Secretion of gelatinases and tissue inhibitors of metalloproteinases by human lung cancer cell lines and revertant cell lines: Not an invariant correlation with metastasis

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Abstract
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 immunoas‐says 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‐I 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.