The Tramp Mouse as a Model for Prostate Cancer

Prostate cancer ranks as one of the most common cancers among men. Consistent with this, prostate cancer is also one of the most frequent causes of male cancer-related death. Adenocarcinoma represents the predominant histologic type of prostate cancer, typically arising from malignant transformation of lumenal epithelial cells within glands comprising the peripheral zone of the prostate. Somewhat unique to this cancer are a number of key features. Androgens play an essential role not only in normal prostate development but also the pathogenesis of prostate cancer. Related to this, most prostate tumors are "androgen-sensitive"—i.e., demonstrate initial regression following androgen removal or blockade, and then subsequent progression due to proliferation of "androgen-inde-pendent" or "androgen-suppressed" tumor cells. Human prostate cancer encompasses a wide spectrum of histologic grades ranging from the putative precursor lesion, prostate intraepithelial neoplasia (PIN), to intermediate-grade cancers that recapitulate rudimentary glandular formation, or more poorly differentiated cancers that infiltrate the prostatic stroma and its surrounding tissues. Likewise, metastases can be disseminated over a wide distribution, most frequently involving the pelvic lymph nodes, bone and marrow, and (less frequently) the lungs and other viscera (for more information see Epstein, 1998).

To date, a number of different rodent prostate tumor models have been described in the literature. These models, including the Dunning rat prostate tumor model (Lubaroff et al., 1980; Isaacs et al., 1986), have played an instrumental role in the elucidation of mechanisms involved in the pathogenesis of prostate cancer as well as the development and testing of experimental treatments including gene- and immune-based therapies. Recently, a unique model, the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, has garnered widespread attention due to its ability to closely mirror disease pathogenesis as seen in man (Greenberg et al., 1995). Unlike prior rodent models, male TRAMP mice uniformly and spontaneously develop autochthonous (orthotopic) prostate tumors following the onset of puberty (see Basic Protocol 1). Prostate cancer occurs consequent to the expression of the oncoprotein, SV40 T antigen (TAg), which is under transcriptional control of the rat probasin promoter. The probasin promoter appears to maintain high specificity, restricting TAg expression to epithelial cells within the prostate (Greenberg et al., 1995). Another unique feature of TRAMP is that TAg expression is androgen-driven and developmentally regulated. Related to this, autochthonous TRAMP tumors transiently regress following androgen withdrawal (e.g., by castration), but subsequently recur in a high percentage of mice, paralleling the ultimate emergence of fatal androgen-independent prostate cancer as is commonly observed in man.

The versatility of the TRAMP model has been extended further by the establishment of several TRAMP-derived prostate tumor cells lines (including TRAMP-C1 and TRAMP-C2) that can be injected into the syngeneic male nontransgenic C57BL/6 host to induce ectopic prostate tumorigenesis (see Basic Protocol 2). These tumor cell lines can also be genetically manipulated in vitro for establishment of tumor-cell vaccine preparations intended to induce immunologic responses directed against syngeneic TRAMP tumors (Kwon et al., 1997; Hurwitz et al., 2000). Subcutaneous tumor induction using the TRAMP-C cell lines has provided the basis for two additional TRAMP-based murine models, the first of which can be used for rapid screening of experimental therapies that might prove effective for the treatment of primary prostate tumors (see Basic Protocol 2) and the second for testing the effectiveness of adjunctive therapies targeting prostate cancer metastases (see Alternate Protocol). These models, combined with the Animal M°dels for Tumor

Immunology

Contributed by Arthur A. Hurwitz, Barbara A. Foster, James P. Allison, Norman M. Greenberg, 20.5.1

and Eugene D. Kwon

Current Protocols in Immunology (2001) 20.5.1-20.5.23 Supplement 45

Copyright © 2001 by John Wiley & Sons, Inc.

autochthonous TRAMP model and its derivative cell lines, provide a comprehensive model system that readily lends itself to studies related to prostate cancer. Detailed descriptions for the harvesting and microdissection of TRAMP prostates and tumors (see Support Protocol 1), and the evaluation and scoring of tumors (see Support Protocol 2) are also provided. Finally, a protocol for androgen withdrawal by castration is provided (see Support Protocol 3) for studies intended to examine the biological effects of hormone manipulation as it pertains to prostate cancer biology and immunotherapy.

The TRAMP Mouse as a Model for Prostate Cancer

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