The goal of the project is to understand the role of matrix-degrading metalloproteinases (MMPs) in the progression of chemically-induced mouse cutaneous squamous cell carcinoma (SCC). In the early stages of SCC progression, stromelysin-1/transin is expressed in the stromal component of benign and malignant tumors. However, when squamous carcinomas convert to spindle carcinomas with a concomitant increase in metastatic potential, stromelysin-1 is expressed in the neoplastic cells as well. We will test the hypothesis that host/tumor interactions manifest by stromal cell expression of stromelysin-1 in early stages of tumor progression contributes to the growth of the tumor, and spindle cell expression of stomelysin-1 during late stages of tumor progression contributes to tumor metastasis. Transgenic and gene """"""""knockout"""""""" mouse model systems in which the expression of stromelysin-1 has been abrogated or selectively enhanced will be employed for these studies. In addition, squamous and spindle carcinoma-derived cell lines will be injected into thymectomized wildtype or stromelysin-1 null mice to distinguish between effects of stromal and tumor MMP production specifically. We will also generate mice in which the collagenase gene and/or the stromelysin-2 gene in addition to the stromelysin-1 gene has been ablated to test for combinatorial effects of MMP family members on SSC tumor progression. We propose that the expression of stromelysin-1 in spindle tumor cells is a reflection of important cellular or molecular changes that play a causal role in the progression to a metastatic phenotype. Stromelysin-1 gene expression provides a useful tool to identify the molecular basis of such factors. Based on current knowledge of the regulation of stromelysin-1 gene expression, squamous and spindle tumor -derived cell lines will be compared for alterations in AP-1 binding complexes and the levels and phosphorylation state of members of the Fos and Jun families of transcription factors. The possibility that novel suppressor genes can be cloned using stromelysin-1 gene expression as an indicator will be explored. The studies proposed in this application could provide important new insights into molecules mediating host/tumor interactions and tumor invasion and metastasis in a well defined model of tumor progression.
Showing the most recent 10 out of 42 publications
