Two factors which may play important roles in the progression of tumors are host immunocompetent cells at the site of tumor growth and tumor adhesion to extracellular matrix proteins mediated by integrins on the tumor cell surface. The possible significance of these two factors are being investigated here utilizing a SCID mouse model. Our immediate goal is to determine whether or not the immunocompetent cells coengrafted with a patient's lung tumor biopsy into SCID mice have the ability to alter tumor growth. To address this question T lymphocyte subsets, B lymphocytes, NK cells, and monocytes are selectively eliminated from the tumor either prior to engraftment or subsequent to engraftment, and the effect of this depletion on tumor growth is monitored. Mice engrafted with tumor biopsies will also be evaluated for the existence of humoral and cell mediated tumor specific immunity, and we shall establish whether or not the immune- reactive repertoire of B-lymphocytes resident in tumor biopsies is more restricted than the repertoire of lymphocytes derived from the peripheral blood. Our recent finding that human lung tumors, but not normal adult lung tissue, express an adhesion molecule (VLA-2) which binds collagen and laminin adds to a rapidly growing body of evidence that supports the notion that this class of molecules called integrins is involved in tumorigenicity and invasiveness. Since it has been determined that the integrin VLA-2 on human lung tumors binds to mouse collagen as well as human collagen the possible significance of this receptor with regard to tumor growth and invasion of tissues is being tested by determining the effect on tumor growth in SCID mice that occurs following the blocking of this receptor (either by excess free collagen or by a site specific monoclonal antibody). The issue will also be addressed by comparing the growth and metastasis of non-collagen binding human lung tumor cell lines before and after transfection with the genes encoding the alpha and beta chains of VLA-2 and by comparing the growth and metastasis of VLA-2 expressing lung tumors before and after transfection with the VLA-2 alpha gene in the anti-sense orientation. The difficulties encountered currently by individuals attempting to treat established tumors by adoptive cellular immunotherapy and our relatively limited knowledge regarding tumor cell biology and pathogenesis punctuate the critical need for novel animal models with which to address and define the factors that are involved in either restricting or augmenting tumor progression.
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