Structural changes in the extracellular matrix (ECM) are necessary for cell migration during tissue remodeling and
tumor invasion. The
matrix metalloproteinases (
MMPs) and their inhibitors have been shown to be critical modulators of ECM composition and are thus, crucial in neoplastic cell invasion and
metastasis. Expression of MMP-2, -3, -9, -10, and -13 was investigated in human
lung adenocarcinomas employing an indirect
alkaline phosphatase conjugated immunocytochemical technique. Evaluation of the results was based on (a) the percent of neoplastically transformed cells/surrounding stroma that reacted positively and (b) a measure of staining intensity [graded from A (highest) to D]. The two forms of
stromelysin, MMP-3 and -10, share 82% sequence homology, but exhibit differences in cellular synthesis and inducibility by
cytokines and
growth factors in vitro. Strong overall expression of MMP-3 and -10 was found in
lung adenocarcinomas, especially in the ECM adjacent to blood vessels. Positive immunoreactivity could be seen for these two
MMPs in the ECM surrounding over 90% of the neoplastically transformed cells (++++), and the staining intensity was also the strongest possible (A,B). Focal (+), high intensity (A,B) staining could be detected for MMP-2, -9, and -13. Thus, it seems that the stromelysins are involved in the generalized growth and expansion of the neoplastic cell mass, while MMP-2, -9 and -13 are involved in the neoangiogenic and focal clonal selection and expansion phenomena associated with in situ
tumor progression, invasion of the microvasculature, and
metastasis.