Taniwaki Kaori, Fukamachi Hiroshi, Komori Kiyoshi, Ohtake Yohei, Nonaka Takahiro, Sakamoto Takeharu, Shiomi Takayuki, Okada Yasunori, Itoh Takeshi, Itohara Shigeyoshi, Seiki Motoharu, Yana Ikuo
Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Cancer Res. 2007 May 1;67(9):4311-9. doi: 10.1158/0008-5472.CAN-06-4761.
Matrix metalloproteinase-2 (MMP-2) is a stroma-derived MMP belonging to the type IV collagenase family. It is believed to mediate tumor cell behavior by degrading deposits of type IV collagen, a major component of the basement membrane. The membrane type 1-MMP (MT1-MMP) is a highly potent activator of MMP-2 and is expressed in many tumor and stromal cells. However, the roles played by stromal MMP-2 in tumor progression in vivo remain poorly understood. We established a colon epithelial cell line from an Mt1-mmp(-/-) mouse strain and transfected these cells with an inducible expression system for MT1-MMP (MT1rev cells). Following s.c. implantation into Mmp-2(+/+) mice and induction of MT1-MMP expression, MT1rev cells grew rapidly, whereas they grew very slowly in Mmp-2(-/-) mice, even in the presence of MT1-MMP. This MT1-MMP-dependent tumor growth of MT1rev cells was enhanced in Mmp-2(-/-) mice as long as MMP-2 was supplied via transfection or coimplantation of MMP-2-positive fibroblasts. MT1rev cells cultured in vitro in a three-dimensional collagen gel matrix also required the MT1-MMP/MMP-2 axis for rapid proliferation. MT1rev cells deposit type IV collagen primarily at the cell-collagen interface, and these deposits seem scarce at sites of invasion and proliferation. These data suggest that cooperation between stroma-derived MMP-2 and tumor-derived MT1-MMP may play a role in tumor invasion and proliferation via remodeling of the tumor-associated basement membrane. To our knowledge, this is the first study demonstrating that MT1-MMP-dependent tumor growth in vivo requires stromal-derived MMP-2. It also suggests that MMP-2 represents a potential target for tumor therapeutics.
基质金属蛋白酶-2（MMP-2）是一种源自基质的MMP，属于IV型胶原酶家族。据信它通过降解IV型胶原（基底膜的主要成分）的沉积物来介导肿瘤细胞行为。膜型1-MMP（MT1-MMP）是MMP-2的高效激活剂，在许多肿瘤和基质细胞中表达。然而，基质MMP-2在体内肿瘤进展中所起的作用仍知之甚少。我们从Mt1-mmp(-/-)小鼠品系建立了结肠上皮细胞系，并用MT1-MMP的诱导表达系统转染这些细胞（MT1rev细胞）。将其皮下植入Mmp-2(+/+)小鼠并诱导MT1-MMP表达后，MT1rev细胞迅速生长，而在Mmp-2(-/-)小鼠中，即使存在MT1-MMP，它们也生长得非常缓慢。只要通过转染或共植入MMP-2阳性成纤维细胞提供MMP-2，MT1rev细胞在Mmp-2(-/-)小鼠中的这种MT1-MMP依赖性肿瘤生长就会增强。在三维胶原凝胶基质中体外培养的MT1rev细胞也需要MT1-MMP/MMP-2轴才能快速增殖。MT1rev细胞主要在细胞-胶原界面沉积IV型胶原，而这些沉积物在侵袭和增殖部位似乎很少。这些数据表明，基质来源的MMP-2与肿瘤来源的MT1-MMP之间的合作可能通过重塑肿瘤相关基底膜在肿瘤侵袭和增殖中发挥作用。据我们所知，这是第一项证明体内MT1-MMP依赖性肿瘤生长需要基质来源的MMP-2的研究。它还表明MMP-2是肿瘤治疗的潜在靶点。
