Molecular BIology of
Cancer Topics
CAMs
Cell adhesion molecules (CAMs) allow either cell-to-cell or cell-to-extracellular matrix contact. For example, attachement of endothelial cells is mediated by the cadherins I-CAM and N-CAM. Different organs express these cell surface molecules at different levels, explaining in part the organ specificity in metastasis.
Examples of
CAM types are cadherins and integrins. Cadherins are responsible
for hemophilic cell-cell contact. Epithelial cells contain
E-cadherin, an integral membrane protein with a Ca
-dependent N-terminal domains that bind other
E-cadherins. Integrins are cell surface receptorsa composed of
alpha and beta subunits, and bind cells to extracellular matrix
(ECM) proteins like collagen, vitronectin, fibronectin,
proteoglycans and lamins. Integrins link the ECM to the
cytoeskeleton of the cell. Integrin-ECM protein association is
vital for normal cell survival and proliferation. The basal
lamina i.e. the part of the basement membrane in contact with
epithelial cells, is rich in collagen fibers, lamins,
fibronectin, proteoglycans and other such molecules.
Differences in cell adhesion molecules account for differences in metastatic ability. Expression of the integrin a4b1 on melanoma cells can inhibit the invasive stage of metastasis formation. Three different B16 melanoma clones differ in metastatic activity (Quin et. al. 1994) when injected into animals. The cells expressing a4 shewed the lowest number of lung colony formation. After measuring CAM expression in the three cell lines the only difference was in a4b1 integrin content. a4 expression was undetectable in the most metatastic cell line. When the cells expressing integrin a4 were grown in matrigel, they did not invade the lower cmpartment of the plate. In the matrigel assay, a cell that is able to migrate thru a basement membrane (i.e. is invasive in vivo) should also be able to reach the lower compartment of the dish by migrating through the matrigel. Since a4 integrin inhibits nmetastasis in vivo when caner cells are injected s.c. but not i.v., it seems that a4b1 integrin is involved in the initial detachement and/or invasion but not in extravassation.
Proteases
Some of the proteolytic enzymes that can be released from malignant cells are: plasmin (fibrinolytic, fibronctolytic), cathepsin (collagenolytic), collagenase (collagenolytic), and glycosidases (proteoglyconolytic). These enzymes destroy the proteins of the basement membrane: fibronectin, fibrin, collagens, proteoglycans and others. These same enzymes are used by normal physiological processes that require digestion of the basal membrane: implantation of the embryo, embryomorphogenesis, angiogenesis, leukocyte extravassation, etc.
The key enzymes responsible for ECM breakdown are matrix metalloproteinases (MMPs) like collageneases, stromelysin,s and PUMP-1. Collagenase I breaks down collagen I in the stroma. Collagenase type IV breaks down collagen IV in the basement membrane. Stromelysin, stromelysin-2 and PUMP-1 break down laminin and fibronectin.
TIMPs (tisse inhibitors of metalloproteinases) bind to and inhibit metalloproteases. TIMP-1 inhibits type IV collagenase, collagenase I, stromelysin, stromelysin-2 and PUMP-1. TIMP-2 inhibits collagenase type IV, by blocking both activation of latent collagenase and activity of the full enzyme. The ration of MMP to TIMP determines enzyme activity. If MP > TIMP then the enzyme is active, but if MMP<TIMPthe enzyme is inactive. Both the levels of MMP and TIMP expression may change in a tumor, usually increasing MMP and decreasing TIMP levels if the tumor is malignant.
Transgenic mice overexpressing stronelysin (Str1) in mammary tissue have an increased insidence of bening and malignant cancers (Stenlicht et. al. 1999). TIMP-1 is known to inhibit stromelysin activity, and there was a decrease incidence of mammary hyperplasia in transgenic mice overexpressing both Str1 and TIMP-1 compared to mice oveerexpressing only Str1.
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