Abstract

We study the expression of MHC gene products on metaatatic as distinct from nonmetastatic clones, and their function in controlling the metastatic phenotype. Thus, analyzing a large number of clones of the metastatic 3LL Lewis lung carcinoma (of H-2?b? origin), we found that the lower the H-2K?b?/H-2D?b? ratio on tumor cell surface, the higher their metastatic competence. Interferon alpha and beta and retinoic acid, applied in vitro, caused a net increase in the cell surface expression of H-2D?b? glycoproteins. This was associated with a significant increase of the metastatic properties. Gamma-interferon, on the other hand, caused a relative increase in H-2K?b? expression, resulting in a significant decrease of metastatic competence. Functional studies indicated that clones of high H-2K/H-2D ratio (nonmetastatic) are significantly more immunogenic and more susceptible to immune responses than clones of low H-2K/H-2D ratio (metastatic). T-cell mediated immune responses participate significantly in controlling the expression of the metastatic phenotype. Gene cloning of the MHC of the tumor cells is carried out to investigate the molecular basis of suppression in H-2K expression in metastatic clones. A similar approach is applied to a metastatic model of a heterozygous (H-2?b? x H-2?k?)F?1? origin, the T10 sarcoma. Both metastatic and nonmetastatic clones do not express the H-2K of either haplotype. Immunoselection experiments indicated that the metastatic phenotype is determined just by the expression of the H-2D?k?. Nonmetastatic clones, which differ from the metastatic only in H-2 expression, are significantly more immunogenic. Transfection of a metastatic clone with H-2K?b? or H-2K?k? genes, followed by the cell surface expression of these genes, resulted in the abrogation of the metastatic competence. This was correlated with a significant increase in the immunogenic properties of the transfected cells. The molecular basis of the differential structure, expression, and function of class 1 antigens on metastatic tumors is investigated. This is carried out in parallel with studies on oncogenes in metastatic and nonmetastatic clones. (IB)

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA028139-06
Application #
3168018
Study Section
Experimental Immunology Study Section (EI)
Project Start
1980-09-30
Project End
1986-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
6
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
Weizmann Institute of Science
Department
Type
DUNS #
City
Rehovot
State
Country
Israel
Zip Code
76100

  Publications

Porgador, A; Tzehoval, E; Vadai, E et al. (1995) Combined vaccination with major histocompatibility class I and interleukin 2 gene-transduced melanoma cells synergizes the cure of postsurgical established lung metastases. Cancer Res 55:4941-9
Yamit-Hezi, A; Plaksin, D; Eisenbach, L (1994) c-fos and c-jun overexpression in malignant cells reduces their tumorigenic and metastatic potential, and affects their MHC class I gene expression. Oncogene 9:1065-79
Fitzer-Attas, C; Eldar, H; Eisenbach, L et al. (1994) The expression of PDGF-alpha but not PDGF-beta receptors is suppressed in Swiss/3T3 fibroblasts over-expressing protein kinase C-alpha. FEBS Lett 342:165-70
Katz, A; Shulman, L M; Revel, M et al. (1993) Combined therapy with IL-6 and inactivated tumor cells suppresses metastasis in mice bearing 3LL lung carcinomas. Int J Cancer 53:812-8
Fitzer-Attas, C; Feldman, M; Eisenbach, L (1993) Expression of functionally intact PDGF-alpha receptors in highly metastatic 3LL Lewis lung carcinoma cells. Int J Cancer 53:315-22
Plaksin, D; Baeuerle, P A; Eisenbach, L (1993) KBF1 (p50 NF-kappa B homodimer) acts as a repressor of H-2Kb gene expression in metastatic tumor cells. J Exp Med 177:1651-62
Katz, A; Shulman, L M; Porgador, A et al. (1993) Abrogation of B16 melanoma metastases by long-term low-dose interleukin-6 therapy. J Immunother Emphasis Tumor Immunol 13:98-109
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
Porgador, A; Bannerji, R; Watanabe, Y et al. (1993) Antimetastatic vaccination of tumor-bearing mice with two types of IFN-gamma gene-inserted tumor cells. J Immunol 150:1458-70

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