In order for an epithelial malignancy to become established, it must first traverse the basement membrane, invade the surrounding stroma, recruit capillary endothelial cells and develop an effective tumor vasculature. In the absence of tumor angiogenesis, malignant cells become apoptotic and tumors fail to grow beyond 3-4 mm in size. The investigator postulates that a series of specific interactions between malignant epithelial cells and surrounding stromal elements promote the development of an effective tumor vasculature and enhance tumor cell viability and that a unique matrix metalloproteinase, stromelysin-3 (STR-3) contributes to this process. This hypothesis is based on the following observations: 1) STR-3 is consistently and dramatically overexpressed by stromal elements in every primary epithelial malignancy examined to date; 2) STR-3 is also expressed by stromal elements in precursor lesions and linked with grade and local invasiveness of early stage tumors; 3) STR-3 promotes the establishment of local tumors in nude mice by contributing to tumor cell survival and implantation in host tissues. We have developed a tumor-stroma co-culture model that mimics the earliest stages of invasive carcinoma in which malignant epithelial cells come into direct contact with normal stromal cells. In this assay, tumor cells induce stromal cells to release a potent angiogenic factor, bFGF, and to secrete STR-3. Preliminary studies suggest that in tumor/stroma co-cultures, STR-3 also modulates the release of extracellular bFGF and bFGF stimulates the subsequent processing and inactivation of STR-3. If STR-3 promotes the development of tumor vasculature and enhances tumor cell viability, bFGF-mediated processing of the enzyme may represent a tightly regulated feedback loop. The newly developed tumor/stroma co-culture assay and related model systems will be used to further characterize the interactions between malignant epithelial cells and normal stromal elements and to define the role of STR-3 in tumor angiogenesis and tumor cell viability. For these reasons, it will be to: 1) determined whether STR-3 modulates the release and bioactivity of bFGF in tumor/stroma co-cultures; 2) determine whether STR-3 modulates programmed cell death in tumor/stroma co-cultures; 3) generate informative STR-3 cat- and proc-constructs and characterize their function in vitro and in vivo; and 4) characterize the enzyme responsible for the bFGF-mediated processing and inactivation of STR-3.
| Anderson, I C; Mari, S E; Broderick, R J et al. (2000) The angiogenic factor interleukin 8 is induced in non-small cell lung cancer/pulmonary fibroblast cocultures. Cancer Res 60:269-72 |
