6768

ST14

suppression of tumorigenicity 14 (colon carcinoma);ST14;suppression of tumorigenicity 14 (colon carcinoma)

membrane-type serine protease 1|prostamin|serine protease 14|serine protease TADG-15|suppression of tumorigenicity 14 (colon carcinoma, matriptase, epithin)|suppressor of tumorigenicity 14 protein|tumor associated differentially expressed gene 15 protein|

11q24-q25

protein-coding

A better understanding of tumor metastasis requires development of animal models that authentically reproduce the metastatic process. By modifying an existing mouse model of breast cancer, we discovered that macrophage-stimulating protein promoted breast tumor growth and metastasis to several organs. A special feature of our findings was the occurrence of osteolytic bone metastases, which are prominent in human breast cancer. To explore the clinical relevance of our model, we examined expression levels of three genes involved in activation of the MSP signaling pathway (MSP, MT-SP1, and MST1R) in human breast tumors. We found that overexpression of MSP, MT-SP1, and MST1R was a strong independent indicator of both metastasis and death in human breast cancer patients and significantly increased the accuracy of an existing gene expression signature for poor prognosis. These data suggest that signaling initiated by MSP is an important contributor to metastasis of breast cancer and introduce an independent biomarker for assessing the prognosis of humans with breast cancer.

BACKGROUND: tumor-associated differentially expressed gene-15 (TADG-15/matriptase/MT-SP1) is a novel transmembrane serine protease involved in numerous biologic processes, including activation of growth and angiogenic factors and degradation of extracellular matrix components. To assess the value of TADG-15 as a possible marker for tumor detection and/or as a target for therapeutic intervention, the authors investigated the frequency of expression of TADG-15 in human cervical tumors. METHODS: TADG-15 expression was evaluated in 19 cervical carcinoma cell lines (i.e., 11 primary tumor cell lines and 8 established cell lines) and in 8 normal cervical keratinocyte control cultures using reverse transcriptase-polymerase chain reaction (RT-PCR). In addition, to validate gene expression data at the protein level, TADG-15 expression was evaluated by immunohistochemistry on paraffin embedded tissue from which all 11 primary tumor cell lines were established. RESULTS: TADG-15 was expressed at high levels in 8 of 11 (73%) primary cervical carcinoma cell lines and in 6 of 8 (75%) established cervical carcinoma cell lines by RT-PCR. expression of TADG-15 was found in 6 of 6 (100%) primary squamous cell cervical carcinomas, whereas 2 of 5 (40%) primary adenocarcinomas expressed TADG-15. In contrast, none of the normal cervical keratinocyte control cultures (n = 4) or flash-frozen normal cervical biopsy specimens (n = 4) expressed TADG-15. Immunohistochemistry staining of paraffin embedded cervical carcinoma specimens confirmed TADG-15 expression in tumor cells and its absence on normal cervical epithelial cells. CONCLUSIONS: Cervical carcinoma cells expressed high levels of TADG-15, suggesting that this protease may play an important role in invasion and metastasis. Because TADG-15 appears only in abundance in squamous tumor tissue and contains a proteolytic cleavage site, suggesting that the TADG-15 protease domain is released, it may prove to be a useful diagnostic tool for the early detection of recurrent/persistent cervical carcinoma after standard treatment or as a novel molecular target for therapy in patients with cervical carcinoma.

The precise mechanisms of metastasis in prostatic cancer are still unknown. A subculture cell line (PC-J) was isolated from the metastasis human prostate cell line PC-3. In vitro cell proliferation, wound healing and invasion assays revealed that tumorigenesis and metastasis differed between PC-3 and PC-J cells. Eight weeks after nude mice were prostate-injected with PC-J and PC-3 cells, the PC-3 group had low tumor volume and exhibited metastasis whereas the PC-J group had high tumor volume and no metastasis. Subsequent RT-PCR and immunoblot assays indicated that matriptase was the putative metastatic gene. Overexpression of bikunin significantly reduced the gene expression of matriptase, which attenuated in vitro cell invasion in the PC-3 cells. In vitro and xenograft animal models indicated different metastatic characteristics between PC-3 and PC-J cells, suggesting that matriptase plays an important role in the metastasis of prostate cancer.