The main objective is to elucidate the control of the metastatic phenotype of tumor cells exerted by genes determining the immunogenic properties of the neoplastic cells, in particular genes coding for class I antigens of the MHC. This is associated with experimental attempts to alter gene expression, and thus alter the metastatic competence of tumor cells. Having found that the metastatic phenotype of individual clones of mouse tumors is correlated with the relative expression of class I antigens, we shall study the molecular organization and structural properties underlying the impaired expression of the H-2K gene in metastatic clones. Having demonstrated that transfection of H-2K-, H-2D+ metastatic cells, with H-2K genes, resulted in the abrogation of the metastatic phenotype, we shall analyze the immunogenic properties acquired by the H-2K transfected cells, to determine whether they are causally related to the abolishment of the metastatic properties. We shall subsequently test whether transfection with H-2D genes would convert nonmetastatic to metastatic phenotypes, and whether such cells would now elicit suppressor lymphocytes. Demonstrating that treatmet of tumor cells with Alpha and Beta interferon or retinoic acid decreased the H-2K/H-2D ratio, resulting in significant increase of their metastatic competence, whereas Gamma interferon increased this ratio, and thus decrease the metastatic potential, studies will be carried out to elucidate the molecular basis of these effects. Studies are planned to investigate our observation that the c-myc gene manifests 60-fold gene amplification in both the metastatic and nonmetastatic clones, and that the c-fos is exprssed only in the nonmetastatic 3LL clones. Whether transfection of metastatic phenotypes with c-fos gene would abrogate the metastatic competence, and if so will this be associated with increasing the K-D ratio are questions which might elucidate the possible co-regulation of the c-fos and H-2 genes. The growht of metastatic cells in their target organs might reflect a response to local growth factor, via cell surface receptors. The high activity of tyrosine kinase that metastatic clones of both the 3LL and T10 tumors manifest, might reflect activity of such receptors; it is therefore tempting to identify our thyrosine kinase, aiming at defining its functions regarding growth signals which might be relevant to the capacity of metastatic cells to grow in specific target organs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA028139-07
Application #
3168014
Study Section
Experimental Immunology Study Section (EI)
Project Start
1980-09-30
Project End
1989-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
7
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Weizmann Institute of Science
Department
Type
DUNS #
City
Rehovot
State
Country
Israel
Zip Code
76100
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Porgador, A; Tzehoval, E; Vadai, E et al. (1993) Immunotherapy via gene therapy: comparison of the effects of tumor cells transduced with the interleukin-2, interleukin-6, or interferon-gamma genes. J Immunother Emphasis Tumor Immunol 14:191-201
Porgador, A; Gansbacher, B; Bannerji, R et al. (1993) Anti-metastatic vaccination of tumor-bearing mice with IL-2-gene-inserted tumor cells. Int J Cancer 53:471-7

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