Interactions between tumor cells and surrounding stroma have been implicated in tumor progression. Stromal expression of the 92 kDa type IV collagenase/gelatinase (MMP-9) is associated with the metastatic phenotype in human tumors. The goal of this application is to test the hypothesis that normal fibroblasts are induced to express MMP-9 by direct contact with a metastatic tumor cell surface protein. An in vitro model for studying stromal production of MMP-9 in response to contact with metastatic tumor cells has been developed. Preliminary studies demonstrated that: 1) normal rat embryo fibroblasts expressed MMP- 9 in coculture with a metastatic v-myc and H-ras transformed rat embryo cell line, 2.8, but not with a non-metastatic H-ras and E1A transformed cell line, RA3, 2) fibroblast MMP-9 expression in coculture with metastatic tumor cells required cell-cell contact with a tumor cell surface-associated protein, 3) MMP-9 expression in response to tumor cell contact was transcriptionally regulated, and 4) contact-dependent MMP-9 expression appeared to occur independently of protein kinase C activation. Finally, in situ hybridization demonstrated stromal MMP-9 mRNA in 2.8 but not in RA3-derived tumors in nude mice. The principal investigator plans to begin to characterize the molecular mechanisms responsible for the contact-dependent induction of MMP-9 in stromal cells, and to isolate and characterize the tumor cell protein(s) and gene(s) responsible for stromal MMP-9 induction. These laboratory studies will be incorporated into an overall academic plan at the University of Pennsylvania and at the Children's Hospital of Philadelphia which combines graduate course work seminars, journal clubs, and continued clinical activities in order to prepare the principal investigator to become a productive, independent biomedical investigator in pediatric oncology.
| Himelstein, B P; Lee, E J; Sato, H et al. (1998) Tumor cell contact mediated transcriptional activation of the fibroblast matrix metalloproteinase-9 gene: involvement of multiple transcription factors including Ets and an alternating purine-pyrimidine repeat. Clin Exp Metastasis 16:169-77 |
| Himelstein, B P; Lee, E J; Sato, H et al. (1997) Transcriptional activation of the matrix metalloproteinase-9 gene in an H-ras and v-myc transformed rat embryo cell line. Oncogene 14:1995-8 |
