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 tumor incidence and growth. We have been able to culture new highly differentiated human tumor cell lines from the tumors grown in mice including certain colon and prostate cell lines. Laminin, a major basement membrane component, has been found to promote the malignant phenotype. Laminin adherent cells are more malignant than either the non-adherent cells or the parental cells. Various biologically active laminin-derived synthetic peptides have been identified. One, YIGSR (tyr-ile-gly-ser-arg) reduces tumor growth, metastases, and angiogenesis whereas IKVAV increases these activities. Another peptide LQVQLSIR increases metastases and binds to the receptor CD44 which has already been shown by others to be important in metastasis. Our goal is to define the molecular mechanisms involved in tumor growth and metastases. Our approach is to (1) select for and isolate highly malignant cells, (2) define their cellular laminin receptors, (3) identify additional sequences on laminin which promote or reduce the malignant phenotype, (4) identify genes involved in malignancy and (5) define molecules in bone responsible for prostate and breast cancer organ-specific metastases. We work with several models including B16F10 melanoma cells, breast, prostate and salivary gland tumor cells. We have also begun to define the mechanisms by which estrogen promotes angiogenesis and malignancy. We find that it regulates the enzyme heparanase which indirectly controls growth factor activity. Estrogen also regulates the expression of certain growth factor receptors. We hope to define regulatory events involved in metastases and develop therapeutic and diagnostic reagents.
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