Stromelysin-3 is induced in tumor/stroma cocultures and inactivated via a tumor-specific and basic fibroblast growth factor-dependent mechanism.
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.
Mari
B P
BP
Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Anderson
I C
IC
Mari
S E
SE
Ning
Y
Y
Lutz
Y
Y
Kobzik
L
L
Shipp
M A
MA
D000595:Amino Acid Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000473:pathology; D002384:Catalysis; D002450:Cell Communication; D018920:Coculture Techniques; D004790:Enzyme Induction; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D053507:Matrix Metalloproteinase 11; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000737:chemistry; D008969:Molecular Sequence Data; D017154:Stromal Cells / Q000201:enzymology*; D014407:Tumor Cells, Cultured; D000511:alpha-Macroglobulins / Q000378:metabolism
D000511:alpha-Macroglobulins; D016222:Fibroblast Growth Factor 2; D053507:Matrix Metalloproteinase 11; D008666:Metalloendopeptidases