Deletion of PSCA increases metastasis of TRAMP-induced prostate tumors without altering primary tumor formation

作者：Moore Miranda L; Teitell Michael A; Kim Yoon; Watabe Tetsuro; Reiter Robert E; Witte Owen N; Dubey Purnima^*

来源：Prostate, 2008, 68(2): 139-151.

DOI：10.1002/pros.20686

• PSCA
• metastasis
• gene deletion
• GPI-anchored protein
• prostate cancer

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 gamma-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.

• 出版日期2008-2-1