Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gelatinase A (MMP-2) and cathepsin B are proteinases which have been proposed to participate in human tumor invasion and metastasis. Precise quantitation of the activity of these enzymes in invading tumors has not been previously described. We utilized a novel tissue microdissection technique to determine levels of enzyme activity in specific microscopic areas of invasive human colon cancer. Tissue specimens smaller than one high power field can be extracted from the samples and analyzed. Increased levels of pro-enzyme and active enzyme forms of gelatinase A (MMP-2) and increased cathepsin B activity were localized in regions of tumor invasion as compared with a matched number of normal epithelial cells from the same patient. Levels of progelatinase B (MMP-9) were also increased in the tumors; however, we did not observe activation of this enzyme. To investigate the mechanism of gelatinase A activation, we amplified DNA of specific microdissected tumor cell populations using polymerase chain reaction. We did not detect a mutation in the activation locus of the enzyme in any of the tumors studied, which suggests that activation may be due to up-regulation of a tumor-associated gelatinase A activating species. Microdissection of frozen tissue sections may prove valuable in the study of proteinases in human tumor invasion as well as in the detection of genetic alterations in human cancers.
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PMID:Increased gelatinase A (MMP-2) and cathepsin B activity in invasive tumor regions of human colon cancer samples. 799 33

Overproduction of matrix metalloproteinases (MMPs) is a common characteristic of metastatic cancer cells. Since MMPs can be identified in plasma, we proposed that enhanced MMP-9 secretion by invasive cancer cells may be detected by plasma assay. To this end, we developed a specific sandwich enzyme-linked immunosorbent assay which uses two mouse monoclonal antibodies to human M(r) 92,000 type IV collagenase (MMP-9). The plasma concentration of MMP-9 (mean +/- SD) in 60 healthy subjects (9 +/- 11 ng/ml), 136 patients without cancer, and 179 patients with cancer of the lung, genitourinary tract, or lymphomas-leukemias did not differ significantly. In contrast, plasma MMP-9 was significantly increased (P < 0.01) in 122 patients with gastrointestinal tract cancer and breast cancer (18 +/- 23 and 21 +/- 22 ng/ml, respectively). Whereas carcinoembryonic antigen levels were significantly increased in patients with stage IV gastrointestinal cancer, MMP-9 concentrations were not significantly increased in patients with metastatic disease as compared to those with nonmetastatic cancer. Combining both assays improves sensitivity of detection of colon cancer. MMP-9 was also significantly increased during pregnancy which is consistent with the extensive ongoing tissue remodeling and the leaching of the tissue proteinase into plasma.
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PMID:M(r) 92,000 type IV collagenase is increased in plasma of patients with colon cancer and breast cancer. 841 38

MMP-9 (gelatinase B) and urokinase-type plasminogen activator receptor (u-PAR), which are involved in cancer cell invasion and metastasis, are reported to be predominantly expressed by immune/inflammatory cells in human colorectal cancers. To investigate their significance in cancer progression, we morphometrically analyzed the tissue expression of MMP-9 and u-PAR among different stages of colorectal cancer. The numbers of MMP-9- and u-PAR-positive cells along the invasive margin were significantly smaller in cases with liver metastasis than in cases without liver metastasis, and were also smaller in cases with an infiltrating margin than in cases with an expanding margin. Both variables were larger in colon cancer cases with conspicuous lymphocytic infiltration. These results indicated that the degree of tissue expression of MMP-9 and u-PAR by host cells is inversely associated with liver metastasis and an infiltrating growth pattern in human colorectal cancers. Essentially the same results were obtained for the number of macrophages distributed along the invasive margin. We also found that the expression pattern of MMP-9 was similar to that of MMP-8 (polymorphonuclear leukocyte collagenase). These data are consistent with clinicopathologic studies of host cells. Therefore, our data suggest a dual role of MMP-9 and u-PAR expression in colon cancer tissue; i.e., not only are these proteinases cancer-promoting factors, but also they are related to the host defensive mechanism when they are expressed by host cells.
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PMID:Stromal expression of MMP-9 and urokinase receptor is inversely associated with liver metastasis and with infiltrating growth in human colorectal cancer: a novel approach from immune/inflammatory aspect. 904 99

Destruction of the basement membrane (BM) is mandatory for tumor spread, and matrix metalloproteinases (MMPs) are known to be implicated in colon cancer invasion and metastasis by digesting type IV collagen, a main component of the BM. The current study analyzed the expression of MMP-2 and MMP-9 in pancreatic cancer tissues. Frozen specimens of pancreatic cancer (n = 10), a liver metastatic nodule from pancreatic cancer (n = 1), and normal pancreas (n = 3) were homogenized and analyzed by zymography. The activated form of MMP-9 (82 kDa) was detected in all of the normal and malignant tissues, while the activated form of MMP-2 (62 kDa) was detected in all of the pancreatic cancers and its metastatic tissue, but not in the normal pancreatic tissues. These results indicate that expression of the activated form of MMP-2 may be specific to pancreatic cancer, while that of MMP-9 may be unrelated to it.
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PMID:Detection of matrix metalloproteinase activity in human pancreatic cancer. 908 44

