Secretion of gelatinases and tissue inhibitors of metalloproteinases by human lung cancer cell lines and revertant cell lines: not an invariant correlation with metastasis.
Numerous studies have reported a correlation between production of 72-kDa (MMP-2) and 92-kDa (MMP-9) type-IV collagenases/gelatinases and the metastatic potential of cancer cells. An abrogating effect of tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) on metastases has also been noted. In this report we have used sensitive enzyme-linked immunoassays to measure MMP-2, MMP-9, TIMP-1 and TIMP-2 levels in eight human lung-cancer cell lines which were characterized for biological behavior in nude mice. We demonstrated that the Calu-6 and A549 cell lines with the highest metastatic, invasive and tumorigenic potential secreted the highest levels of MMP-2. MMP-9 and TIMP-1 secretions were comparatively low in all cell lines. TIMP-2 secretion, which exceeded MMP-2 secretion for all cell lines, did not correlate with metastatic potential. To further explore these correlations, the metastatic Calu-6 cell line was transfected with a K-rev-1 cDNA expression construct. The K-rev revertant cell lines demonstrated a more differentiated phenotype and were less tumorigenic, invasive and metastatic in nude mice. Nonetheless, the Calu-6 revertant cell lines secreted higher levels of MMP-2 than the parent cell line. In conclusion, invasion and metastasis by lung-cancer cells requires not only enhanced MMP production, but also other less well-understood tumorigenic characteristics. The multiplicity of factors required by cancer cells for dissemination helps to explain the minute fraction of cancer cells from a primary tumor that ever develop into a metastasis.
Zucker
S
S
Department of Research, Department of Veterans Affairs Medical Center, Northport, NY 11768.
Lysik
R M
RM
Malik
M
M
Bauer
B A
BA
Caamano
J
J
Klein-Szanto
A J
AJ
D000818:Animals; D017364:Collagenases / Q000032:analysis / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005780:Gelatin / Q000378:metabolism; D006023:Glycoproteins / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D020780:Matrix Metalloproteinase 9; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009857:Oncogenes; D019714:Tissue Inhibitor of Metalloproteinases; D014162:Transfection; D014407:Tumor Cells, Cultured
D006023:Glycoproteins; D019714:Tissue Inhibitor of Metalloproteinases; D005780:Gelatin; D017364:Collagenases; D020780:Matrix Metalloproteinase 9