One of the major difficulties encountered in treating cancer effectively is the incredible capacity of cancer cells to take control of two processes associated with the normal functioning of an organism - processes which allow them to grow and invade healthy tissue. In the first, tumours stimulate the formation of new blood vessels through the process of angiogenesis; the new vessels created through this process are required for tumour growth and for the development of metastases. Recent data also suggest that tumours use an organism's normal coagulation system to grow, which at the same time leads to a number of coagulation disorders (coagulopathies) in cancer patients. In fact, it is estimated that nearly 80% of cancer patients suffer from coagulopathies and that these disorders are responsible for a large number of cancer-related deaths. Understanding the mechanisms involved in the relationship that exists between cancer cells, angiogenesis and the coagulation system is therefore vital for cancer prevention and for the development of new therapeutic approaches to treating this disease..
We were the first to show that a metalloproteinase associated with endothelial cell membranes, MT1-MMP, plays a key role in angiogenesis by cooperating with certain coagulation system factors, in particular platelet-derived sphingosine-1-phosphate [1, 2]. We subsequently observed that the mechanisms governing this link between angiogenesis and hemostasis are excessively complex and involve the process of apoptosis [3] and the physical association of MT1-MMP with the anti-oncogene caveolin-1 [4], as well as the participation of the Src oncogene and the EGF receptor, two well-known oncogenic proteins [5]. Our recent results indicate that the entire process is even more complex since MT1-MMP is tyrosine phosphorylated, which induces its relocalization to certain specific regions in the cell membrane[6, 7]. The phosphorylation of MT1-MMP appears to be very important for tumour cell proliferation because the inactivation of the phosphorylation site completely abolishes tumour growth in mice [8]. These studies are important for the development of new anti-angiogenic and anti-cancer strategies that target the activity of MT1-MMP.
[1] Langlois S, Gingras D and Béliveau R (2004) Membrane type 1-matrix metalloproteinase (MT1-MMP) cooperates with sphingosine 1-phosphate to induce endothelial cell migration and morphogenic differentiation. Blood 103, 3020-3028.
[2] Pilorget A, Annabi B, Bouzeghrane F, Malvardi J, Luis J, Béliveau R (2005) Inhibition of angiogenic properties of brain endothelial cells by platelet-derived sphingosine-1-phosphate. J. Cereb. Blood Flow Metab. 25, 1171-1182.
[3] Langlois S, Di Tomasso G, Boivin D, Roghi C, Murphy G, Gingras D, Béliveau R (2005) Membrane type-1 matrix metalloproteinase induction of endothelial cell morphogenic differentiation involves a caspase-dependent mechanism. Exp. Cell Res. 307, 452-464.
[4] Labrecque L, Nyalendo C, Langlois S, Durocher Y, Roghi C, Murphy G, Gingras D, Béliveau R. (2004) Src-mediated tyrosine phosphorylation of caveolin-1 induces its association with membrane type 1 matrix metalloproteinase. J. Biol. Chem. 279, 52132-52140.
[5] Langlois S, Nyalendo C, Di Tomasso G, Labrecque L, Roghi C, Murphy G, Gingras D and Béliveau R (2007) Membrane-type 1 matrix metalloproteinase stimulates cell migration through epidermal growth factor receptor transactivation. Mol. Cancer Res. 5, 569-583.
[6] Nyalendo C, Michaud M, Roghi C, Murphy G, Gingras D, Béliveau R (2007) Src-dependent phosphorylation of membrane-type 1 matrix metalloproteinase on cytoplasmic tyrosine 573 : Role in endothelial and tumor cell migration. J. Biol. Chem. 282, 15690-15699.
[7] Gingras D, Michaud M, Di Tomasso G, Béliveau E, Nyalendo C, Béliveau R (2008) Sphingosine-1-phosphate induces the interaction of membrane type-1 matrix metalloproteinase with p130Cas in endothelial cells. FEBS Lett. 582, 399-404.
[8] Nyalendo C, Michaud M, Beaulieu É, Sartelet H, Gingras D, Béliveau R (2008) Impaired tyrosine phosphorylation of membrane-type 1 matrix metalloproteinase reduces tumor cell proliferation in three-dimensional matrices and abrogates tumor growth in mice. Carcinogenesis 29, 1655-1664.
