One approach to cancer therapy has been the use of differentiation to prevent the growth of the tumor cells. In order to intelligently apply differentiation therapy to cancer treatment, a mechanistic understanding of differentiation in tumor cells must be attained. Retinoids, compounds related to vitamin A such as retinoic acid, are modulators of epithelial cell proliferation and differentiation. Retinoids have been used for differentiation therapy to prevent human epithelial tumors and may provide a new therapeutic approach to ovarian tumors. The initiation of differentiation of human ovarian teratocarcinoma cells in culture requires changes in gene expression mediated by transcriptionally regulated proteins. Hox genes are developmentally regulated genes whose expression is temporally related to position of each Hox gene in the cluster. We have been able reestablished differentiation in a differentiation-resistant ovarian teratocarcinoma cell by constitutive expression of the Hox 1.4 gene. In this study, we will employ a human teratocarcinoma cell line, PA-1 cells, as a model for ovarian teratocarcinoma differentiation. These cells differentiate in response to retinoic acid in monolayer culture forming multiple cell types including neural, epithelial and mesenchymal cells. The control of differentiation requires changes in programs of gene expression under the control of genes with transcription factor activity. The goal of this study is to understand the mechanisms by which oncogenic events, such as activation of an oncogene, interfered with the program of differentiation and how to reverse that interference. We will utilize clones of transcription factors, homeobox genes and AP-2, to determine how they regulate differentiation in ovarian teratocarcinoma cells. We will study how homeobox genes are regulated during retinoic acid induced differentiation of ovarian teratocarcinoma cells, how N-ras oncogene inhibits differentiation and how expression vectors driving these transcription factors alter transcriptional activity of Hox cluster genes thereby reestablishing the ability to differentiate to a teratocarcinoma cell tumor. We will determine how homeobox genes reestablish differentiation and how they are transcriptionally controlled as a potential mechanistic approach to reverse human ovarian teratocarcinoma. This study may provide a mechanistic basis for a combined modality of gene therapy and retinoic acid based- differentiation therapy.
