Early oral neoplasia begins as a small nest of tumorigenic cells which undergoes expansion while in contact with non-tumorigenic cells. While it is known that interactions between normal and tumorigenic cells are important in the progression of advanced neoplasia, it is not clear if they play a ole in early neoplasia. A major problem in studying cell interactions during the early events in carcinogenesis has been the lack of model systems wherein one could identify small numbers of tumorigenic cells in a """"""""sea"""""""" of non-tumorigenic cells. Using techniques developed during my previous training, this impediment can now be overcome by genetic marking with suitable retroviral vectors. This will allow investigation of the regulatory role that cell interactions play in the expansion of premalignant keratinocytes within the oral mucosa or epidermis and to begin an exploration of the mechanisms involved in these early steps. The hypothesis to be tested in this proposal is that cell-cell interactions play a crucial role in the development of early epithelial neoplasia and control its progression. Using genetically marked normal oral and epidermal keratinocytes, as well as cell lines with varying tumorigenic phenotypes, four specific aims are developed; 1) develop culture and animal models which mimic early neoplasia and contain genetically marked keratinocytes exhibiting a spectrum of tumorigenic and non-tumorigenic phenotypes; 2) determine if interactions between non-tumorigenic and tumorigenic keratinocytes regulate clonal expansion during early neoplastic progression; 3) determine if epithelial-mesenchymal cell interactions regulate clonal expansion during early neoplastic progression and 4) explore the mechanism through which cell interactions modulate early neoplastic progression. These objectives investigate the role of the signalling network inherent in tissue organization and in cell interactions which regulate clonal expansion in early neoplasia. Insight into these events may be helpful in providing indicators predicting individuals at risk for progression and in developing therapeutic strategies to direct this progression to a more benign course.
