Oncogenesis is a multistep process during which sequential damage to critical cellular genes (proto-oncogenes) eventually generates a malignant clone with unrestrained growth and metastatic properties. Each genetic alteration is thought to represent a single step in the process of tumor development since activation of more than one oncogene is generally required to achieve malignant transformation. The hypothesis that different activated oncogenes synergize in tumor initiation and/or promotion has received substantial experimental support. This concept supports the notion that different etiologic agents such as viruses and chemicals induce genetic damage in distinct, yet functionally cooperative genetic loci. Although it seems reasonable to propose that proviral insertion and carcinogen mediated point mutation could activate complimentary oncogenes, the potential role of endogenous retroviruses in chemical carcinogenesis is not clear. An excellent model to address this issue is the AKR mouse strain in which endogenous murine leukemia viruses (MuLV) induce """"""""spontaneous"""""""" thymic lymphomas. Injection of young mice with N-methyl-N-nitrosourea (MNU) accelerates lymphomagenesis. The AKR strain develops MNU induced lymphomas with higher incidence and shorter latent period than low lymphoma incidence strains, suggesting a cooperative interaction between MNU and endogenous MuLVs. Since we find that MNU induced AKR lymphomas contain newly acquired proviruses that confer a selective growth advantage, we propose that endogenous MuLVs synergize with MNU by promoting a more malignant phenotype perhaps through specific oncogene activation.
The aims of this project are: 1. to determine whether somatically acquired proviruses confer enhanced growth and/or metastatic properties on MNU induced lymphomas. 2. to define the molecular structure of somatically acquired proviruses. 3. to identify new oncogenes activated via proviral insertion. 4. using a novel approach involving multiparameter flow cytometry and cell sorting early neoplastic cells will be isolated at intervals from thymi of MNU treated mice for analysis of: clonality; growth potential in vivo and in vitro; proviral integrations; and molecular alterations in oncogene structure or expression. Long term goals are also described to indicate the future direction of this project.
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