We have established a series of oncogene transformed rat embryo cells (REC) as a system for studying features of tumor progression including metastasis. Clones of REC transformed by the oncogene H-ras plus the cooperating oncogene v-myc invariably are metastatic to the lungs in nude mice as judged by both the spontaneous and the experimental metastasis assays. In contrast REC transformed by H-ras plus the cooperating oncogene ElA from the early region of Adenovirus 2 (EIA) are not metastatic in these assays but are equally tumorigenic and express H-ras at equivalent levels to those transformed by H-ras plus v-myc. The tumors formed by each combination of oncogenes also grow at equivalent rates although those formed by H-ras plus ElA appear to be encapsulated. Many properties of these cells were examined in order to identify differences between the two cell types, which might account for their different metastatic properties. The most significant difference we found was in their release of enzymes capable of degrading collagens. The REC transformed by the oncogene H-ras plus v-myc are highly metastatic and released a 92 kDa gelatinase which is capable of degrading Type IV collagen. In contrast, the non-metastatic cells transformed by H-ras plus EIA did not release the 92 kDa gelatinase. The ElA gene appears to suppress the expression of the 92 kDa gelatinase. These correlations held both in vitro and in vivo. No difference was observed between the cells in regard to other collagenases or other markers for metastatic potential. These results suggest that the 92 kDa gelatinase is required for metastasis in this system and is thus an excellent candidate for a marker of metastatic potential. In some metastatic lines the 92 kDa gelatinase is seen only after growth as a tumor in vivo. These results suggest a mechanism through which tumor behavior may be modified through interaction with the host. Attempts have been made to duplicate this effect in culture. Cocultivation with fibroblasts was able to augment the release of the 92 kDa gelatinase in the metastatic lines, but not the non-metastatic. Although these cocultivation experiments may not duplicate all of the possible host-tumor interactions, the results do suggest that the enhancement of 92 kDa gelatinase release as induced through cocultivation is now amenable to experimental analysis. This proposal is designed to explore the mechanisms which control the expression of the 92 kDa gelatinase and to determine the role of the 92 kDa gelatinase in tumor metastasis. The role of other proteases, plasminogen activator and cathepsins B and L, which have been identified as possible effectors of metastasis and which can activate the latent form of the 92 kDa gelatinase will also be explored.
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