Studies are conducted to define the mechanisms involved in tumor growth and metastasis and to develop new animal models of human cancers. We have found that a basement membrane extract (Matrigel) when premixed with human tumor cells (which do not grow well in mice) promotes their incidence and growth. Very low cell numbers can be used. We have been able to culture new highly differentiated human tumor cell lines from the tumors grown in mice including certain colon cell lines and a Nelson's pituitary tumor cell line. Laminin, a major basement membrane component, has been found to promote the malignant phenotype. Various biologically active laminin-derived synthetic peptides have been identified. YIGSR from the B1 chain blocks lung colonization, reduces tumor growth, and inhibits angiogenesis. Using multiple cycles of YIGSR adhesion, YIGSR adherent melanoma cells were derived and formed more tumors in lung colony assays and larger tumors in the subcutaneous model than the parent cells. The YIGSR non-adherent cells formed few tumors. Selection for adhesion to laminin was carried out with a human colon cancer and the adherent cells were found to be highly malignant when injected intracecally with Matrigel. These cells grew well and metastasized to the liver and surrounding tissues. This progression models the pathological process in humans. Another laminin-derived peptide containing SIKVAV from the A chain has been found to increase tumor growth, lung colonization, and angiogenesis as well as collagenase IV activity and plasminogen activation. This peptide was found to promote angiogenesis in one in vivo model by increasing the recruitment of neutrophils. Using this information and the newly developed models of human tumors, the development of new therapeutic strategies for cancer should be facilitated.
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