Increased matrix metalloproteinase 2 concentration and transcript expression in advanced colorectal carcinomas

Abstract

Colorectal cancer is one of the most common malignant tumors and entails a relatively poor prognosis. Clinical outcome depends on the extent of local and metastatic tumor spread. Results of in vivo and in vitro studies suggest that the balance between matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of metalloproteinases TIMPs) is altered in neoplasia, contributing to the invasive and metastatic properties of malignant tumors. We quantified tissue concentrations of MMP-2 and TIMP-2 in 65 malignant colorectal lesions and corresponding normal mucosa by enzyme-linked immunosorbent assay, western blotting, and in situ hybridization. In situ hybridization and western blot analyses demonstrated a clear increase in both stromal expression of MMP-2 transcripts and protein in primary carcinomas. The protein concentration of MMP-2 was higher in all tumor stages, except stage I tumors, than in normal mucosa and adenomas. MMP-2 concentrations were not related to tumor differentiation or to colonic versus rectal location. Surprisingly, the MMP-2 concentration was not increased in metastases. Interestingly, tissue concentrations and epithelial mRNA expression of TIMP-2 decreased significantly in primary colorectal cancer (UICC stages III and IV) but increased in metastases. Therefore an increased ratio of MMP-2 to TIMP-2 is strongly associated with advanced tumor stages, but a decreased ratio was observed in metastases. These findings suggest that the MMP-2:TIMP-2 ratio may prove useful as a marker of local invasion but not of metastasis in colorectal cancer.

Small Integrin Binding Ligand N -Linked Glycoprotein Gene Family Expression in Different Cancers

“…The observed increase in MMP-2 expression observed in tumor samples is consistent with previous studies of breast (41,42), colon (43)(44)(45)(46)(47), stomach (48,49), lung (50 -53), rectal (43,54), and kidney cancer (55)(56)(57). Whereas a strong association of increased MMP-3 has been found in breast cancer (41, 58 -61), the increased expression levels observed in other tumor types are not as well supported by published literature.…”

Immunohistochemically Detected High Expression of Matrix Metalloproteinase-2 as Predictor of Poor Prognosis in Duke’s B Colon Cancer

“…Similar to studies by Ring (16) and Papandopoulou (25), we found higher MMP-2 expression in high-grade tumors, although some studies show the opposite finding (13,19). Since tumor grade and vascular invasion are well-known prognostic factors (26), their correlation with MMP-2 positive immunostaining puts them in the group of pathohistological parameters characteristic for aggressive tumor behavior.…”

“…Previous studies on MMP-2 protein expression as a prognostic marker in colon carcinoma used various methods, including gelatin zymography (19), enzyme linked immunosorbent assays (19), quenched fluorescence substrate hydrolysis (20), Western blot (19), in situ hybridization (19), and immunohistochemistry on formalin fixed, paraffin embedded tissue (17,18). Immunohistochemistry has several advantages over other methods -it allows direct correlation with morphology and it can be performed on paraffin embedded specimens, which makes it practical for the routine assessment of MMPs in diagnostic practice.…”

Clinical Prospects of Tumor-Associated Proteases and Their Tissue Inhibitors Investigation in Oncologic Patients

“…Роль матриксных металлопротеиназ (ММП) в опухолевой прогрессии [2]. [13][14][15][16][17][18][19][20][21], а использование природных и синтетических ингибито-ров ММП считается перспективным подходом к противо-опухолевой терапии [2,13].…”