority of CaPs at presentation. To determine the consequence of PTEN dose variations on cancer progression, we have generated by homologous recombination a hypomorphic Pten mouse mutant series with decreasing Pten activity: Ptenhy/+ > Pten+/− > Ptenhy/− (mutants in which we have rescued the embryonic lethality due to complete Pten inactivation) > Pten prostate conditional knockout (Ptenpc) mutants. In addition, we have generated and comparatively analyzed two distinct Ptenpc mutants in which Pten is inactivated focally or throughout the entire prostatic epithelium. We find that the extent of Pten inactivation dictate in an exquisite dose-dependent fashion CaP progression, its incidence, latency, and biology. The dose of Pten affects key downstream targets such as Akt, p27Kip1, mTOR, and FOXO3. Our results provide conclusive genetic support for the notion that PTEN is haploinsufficient in tumor suppression and that its dose is a key determinant in cancer progression.

This study will serve as the basis for the rational design of pre-clinical studies with genetically engineered mouse models.

Toward the goal of developing an optical imaging contrast agent that will enable surgeons to intraoperatively distinguish cancer foci from adjacent normal tissue, we developed a chlorotoxin:Cy5.5 (CTX:Cy5.5) bioconjugate that emits near-IR fluorescent signal. The probe delineates malignant glioma, medulloblastoma, prostate cancer, intestinal cancer, and sarcoma from adjacent non-neoplastic tissue in mouse models. Metastatic cancer foci as small as a few hundred cells were detected in lymph channels. Specific binding to cancer cells is facilitated by matrix metalloproteinase-2 (MMP-2) as evidenced by reduction of CTX:Cy5.5 binding in vitro and in vivo by a pharmacologic blocker of MMP-2 and induction of CTX:Cy5.5 binding in MCF-7 cells following transfection with a plasmid encoding MMP-2. Mouse studies revealed that CTX:Cy5.5 has favorable biodistribution and toxicity profiles. These studies show that CTX:Cy5.5 has the potential to fundamentally improve intraoperative detection and resection of malignancies. [Cancer Res 2007;67(14):6882-8]

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The identification of potentially useful immune-based treatments for prostate cancer has been severely constrained by the scarcity of relevant animal research models for this disease. Moreover, some of the most critical mechanisms involved in complete and proper antitumoral T cell activation have only recently been identified for experimental manipulation, namely, components involved in the costimulatory pathway for T cell activation. Thus, we have established a novel syngeneic murine prostate cancer model that permits us to examine two distinct manipulations intended to elicit an antiprostate cancer response through enhanced T cell costimulation: (i) provision of direct costimulation by prostate cancer cells transduced to express the B7.1 ligand and (ii) in vivo antibody-mediated blockade of the T cell CTLA-4, which prevents T cell down-regulation. In the present study we found that a tumorigenic prostate cancer cell line, TRAMPC1 (pTC1), derived from transgenic mice, is rejected by syngeneic C57BL͞6 mice, but not athymic mice, after this cell line is transduced to express the costimulatory ligand B7.1. Also, we demonstrated that in vivo antibody-mediated blockade of CTLA-4 enhances antiprostate cancer immune responses. The response raised by anti-CTLA-4 administration ranges from marked reductions in wild-type pTC1 growth to complete rejection of these cells. Collectively, these experiments suggest that appropriate manipulation of T cell costimulatory and inhibitory signals may provide a fundamental and highly adaptable basis for prostate cancer immunotherapy. Additionally, the syngeneic murine model that we introduce provides a comprehensive system for further testing of immunebased treatments for prostate cancer.

The PTEN gene encodes a lipid phosphatase that negatively regulates the phosphatidylinositol 3-kinase pathway and is inactivated in a wide variety of malignant neoplasms. High rates of loss of heterozygosity are observed at the 10q23.3 region containing the human PTEN gene in prostate cancer and other human malignancies, but the demonstrated rate of biallelic inactivation of the PTEN gene by mutation or homozygous deletion is significantly lower than the rate of loss of heterozygosity. The transgenic adenocarcinoma of mouse prostate model is a well characterized animal model of prostate cancer. Analysis of prostate cancer progression in transgenic adenocarcinoma of mouse prostate mice bred to Pten ؉/؊ heterozygous mice, coupled with analysis of the Pten gene and protein in the resulting tumors, reveals that haploinsufficiency of the Pten gene promotes the progression of prostate cancer in this model system. This observation provides a potential explanation for the discordance in rates of loss of heterozygosity at 10q23 and biallelic PTEN inactivation observed in prostate cancer and many human malignancies.T he PTEN tumor suppressor gene (also known as MMAC-1) encodes a phosphatase and is inactivated in a wide variety of human malignant neoplasms, including gliomas, melanomas, and carcinomas of the endometrium, kidney, breast, lung, upper respiratory tract, and prostate (1-4). The tumor suppressor activity of PTEN is thought to be primarily due to its ability to dephosphorylate phosphatidylinositol 3,4,5-phosphate at the 3-position and negatively regulate the activity of the phosphatidylinositol 3-kinase pathway (5, 6). A variety of biological effects have been attributed to loss of PTEN activity that are relevant to its role as a tumor suppressor gene, including enhanced cell proliferation (6), decreased apoptosis (5, 6), and increased tumor angiogenesis (7,8). The PTEN gene is also mutated in Cowden syndrome (9), a hereditary neoplastic syndrome characterized by an increased rate of thyroid cancer and breast cancer in affected females. Thus, the PTEN gene is an important tumor suppressor with a wide range of biological activities relevant to tumor progression.The PTEN tumor suppressor gene maps to human chromosome 10q23.3, and this region shows high rates of loss of heterozygosity (LOH) in a variety of human malignancies. Such LOH is usually due to the loss of relatively large areas of one copy of chromosome 10. It is generally believed that in the presence of such LOH the tumor suppressor gene present on the retained chromosome is inactivated by smaller deletions, resulting in homozygous deletion or by mutation. However, for the PTEN gene, the rate of LOH at 10q23.3 is often much higher than the apparent rate of inactivation of the retained PTEN allele. For example, LOH at 10q23.3 has been detected in 15-49% of clinically localized human prostate cancers, whereas mutation or homozygous deletion of the PTEN gene is detected in less than 10% of these same cases (4, 10-15). Similarly, LOH at 10q23 is present in m...

The androgen receptor signaling axis plays an essential role in the development, function and homeostasis of male urogenital structures including the prostate gland although the mechanism by which the AR axis contributes to the initiation, progression and metastatic spread of prostate cancer remains somewhat enigmatic. A number of molecular events have been proposed to act at the level of the AR and associated coregulators to influence the natural history of prostate cancer including deregulated expression, somatic mutation, and post-translational modification. The purpose of this article is to review the evidence for deregulated expression and function of the AR and associated coactivators and corepressors and how such events might contribute to the progression of prostate cancer by controlling the selection and expression of AR targets. ' 2006 Wiley-Liss, Inc.