Bonfil R Daniel, Dong Zhong, Trindade Filho J Carlos, Sabbota Aaron, Osenkowski Pamela, Nabha Sanaa, Yamamoto Hamilto, Chinni Sreenivasa R, Zhao Huiren, Mobashery Shahriar, Vessella Robert L, Fridman Rafael, Cher Michael L
Department of Urology, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI 48201, USA.
Am J Pathol. 2007 Jun;170(6):2100-11. doi: 10.2353/ajpath.2007.060720.
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.
膜型1基质金属蛋白酶（MT1-MMP）是I型胶原蛋白降解的主要介质。在人类样本中，我们发现骨骼转移灶中的前列腺癌细胞持续表达大量MT1-MMP蛋白。由于前列腺癌骨转移需要重塑富含胶原蛋白的骨基质，我们在肿瘤-骨相互作用的实验模型中研究了癌细胞衍生的MT1-MMP的作用。用人类野生型MT1-MMP（MT1wt）稳定转染MT1-MMP缺陷的LNCaP人前列腺癌细胞。此外，在DU145人前列腺癌细胞中，内源性MT1-MMP通过小干扰RNA被下调。在严重联合免疫缺陷小鼠的胫骨内注射肿瘤用于模拟转移性肿瘤的骨内生长。LNCaP-MT1wt细胞比Neo对照细胞产生更大的骨肿瘤并诱导骨溶解，而DU145 MT1-MMP沉默转染子诱导成骨变化。体外试验表明，MT1wt过表达增强了I型胶原蛋白的降解，而MT1-MMP沉默则起到相反作用，这表明肿瘤衍生的MT1-MMP可能直接促进骨重塑。LNCaP-MT1wt衍生的条件培养基刺激体外多核破骨细胞形成。这种作用被骨保护素（一种核因子κB受体活化剂的诱饵受体）和4-[4-(甲磺酰胺基)苯氧基]苯磺酰甲基硫杂环丙烷（一种MT1-MMP抑制剂）抑制。我们的研究结果与以下假设一致，即前列腺癌相关的MT1-MMP在骨基质降解中起直接和/或间接作用，从而有利于骨内肿瘤扩展。
