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Stromelysin-3 is induced in tumor/stroma cocultures and inactivated via a tumor-specific and basic fibroblast growth
B P Mari1, I C Anderson, S E Mari
1Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
Stromelysin-3 (STR-3) is a recently characterized matrix metalloproteinase (MMP) with a unique pattern of expression and substrate specificity. Unlike other MMPs, STR-3 is consistently and dramatically overexpressed by multiple epithelial malignancies, including carcinomas of the breast, lung, colon, head and neck, and skin. Recent studies suggest that STR-3 promotes the local establishment of epithelial malignancies, contributing to tumor cell survival and implantation in host tissues; however, STR-3's mechanism of action remains undefined. STR-3 is a stromal cell product, prompting speculation that infiltrating stromal cells secrete STR-3 in response to tumor-derived factors. To explore this possibility, we developed a tumor/"stroma" coculture assay in which non-small cell lung cancer (NSCLC) cell lines were grown on confluent monolayers of normal pulmonary fibroblasts. In these tumor/stroma cocultures, NSCLCs stimulate normal pulmonary fibroblasts to secrete STR-3 and release extracellular basic fibroblast growth factor. Thereafter, STR-3 is processed at a unique internal sequence via a basic fibroblast growth factor- and MMP-dependent mechanism to a previously unidentified 35-kDa protein that lacks enzymatic activity. 35-kDa STR-3 is the most abundant STR-3 protein in tumor/stroma cocultures and is only detected when normal pulmonary fibroblasts are cultured with malignant bronchial epithelial cells. Therefore, the tumor-specific processing of STR-3 to the 35-kDa protein is likely to be an important regulatory mechanism.
Insights
Stromelysin-3 (STR-3), an MMP overexpressed in cancers, is processed into a non-enzymatic 35-kDa form by lung cancer cells. This tumor-specific processing of STR-3 may regulate its role in cancer progression.
Area of Science:
- Oncology
- Biochemistry
- Cell Biology
Background:
- Stromelysin-3 (STR-3) is a matrix metalloproteinase (MMP) uniquely overexpressed in various epithelial cancers.
- While STR-3 is implicated in tumor cell survival and implantation, its precise mechanism of action is not fully understood.
- STR-3 is produced by stromal cells, suggesting a response to tumor-derived signals.
Purpose of the Study:
- To investigate the mechanism by which tumor cells influence STR-3 production and processing.
- To elucidate the functional significance of STR-3 in the tumor microenvironment.
Main Methods:
- Development of a tumor/stroma coculture assay using non-small cell lung cancer (NSCLC) cell lines and normal pulmonary fibroblasts.
- Analysis of STR-3 secretion and processing in coculture conditions.
- Characterization of the processed STR-3 product.
Main Results:
- NSCLC cells stimulate pulmonary fibroblasts to secrete STR-3 and release basic fibroblast growth factor (bFGF).
- STR-3 undergoes MMP-dependent processing at an internal site, facilitated by bFGF, yielding a 35-kDa protein lacking enzymatic activity.
- The 35-kDa STR-3 form is abundant in cocultures and specifically detected when fibroblasts are exposed to malignant bronchial epithelial cells.
Conclusions:
- Tumor cells induce fibroblasts to secrete STR-3, which is then processed into an inactive 35-kDa form.
- This tumor-specific processing of STR-3 represents a novel regulatory mechanism potentially crucial for epithelial malignancies.
- Further research is needed to fully understand the implications of this 35-kDa STR-3 form in cancer progression.