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.
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.
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.
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.
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.
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.
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).
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.
The gene expression or activation of matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor (VEGF) and the p42/p44 mitogen-activated protein kinase (MAPK, ERK) that correlated with endothelial cells growth, migration and angiogenesis were also induced by saikosaponin C. From these results, we suggest that saikosaponin C may have the potential for therapeutic angiogenesis but is not suitable for cancer therapy.
MMP-2 was expressed in various cells: HCC cells, vascular wall and sinusoidal endothelial cells in the cancer area of surgically resected tissues; and hepatocytes, bile duct cells, vascular wall, macrophages and Kupffer cells in the non-cancerous area.
These results suggest that claudin-1 up-regulates cancer cell invasion activity through activation of MT1-MMP and MMP-2, which results in enhanced cleavage of laminin-5 gamma2 chains.