METASTATIS: BIOLOGICAL PHENOTYPE AND MODELS FOR THERAPY

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Cells isolated from early and advanced stages of tumor progression of two human malignancies of different embryological origin, colorectal carcinoma and melanoma, have been maintained in tissue culture for immunological, biological, and molecular investigations. The proposed studies are intended to experimentally dissect the sequential steps of the metastatic cascade, i.e., attachment to and invasion of basement membranes, and survival and growth during and after dissemination. Our working hypothesis is that malignant cells from primary lesions require at least two properties for progression to the metastatic phenotype: invasiveness, i,e. the ability to survive and proliferate at clonal densities under nutrient-depleted growth conditions. Our experimental models will be cell variants selected from primary, non-invasive lesions that are invasive in vitro in reconstructed basement membrane models and in vivo in athymic nude mice. We also have cell lines available that were established from primary and metastatic lesions of the same patients. These spontaneously and experimentally derived models will provide the basis for a comparative analysis of the activity of proteolytic enzymes such as metalloproteinases and serine proteinases and of their interactions with specific inhibitors. Endogenous growth factors, including fibroblast growth factors and transforming growth factors, may not only be responsible for growth autonomy of metastatic cells but might also exert a regulatory role in invasion by activating either proteolytic enzymes or enzyme inhibitors. Blocking the attachment of tumor cells to substrate with monoclonal antibodies (MAbs) can effectively disrupt the metastatic cascade. The mechanisms by which MAbs to gangliosides GD2 and GD3 block attachment and invasion of metastatic cells in tissue culture and also inhibit metastatic tumor cell spread in the nude mouse model will be explored. A new class of basement membrane-related antigens as defined with MAbs mi utilize gangliosides as receptors for attachment and thereby may constitute attachment factors for metastasizing cells. The biochemical, and functional analysis of antigens involved in attachment and invasion will help to identify common biological and immunological properties of invasive and metastatic tumor cells in vitro and in vivo as a preclinical study for the development of therapeutic approaches in cancer patients.