Activated oncogenes play a role in a wide variety of common human cancers such as carcinomas of breast, lung, pancreas, colon etc. Their presence in pre-cancerous lesions suggests their role in early steps of tumorigenesis; progression to malignancy requires additional steps. In this light, cancers of mice transgenic for oncogenes are similar to human cancer except that one of the many essential steps - activation of an oncogene - is genetically programmed, instead of being left to chance. These mice are born healthy but develop tumors spontaneously after several months. The transgenic tumor-host system combines a number of unique advantages as a model for human cancer: (i) tumors are spontaneous but can be obtained predictably; (ii) the carcinogenic action is physiological and partly genetically defined; (iii) problems of heterozygosity and allogenicity, long the bane of transplanted tumors, are largely circumvented; (iv) the tumors metastasize; (v) during genesis, tumors undergo the selection processes encountered in 'normal' circumstances; (vi) the period before the onset of tumors is sufficiently long to permit analysis. This proposal aims to explore ras and Jun transgenic mice for immune response to their spontaneous cancers.
The specific aims of this proposal are to: 1. Determine the influence of immune response on genesis of primary cancer: (A) selective in vivo depletion of CD4+, CD8+, asialoGM1+, receptor+ or sIg+ lymphocytes in healthy mice. The end-point would be the kinetics and incidence of appearance of primary cancers. (B) immunization of healthy mice with tumor fragments and tumor-derived cell lines. Endpoint as in A. 2. Determine the influence of immune response on progression and metastasis of cancer: (A) selective in vivo depletion (as in Aim 1A) of tumor bearing mice at progressive stages. Kinetics of growth and metastasis will be measured. (B) analysis of tumor-derived cell lines for expression of MHC, ICAM-1 and LFA-3 and sensitivity to NK cells, TNF and T lymphocytes; (C) analysis in vivo of sensitivity of progression and metastasis of established tumors to agents to which they are sensitive in vitro. 3. Develop reagents for analysis of tumor immunity: T lymphocytes, antibodies, tissues and cell lines will be obtained. Altogether, these studies will generate the framework for immunological analysis of a series of clinically relevant, oncogene-based models for human solid cancers.
| Srivastava, P K; Udono, H; Blachere, N E et al. (1994) Heat shock proteins transfer peptides during antigen processing and CTL priming. Immunogenetics 39:93-8 |
| Heike, M; Blachere, N E; Srivastava, P K (1994) Protective cellular immunity against a spontaneous mammary carcinoma from ras transgenic mice. Immunobiology 190:411-23 |