Matrix metalloproteinases (MMP) have been implicated in tumor invasion and metastasis. We verified, by gelatin zymography, MMP activity in the euglobulin plasma fraction of 82 healthy controls, 66 patients with benign diseases and 149 patients with breast, lung, colon or brain cancer. The euglobulin fractions assayed showed 4 gelatinolytic bands of 62, 92, 120 and 200 kDa. The median (Md) value for 92 kDa-MMP activity was significantly increased in breast (Md 1.34 arbitrary units [AU]/ml plasma, range 0.0-7.2) and lung cancer patients (Md 1.43 AU/ml, range 0.0-3.6) compared with the controls (Md 0.48 AU/ml, range 0.0-1.8). Patients with colon cancer or gliomas presented values of MMP-9 similar to those of the healthy population. Multivariate analysis indicated that plasma MMP-9 activity was not predicted by the known clinicopathological parameters such as age, stage, tumor size, number of positive lymph nodes, histologic grade, histologic type, nuclear grade or mitotic index. Lung cancer patients also presented high values of MMP-9 (Md 1.43, range 0.0-3.6 [n = 26]), without association with tumor stage or histologic type. The levels of 92 kDa-MMP activity in the plasma euglobulin fraction could be a potentially useful tumor marker in breast and lung cancer.
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PMID:Plasma metalloproteinase activity is enhanced in the euglobulin fraction of breast and lung cancer patients. 1095 15

TIMP-2 is a natural matrix metalloproteinase (MMP) inhibitor that prevents the degradation of extracellular matrix proteins. It abolishes the hydrolytic activity of all activated members of the metalloproteinase family and in particular that of MT1-MMP, MMP-2, and MMP-9, which are selective for type IV collagenolysis. Since MMPs have been implicated in both cancer progression and angiogenesis, we generated a recombinant adenovirus to deliver human TIMP-2 (AdTIMP-2) and evaluated its anticancer efficiency in three murine models. Our results demonstrated that overexpression in vitro of TIMP-2 inhibited the invasion of both tumor and endothelial cells without affecting cell proliferation. Its in vivo efficiency has been evaluated in murine lung cancer LLC, and colon cancer C51 in syngeneic mice as well as in human breast cancer MDA-MB231 in athymic mice. Preinfection of tumor cells by AdTIMP-2 resulted in an inhibition of tumor establishment in more than 50% of mice in LLC and C51 models and in 100% mice in the MDA-MB231 model. A single local injection of AdTIMP-2 into preestablished tumors of these three types significantly reduced tumor growth rates by 60--80% and tumor-associated angiogenesis index by 25--75%. Lung metastasis of LLC tumor was inhibited by >90%. In addition, AdTIMP-2-treated mice showed a significantly prolonged survival in all the cancer models tested. These data demonstrate the potential of adenovirus-mediated TIMP-2 therapy in cancer treatment.
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PMID:AdTIMP-2 inhibits tumor growth, angiogenesis, and metastasis, and prolongs survival in mice. 1126 84

Epidermal growth factor (EGF) receptors are expressed at high levels in about one third of epithelial cancers, and autocrine activation of EGF receptors appears to be critical for the growth of many tumors. We hypothesized that blockade of the binding sites for EGF and transforming growth factor-alpha on EGF receptors with an antireceptor monoclonal antibody (mAb) might be an effective anti-cancer therapy. We produced murine mAb 225 against EGF receptors and demonstrated blockade of receptor function, as well as inhibition of cell growth in cultures and in nude mouse xenografts. mAb C225 is the human:murine chimeric version of mAb 225. Cell cycle inhibition occurred in G(1) phase, and was due to upregulation of p27(Kip1), resulting in inhibition of cyclin E/cyclin dependent kinase-2 activity and hypophosphorylation of Rb. In addition, the amount and/or activities of a number of proapoptotic molecules were enhanced. The antitumor activity in vivo against xenografts was at least partly attributable to reduced vascularization, resulting from decreased vascular endothelial growth factor and basic fibroblast growth factor production by the tumor cells. Metastasis of xenografts was curtailed with mAB C225 treatment, accompanied by a decrease in tumor production of MMP-9. Further studies showed that mAbs 225 and C225 enhanced the cytotoxicity of chemotherapy against xenografts of a variety of human cancer cell lines. Well established xenografts resistant to either mAb or drug treatment alone were eradicated by the combination therapy. Drugs for which this has been demonstrated include doxorubicin, paclitaxel, cisplatin, and topotecan. Antibody treatment also potentiated the responsiveness of human tumor xenografts to radiation therapy. These findings led to clinical trials of human:murine chimeric mAb C225 in combination with chemotherapy or radiotherapy. Results from phase I and II trials involving more than 500 patients are quite promising, in particular in advanced head and neck cancer treated with C225 plus cisplatin or radiation, in advanced colon cancer treated with C225 plus CPT-11, and in advanced pancreatic cancer treated with C225 plus gemcitabine. Phase III trials are now underway.
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PMID:The epidermal growth factor receptor as a target for cancer therapy. 1135 Jul 23

