Prostate cancer-associated membrane type 1-matrix metalloproteinase: a pivotal role in bone response and intraosseous tumor growth.
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 kappaB 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.
Bonfil
R Daniel
RD
Department of Urology, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI 48201, USA.
Dong
Zhong
Z
Trindade Filho
J Carlos
JC
Sabbota
Aaron
A
Osenkowski
Pamela
P
Nabha
Sanaa
S
Yamamoto
Hamilto
H
Chinni
Sreenivasa R
SR
Zhao
Huiren
H
Mobashery
Shahriar
S
Vessella
Robert L
RL
Fridman
Rafael
R
Cher
Michael L
ML
D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology / Q000556:secondary; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000378:metabolism; D006801:Humans; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D010014:Osteolysis; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013977:Tibia / Q000166:cytology / Q000378:metabolism / Q000473:pathology
D024042:Collagen Type I; D034741:RNA, Small Interfering; D053511:Matrix Metalloproteinase 14