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Re: Targeting Prostate Cancer Angiogenesis Through Metastasis-Associated Protein 1 (MTA1)
1556
URO-SCIENCE
Re: Targeting Prostate Cancer Angiogenesis Through Metastasis-Associated Protein 1 (MTA1) L. Kai, J. Wang, M. Ivanovic, Y. T. Chung, W. B. Laskin, F. Schulze-Hoepfner, Y. Mirochnik, R. L. Satcher, Jr. and A. S. Levenson Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois Prostate 2011; 71: 268 –280.
Background: Metastasis-associated protein 1 (MTA1) is overexpressed in many forms of cancer types but its role in prostate cancer (PCa) progression and metastasis has not been explored. In this study, we addressed the functional and biological role of MTA1 in PCa. Methods: Gene expression profiling was used to determine MTA1 overexpression during PCa cell-bone interaction. Immunohistochemistry was used to detect MTA1 on tissue microarrays (TMA) and vascular endothelial growth factor (VEGF), CD31, and Ki67 in xenografts. We used retroviral or lentiviral RNAi transduction of PCa cells to establish MTA1 knockdowns. RT-PCR, Western blot, invasion, and endothelial cell migration assays were used to characterize the cells in vitro. The role of MTA1 in PCa tumorigenesis was evaluated in mouse xenografts. Results: We identified MTA1 as a component of bone metastasis signature in PCa, which suggested a possible role for MTA1 in PCa progression and metastasis. MTA1 was expressed at higher levels in PCa cell lines than in normal prostate epithelial cells. Silencing MTA1 significantly suppressed the invasion and angiogenic activity of the cells in vitro and delayed tumor formation and development in mouse xenografts. Tumors that express MTA1 had higher proliferative indices, secreted higher levels of VEGF and were more vascularized. Analysis of the human TMA showed positive correlation between MTA1 nuclear localization/staining intensity and PCa aggressiveness. Conclusions: MTA1 pro-angiogenic and pro-invasive functions create permissive environment for PCa tumor growth and likely support metastasis. Taken together with its predictive values, MTA1 can be utilized both as a prognostic marker and a therapy target in PCa. Editorial Comment: The authors previously demonstrated that metastasis associated protein 1 silencing promotes apoptosis in prostate carcinoma cells, which indicates the antiapoptotic character of metastasis associated protein 1. In this study the authors extend their observation and show that metastasis associated protein 1 has prosurvival, invasive and proangiogenic properties, and has an essential role in promoting prostate carcinoma progression and possibly metastasis. A functional link between metastasis associated protein 1 and angiogenesis was demonstrated in prostate cancer. Metastasis associated protein 1 knockdowns expressed low levels of VEGF and had decreased angiogenicity in vitro and in vivo. Therefore, metastasis associated protein 1 is a potential novel target for developing new prostate carcinoma therapies. Moreover, the tissue microarray results reveal that metastasis associated protein 1 has potential as a prognostic marker for aggressive prostate carcinoma and possibly bone metastasis. Further studies should specify the exact role of metastasis associated protein 1 in bone metastasis. Anthony Atala, M.D.
URO-SCIENCE
Re: Targeting Prostate Cancer Angiogenesis Through Metastasis-Associated Protein 1 (MTA1) L. Kai, J. Wang, M. Ivanovic, Y. T. Chung, W. B. Laskin, F. Schulze-Hoepfner, Y. Mirochnik, R. L. Satcher, Jr. and A. S. Levenson Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois Prostate 2011; 71: 268 –280.
Background: Metastasis-associated protein 1 (MTA1) is overexpressed in many forms of cancer types but its role in prostate cancer (PCa) progression and metastasis has not been explored. In this study, we addressed the functional and biological role of MTA1 in PCa. Methods: Gene expression profiling was used to determine MTA1 overexpression during PCa cell-bone interaction. Immunohistochemistry was used to detect MTA1 on tissue microarrays (TMA) and vascular endothelial growth factor (VEGF), CD31, and Ki67 in xenografts. We used retroviral or lentiviral RNAi transduction of PCa cells to establish MTA1 knockdowns. RT-PCR, Western blot, invasion, and endothelial cell migration assays were used to characterize the cells in vitro. The role of MTA1 in PCa tumorigenesis was evaluated in mouse xenografts. Results: We identified MTA1 as a component of bone metastasis signature in PCa, which suggested a possible role for MTA1 in PCa progression and metastasis. MTA1 was expressed at higher levels in PCa cell lines than in normal prostate epithelial cells. Silencing MTA1 significantly suppressed the invasion and angiogenic activity of the cells in vitro and delayed tumor formation and development in mouse xenografts. Tumors that express MTA1 had higher proliferative indices, secreted higher levels of VEGF and were more vascularized. Analysis of the human TMA showed positive correlation between MTA1 nuclear localization/staining intensity and PCa aggressiveness. Conclusions: MTA1 pro-angiogenic and pro-invasive functions create permissive environment for PCa tumor growth and likely support metastasis. Taken together with its predictive values, MTA1 can be utilized both as a prognostic marker and a therapy target in PCa. Editorial Comment: The authors previously demonstrated that metastasis associated protein 1 silencing promotes apoptosis in prostate carcinoma cells, which indicates the antiapoptotic character of metastasis associated protein 1. In this study the authors extend their observation and show that metastasis associated protein 1 has prosurvival, invasive and proangiogenic properties, and has an essential role in promoting prostate carcinoma progression and possibly metastasis. A functional link between metastasis associated protein 1 and angiogenesis was demonstrated in prostate cancer. Metastasis associated protein 1 knockdowns expressed low levels of VEGF and had decreased angiogenicity in vitro and in vivo. Therefore, metastasis associated protein 1 is a potential novel target for developing new prostate carcinoma therapies. Moreover, the tissue microarray results reveal that metastasis associated protein 1 has potential as a prognostic marker for aggressive prostate carcinoma and possibly bone metastasis. Further studies should specify the exact role of metastasis associated protein 1 in bone metastasis. Anthony Atala, M.D.