The matrix metalloproteinases, MMP-2 and MMP-9, are capable of degrading components of the basement membrane, a vital barrier breached during the progression of colorectal cancer. The regulation of MMP-2 activation and subsequent targets is vital to understanding the metastatic process. MMP-2 was not expressed by colorectal cancer cells (C170 and C170HM(2)) in vitro but by stromal fibroblasts (46BR.1GI). There was induction of this MMP upon transwell co-cultivation of the colon cancer cells with the fibroblasts but in vivo growth did not lead to a similar increase in the metastatic tumour cells (C170HM(2)), MMP-2 again being attributed to the stromal cells. MMP-2 mRNA was overexpressed in human colorectal tumours compared to normal colorectal tissue, which correlated with Dukes' stage and immunolocalized to the stromal compartment of the tumour tissue. The active form of the MMP-2 enzyme was also present in the colorectal tumour tissue (7/8) but essentially absent in all normal colon samples examined (1/8). MMP-2 activation was not related to an increase in MT-1-MMP mRNA or a decrease in the specific inhibitor TIMP-2 in human tissue. There was however an increase in MMP-2/TIMP-2 ratio in tumour compared to normal. MMP-9, a target of active MMP-2, was present in the metastatic cell line but expression was down-regulated in the tumour cells in vivo, gelatin analysis revealed that MMP-9 was almost entirely attributable to the murine host, confirmed by PCR. There was no increase in mRNA for MMP-9 or its specific inhibitor TIMP-1 in colorectal tumour tissue compared to normal, MMP-9 protein localized to the inflammatory infiltrate. Fibroblast cells may provide malignant epithelial cells with a ready source of enzyme which is crucial to the metastatic process.
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PMID:Spectrum of matrix metalloproteinase expression in primary and metastatic colon cancer: relationship to the tissue inhibitors of metalloproteinases and membrane type-1-matrix metalloproteinase. 1140 21

We have evaluated the degree of MMP-9 and TIMP-1 messenger RNA (mRNA) expressions according to cell types in tumor tissues, and evaluated the implication of balance between the MMP-9 mRNA and the TIMP-1 mRNA expression in liver metastasis using orthotopic-implanted colon cancer in nude mouse, and also in 47 patients with colorectal cancer. The grade of MMP-9 or TIMP-1 mRNA expression was classified into 4 categories according to positive cell ratio. A higher grade of MMP-9 mRNA expression in tumor cells was correlated with liver metastasis in the experimental colon cancer, but was not statistically correlated in the clinical colorectal cancer. In contrast, the expression of TIMP-1 mRNA in the stromal cells of human colorectal cancer was correlated with liver metastasis. In both experimental and clinical colorectal cancer, a balance between the expression of MMP-9 mRNA and that of TIMP-1 mRNA was correlated with the occurrence of liver metastasis. The imbalance of MMP-9 dominance in tumor cells was implicated in liver metastasis. However, there was no significant relationship between the incidence of liver metastasis and the expression patterns of MMP-9 and TIMP-1 mRNA in the stromal cells. These results suggest that the balance between the expressions of MMP-9 and TIMP-1 in the tumor cells is more closely related to tumor biological behavior rather than the balance in the stromal cells.
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PMID:Imbalance between matrix metalloproteinase 9 and tissue inhibitor of metalloproteinases 1 expression by tumor cells implicated in liver metastasis from colorectal carcinoma. 1168 Sep 36

MMI-166 is a selective inhibitor of matrix metalloproteinase (MMP)-2 and MMP-9. Mice implanted a human colon cancer orthotopically received 200 mg/kg of MMI-166 orally for 5 weeks. Gelatin zymography demonstrated that the administration of MMI-166 remarkably decreased the active MMP-2 expression. Histological examination revealed that MMI-166 showed prominent effect on reduction of the invasive feature of the cancer cells and showed inhibitory effect on tumor vasculature, resulting in the significant decrease of microvessel density of the implanted tumor and liver metastasis compared with the control group. Conclusively, MMI-166 is a potent antiangiogenic oral agent for a human colon cancer.
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PMID:Prevention of liver metastasis of human colon cancer by selective matrix metalloproteinase inhibitor MMI-166. 1173 35


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