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


CONCLUSIONS
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.
Department of Pathology, Section on Tumor Biology, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA.
Miranda L
ML
Moore
Michael A
MA
Teitell
Yoon
Y
Kim
Tetsuro
T
Watabe
Robert E
RE
Reiter
Owen N
ON
Witte
Purnima
P
Dubey
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000367:Age Factors; D000818:Animals; D000951:Antigens, Neoplasm; D017209:Apoptosis / Q000235:genetics; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D049109:Cell Proliferation; D018450:Disease Progression; D058851:GPI-Linked Proteins; D015994:Incidence; D051034:Inhibitor of Apoptosis Proteins; D007680:Kidney Neoplasms / Q000235:genetics / Q000556:secondary*; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary*; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins; D000077022:Survivin
D000951:Antigens, Neoplasm; C117749:Birc5 protein, mouse; D058851:GPI-Linked Proteins; D051034:Inhibitor of Apoptosis Proteins; D008562:Membrane Glycoproteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; C504399:Psca protein, mouse; D053219:Receptors, Tumor Necrosis Factor, Member 25; D012097:Repressor Proteins; D000077022:Survivin; C506034:Tnfrsf25 protein, mouse; C576918:Aurka protein, mouse; C576924:Aurkb protein, mouse; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases