Prostate Cancer-Associated Membrane Type 1-Matrix Metalloproteinase
| Autor: | Pamela Osenkowski, Sreenivasa R. Chinni, Shahriar Mobashery, J. Carlos Trindade Filho, Sanaa Nabha, Hamilto Akihissa Yamamoto, R. Daniel Bonfil, Aaron Sabbota, Robert L. Vessella, Huiren Zhao, Michael L. Cher, Zhong Dong, Rafael Fridman |
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| Rok vydání: | 2007 |
| Předmět: |
musculoskeletal diseases
Pathology medicine.medical_specialty Osteolysis Bone metastasis Biology medicine.disease Pathology and Forensic Medicine Prostate cancer medicine.anatomical_structure stomatognathic system DU145 Osteoprotegerin Osteoclast embryonic structures Cancer cell LNCaP Cancer research medicine |
| Zdroj: | The American Journal of Pathology. 170:2100-2111 |
| ISSN: | 0002-9440 |
| DOI: | 10.2353/ajpath.2007.060720 |
| Popis: | Membrane type 1-matrix metalloproteinase (MT1-MMP) is a major mediator of collagen I degradation. In human samples, we show that prostate cancer cells in skeletal metastases consistently express abundant MT1-MMP protein. Because prostate cancer bone metastasis requires remodeling of the collagen-rich bone matrix, we investigated the role of cancer cell-derived MT1-MMP in an experimental model of tumor-bone interaction. MT1-MMP-deficient LNCaP human prostate cancer cells were stably transfected with human wild-type MT1-MMP (MT1wt). Furthermore, endogenous MT1-MMP was down-regulated by small interfering RNA in DU145 human prostate cancer cells. Intratibial tumor injection in severe combined immunodeficient mice was used to simulate intraosseous growth of metastatic tumors. LNCaP-MT1wt cells produced larger osseous tumors than Neo control cells and induced osteolysis, whereas DU145 MT1-MMP-silenced transfectants induced osteogenic changes. In vitro assays showed that MT1wt overexpression enhanced collagen I degradation, whereas MT1-MMP-silencing did the opposite, suggesting that tumor-derived MT1-MMP may contribute directly to bone remodeling. LNCaP-MT1wt-derived conditioned medium stimulated in vitro multinucleated osteoclast formation. This effect was inhibited by osteoprotegerin, a decoy receptor for receptor activator of nuclear factor κB ligand, and by 4-[4-(methanesulfonamido) phenoxy] phenylsulfonyl methylthiirane, an MT1-MMP inhibitor. Our findings are consistent with the hypothesis that prostate cancer-associated MT1-MMP plays a direct and/or indirect role in bone matrix degradation, thus favoring intraosseous tumor expansion. |
| Databáze: | OpenAIRE |
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