Tissue inhibitors of metalloproteinases (TIMP) in invasion and proliferation

Tissue inhibitors of matrix metalloproteinases (TIMPs) are a family of natu ral inhibitors that control the activity of matrix metalloproteinases (MMPs ) in the extracellular matrix (ECM). Four members of this family have been so far characterized in a variety of species. These inhibitors share a simi lar structural feature characterized by the presence of 12 cysteine residue s involved in disulfide bonds and a similar function by their ability to fo rm inhibitory complexes with MMPs. The role of TIMPs in cancer has been the subject of conflicting reports with an antitumor activity reported by some investigators and a growth stimulation activity reported by others. Here w e will discuss a series of data obtained in our laboratory supporting a rol e of TIMPs not only as inhibitors of invasion but also as regulators of cel l growth. Using placental development as an example of a regulated invasive process, we have observed that the levels of TIMP-2 and TIMP-3 steadily in crease between day 14.5 and 17.5 post-coitus. TIMPs are selectively express ed by spongiotrophoblastic cells that separate the labyrinthine zone, rich in fetal blood vessels and maternal blood sinuses, from the zone of giant c ells forming the border between fetal and maternal tissues. TIMPs are also potent inhibitors of tumor growth in vivo. In melanoma cells, we have previ ously reported that over-expression of TIMP-2 inhibits the growth of tumors implanted in the skin of scid mice. This growth inhibition seems independe nt of angiogenesis but dependent on the collagen matrix. We observed that i n the presence of fibrillar type I collagen, melanoma cells undergo a growt h arrest at the G(1) to S interphase transition of the cell cycle. This arr est is specific to the fibrillar structure of collagen because it is not ob served in the presence of non-fibrillar collagen or other ECM components. I t is associated with a specific upregulation of the cyclin inhibitor p27(KI P1). The, data therefore indicate that anchorage independent cells remain s ensitive to growth regulatory signals that originate from the ECM and that these signals can specifically block tumor cell cycle. Thus our concept of the role of protease inhibitors such as TIMPs in cancer has substantially c hanged from an initial focus on inhibition of tumor invasion and metastasis to a broader focus on being molecules that - via their function as regulat ors of the ECM homeostasis - can control tumor cell growth.