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Two distinct target cells for v-jun mediated wound tumorigenesis
F Shalaby1, A C Schuh, M L Breitman
1Division of Molecular and Developmental Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Abstract:
Transgenic mice expressing v-jun under the control of the H-2K promoter develop dermal fibrosarcomas and rhabdomyosarcomas via a multistep process following wounding. To assess the relative roles that wounding and the H-2K promoter play in this process, we compared the phenotype of H-2K-v-jun mice with that of animals expressing v-jun under the control of the metallothionein I (MTI) promoter. MT-v-jun animals also develop wound-induced neoplasms by a multistage process. Both early and late features of tumorigenesis in MT-v-jun mice are different, however, from what is observed in H-2K-v-jun animals. First, the acute hyperplastic response that is characteristic of H-2K-v-jun granulation tissue is not observed in MT-v-jun wounds. Second, the myogenic components that are readily detected in the majority of late stage H-2K neoplasms are never observed in their MT counterparts. Moreover, analysis of wound tumours arising in animals expressing both MT-v-jun and H-2K-v-jun reveals that the two transgenes are not expressed in identical malignant cell populations. These results imply that mesenchymal granulation tissue is heterogeneous in composition and that the different cellular phenotypes of MT-v-jun and H-2K-v-jun malignancies result from oncogenic activation of wound-derived cells which differ in their differentiation potential. Thus, whereas the wounding component of multistage tumorigenesis is attributable to the action of v-jun, the transcriptional regulatory elements which drive its expression determine the nature of the target cells which give rise to wound-induced neoplasms.
Insights
Wounding combined with specific gene promoters can trigger cancer in mice. The promoter type influences the cancer type, indicating that wound-healing cells have varied potentials for tumor development.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Transgenic mice expressing v-jun under the H-2K promoter develop specific tumors after wounding.
- The role of the promoter in directing tumor development requires further investigation.
Purpose of the Study:
- To compare the tumor development process in mice with v-jun expression driven by the H-2K promoter versus the metallothionein I (MTI) promoter.
- To determine how transcriptional regulatory elements influence the cell types targeted for oncogenesis following wounding.
Main Methods:
- Generated and analyzed transgenic mice expressing v-jun under the H-2K and MTI promoters.
- Compared the phenotypic characteristics of wound-induced tumors in H-2K-v-jun and MT-v-jun mice.
- Analyzed transgene expression in malignant cell populations of co-expressing mice.
Main Results:
- Both H-2K-v-jun and MT-v-jun mice developed wound-induced neoplasms via a multistage process.
- MT-v-jun mice lacked the acute hyperplastic response seen in H-2K-v-jun mice.
- Myogenic components were present in H-2K-v-jun tumors but absent in MT-v-jun tumors, indicating different cellular phenotypes and heterogeneity in mesenchymal granulation tissue.
Conclusions:
- The transcriptional regulatory elements driving v-jun expression dictate the specific cell types targeted for oncogenesis.
- Wounding initiates tumorigenesis, but the promoter determines the nature of the resulting wound-induced neoplasms.
- Mesenchymal granulation tissue is heterogeneous, with wound-derived cells possessing different differentiation potentials.