However, since these cell lines did not show a fully malignant phenotype, we concluded that, in addition to the degradation of extracellular matrix macromolecules, including basement membrane components by MMP-2, -3, and/or -9, some additional factors must be involved for the malignancy of fully transformed cells and that these immortalized human aortic SMC, which share many characteristics with normal SMC, will prove useful to study the role(s) of metalloproteinases in atherosclerosis.
To clarify this, we conducted immunoelectron microscopic study of gelatinase A in cancer and stromal cells in human gastrointestinal and skin carcinomas.
Simultaneous presence of gelatinase A (MMP-2) and MMP-2 messenger RNA (mRNA) in 30 malignant tumors with various degrees of differentiation and biological behavior was evaluated by immunohistochemistry and in situ hybridization.
A 72-kDa type IV collagenase, also referred to as gelatinase A or MMP-2, has been proposed to potentiate the invasion and metastasis of malignant tumors.
Thus, we have shown that BM-MNCs continuously produce MMP-9 and TIMP-1 and demonstrated that leukemic blast cells additionally secrete MMP-2 representing a potential marker for dissemination in myeloproliferative malignancies.
Our study demonstrates that of all tested components of the matrix metalloproteinase system, only expression of activated MMP-2 correlates with increased malignancy in our melanoma xenograft model, corroborating an important role of MMP-2 in human melanoma invasion and metastasis.
The presence of gelatinase A mRNA in parathyroid tumors strengthens the suspicion of malignancy but cannot be used as a definitive marker of malignancy.
They also suggest MMP-2 is secreted in its pro form by stromal fibroblasts surrounding the cancer cells and activated by MT1-MMP localized on the cancer cells.
In pancreatic adenocarcinomas, MT1-MMP and MMP-9 mRNA were seen at moderate levels both in cancer and in stromal cells, whereas MMP-2 mRNA was predominantly expressed by the tumor stroma.
A high level of the active form of MMP-2 in almost all of the carcinomas and the near lack of its activation in normal lung parenchyma shows that MMP-2 activation is associated with the malignant phenotype and may serve as a good marker of malignancy.
Our results suggest that the elevated levels of MMP-2 and -9 observed in prostate development and cancer may be due to the elevated TGF-beta associated with these tissues.
These findings are consistent with our initial observation for lung cancer and further support the hypothesis that MMP2 genotype may influence individual susceptibility to the development of certain cancer.
Ras expression has been suggested as a marker for tumor aggressiveness of breast cancer,including the degrees of invasion and tumor recurrence.We showed previously that H-ras, but not N-ras, up-regulates matrix metalloproteinase 2 expression and induces invasive phenotype in MCF10A human breast epithelial cells (A.Moon, et al.Int.J.Cancer, 85: 176-181, 2000).
We examined the expression of MMP-2 and -9 (gelatinase-A and -B respectively), by gelatin zymography, in a series of 18 cell cultures derived from human meningiomas of a range of histological subtypes and grades of malignancy, including 7 meningothelial, 6 transitional, 2 fibroblastic and 3 atypical meningiomas.