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Deletion of PSCA increases metastasis of TRAMP‐Induced prostate tumors without altering primary tumor formation
Author(s) -
Moore Miranda L.,
Teitell Michael A.,
Kim Yoon,
Watabe Tetsuro,
Reiter Robert E.,
Witte Owen N.,
Dubey Purnima
Publication year - 2007
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20686
Subject(s) - tramp , metastasis , prostate , carcinogenesis , prostate cancer , cancer research , pathology , knockout mouse , biology , tumor progression , medicine , cancer , receptor
BACKGROUND Prostate stem cell antigen (PSCA) is expressed in normal epithelium of various tissues, in embryos and adult animals. PSCA expression is upregulated in up to 70% of prostate tumors and metastases, and a subset of bladder and pancreatic cancers. However, its function is unknown. We studied the effect of targeted gene deletion of PSCA on normal organ development and prostate carcinogenesis. METHODS PSCA +/+, PSCA +/−, and PSCA −/− mice were bred and aged to 22 months. A cohort of animals was treated with γ‐irradiation at 2 and 6 months of age. PSCA knockout mice were crossed to TRAMP mice and TRAMP+ PSCA +/+, TRAMP+ PSCA +/−, and TRAMP+ PSCA −/− mice and offspring aged to 10 months of age. Tissues were analyzed by RT‐PCR, histology, and immunohistochemistry for markers of proliferation, apoptosis, angiogenesis, and tumor progression. RESULTS PSCA knockout animals were viable, fertile and indistinguishable from wild‐type littermates. Spontaneous or radiation‐induced primary epithelial tumor formation was also similar in wild‐type and PSCA knockout mice. We observed an increased frequency of metastasis in TRAMP+ PSCA heterozygous and knockout mice, compared to TRAMP+ wild‐type mice. Metastases were largely negative for PSCA and androgen receptor. Cleaved‐caspase 3 and CD31 staining was similar in all genotypes. Aurora‐A and Aurora‐B kinases were detected in the cytoplasm of PSCA heterozygous and knockout tumors, suggesting aberrant kinase function. CONCLUSION These data suggest that PSCA may play a role in limiting tumor progression in certain contexts, and deletion of PSCA may promote tumor migration and metastasis. Prostate 68: 139–151, 2008. © 2007 Wiley‐Liss, Inc.