Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix proteases and the transcription factor c-Ets-1, which regulates in vitro stromelysin 1, collagenase 1, and urokinase type plasminogen activator gene promoters, are frequently expressed in invasive carcinomas. Using in situ hybridization and immunohistochemistry, we analyzed collagenase 1, stromelysins 1 and 3, matrilysin, urokinase type plasminogen activator, and c-Ets-1 gene expression on serial frozen sections of 39 intraepithelial bronchial lesions, including areas of hyperplasia, metaplasia, dysplasia, carcinoma in situ, and corresponding lung carcinomas in 13 patients. In intraepithelial lesions, expression of all matrix proteases was detected in epithelial cells. Conversely, in microinvasive or invasive lesions, a fibroblastic expression was observed. Collagenase 1 and matrilysin were expressed seldomly in intraepithelial lesions and frequently in carcinomas (p = 0.0016 and p < 0.0001, respectively). Stromelysin 1 was expressed inconsistently in 31% of intraepithelial lesions of all grades and in 50% of carcinomas. Stromelysin 3 and urokinase type plasminogen activator were expressed only, but frequently, in preinvasive lesions (dysplasia, carcinoma in situ) and in carcinomas. The expression of stromelysin 3 in fibroblasts started with dysplasia and carcinoma in situ, but was more frequent in invasive than preinvasive lesions (p = 0.0012). c-Ets-1 was more often expressed in carcinomas than in intraepithelial lesions (p < 0.0001) and was always expressed in fibroblasts. Comparing preinvasive lesions adjacent to or at a distance from squamous lung carcinoma, stromelysin 3 epithelial expression was more frequent in preinvasive lesions adjacent to invasive foci than in others (p = 0.036). We conclude that (a) both epithelial expression of matrix proteases in intraepithelial bronchial lesions and their stromal expression in microinvasive and invasive lesions suggest their role in lung tumor development; (b) c-Ets-1 does not act as a transcriptional activator for matrix proteases genes in preinvasion, although it might regulate collagenase 1 gene during lung tumor progression; and (c) matrix proteases might offer new therapeutic targets for chemoprevention of lung cancer.
 ...
PMID:Changes in the expression of matrix proteases and of the transcription factor c-Ets-1 during progression of precancerous bronchial lesions. 868 34

Tumor cell-derived collagenase stimulatory factor (TCSF) stimulates in vitro the biosynthesis of various matrix metalloproteinases involved in tumor invasion, such as interstitial collagenase, gelatinase A, and stromelysin 1. The expression of TCSF mRNAs was studied in vivo, using in situ hybridization and Northern blotting analysis, in seven normal tissues and in 22 squamous cell carcinomas of the lung, and in seven benign proliferations and in 22 ductal carcinomas of the mammary gland. By in situ hybridization, TCSF mRNAs were detected in 40 of 44 carcinomas, in pre-invasive and invasive cancer cells of both lung and breast cancers. TCSF mRNAs and gelatinase A mRNAs were both visualized in the same areas in serial sections in breast cancers, and were expressed by different cells, tumor cells, and fibroblasts. The histological results were confirmed by Northern blot analysis, which showed a higher expression of TCSF mRNAs in cancers than in benign and normal tissues. These observations support the hypothesis that TCSF is an important factor in lung and breast tumor progression.
 ...
PMID:Tumor collagenase stimulatory factor (TCSF) expression and localization in human lung and breast cancers. 915 57

Studies from model systems suggest that matrix metalloproteinases (MMPs) are causally involved in tumor progression while tissue inhibitors of MMPs (TIMPs) prevent this progression. Here, we show that concentrations of TIMP-1 are significantly higher in breast carcinomas than in fibroadenomas. In primary breast cancers, TIMP-1 concentrations increased with increasing tumor size but showed an inverse relationship with estrogen receptor concentrations. In primary breast cancers also, TIMP-1 levels were weakly but significantly correlated with those for MMP-1, proMMP-2, active MMP-2, MMP-3 and proMMP-9. Contrary to what might be expected from published data on model systems, high concentrations of TIMP-1 predicted a poor outcome in patients with breast cancer. We conclude that in human breast cancer, endogenous TIMP-1 does not inhibit tumor progression but may enhance the process.
 ...
PMID:High levels of tissue inhibitor of metalloproteinase-1 predict poor outcome in patients with breast cancer. 998 31

Although matrix metalloproteinases (MMPs) are implicated in breast cancer progression, the contribution of MMP-1 and MMP-3 to this process, has not been thoroughly investigated. Matrix metalloproteinases (MMPs) are important at several points during multistage neoplastic progression. Immunohistochemistry (Strept-ABC-HRP method) and in situ hybridization were performed to detect MMP-1, MMM-3 proteins, and MMP-3 mRNA, respectively, in 77 infiltrative breast carcinomas. MMP-1, MMP-3 protein, and MMP-3 mRNA detection were analyzed in parallel with clinicopathologic features (menopausal status, histological type, nuclear and histological grade, stage) and the immunohistochemical reactivity of estrogen (ER), progesterone (PR) receptors, and c-erbB-2 oncoprotein in breast carcinomas. Statistical analysis was performed using the multiple linear regression test. Immunoreactivity for MMP-1 and MMP-3 was observed in 59 of 77 (77%) and 22 of 77 (28.5%) breast carcinomas and was evaluated separately in cancer cells and in stromal fibroblasts. MMP-3 mRNA was detected in 72 of 77 (93.5%) carcinomas exclusively in stromal cells within the tumors or in the marginal portion of tumors. MMP-1 protein immunoreactivity in stromal fibroblasts but not in cancer cells showed a statistically significant correlation with tumor stage (P=.04). MMP-1 reactivity either in stromal or in cancer cells showed a statistically significant inverse correlation with PR expression (P=.04 and P=.04, respectively). MMP-3 protein immunoreactivity in cancer or stromal cells and MMP-3 mRNA expression was not associated with the clinicopathologic features studied. MMP-3 mRNA was detected more often in ductal carcinomas. These results indicate that MMP-1 may contribute to breast cancer invasiveness. Furthermore, they suggest differential functions for MMP-1 and MMP-3 in breast cancer progression.
 ...
PMID:Matrix metalloproteinase-1 and -3 in breast cancer: correlation with progesterone receptors and other clinicopathologic features. 1020 54

Expression of HPV16 early region genes in basal keratinocytes of transgenic mice elicits a multistage pathway to squamous carcinoma. We report that infiltration by mast cells and activation of the matrix metalloproteinase MMP-9/gelatinase B coincides with the angiogenic switch in premalignant lesions. Mast cells infiltrate hyperplasias, dysplasias, and invasive fronts of carcinomas, but not the core of solid tumors, where they degranulate in close apposition to capillaries and epithelial basement membranes, releasing mast-cell-specific serine proteases MCP-4 (chymase) and MCP-6 (tryptase). MCP-6 is shown to be a mitogen for dermal fibroblasts that proliferate in the reactive stroma, whereas MCP-4 can activate progelatinase B and induce hyperplastic skin to become angiogenic in an in vitro bioassay. Notably, premalignant angiogenesis is abated in a mast-cell-deficient (KITW/KITWWv) HPV16 transgenic mouse. The data indicate that neoplastic progression in this model involves exploitation of an inflammatory response to tissue abnormality. Thus, regulation of angiogenesis during squamous carcinogenesis is biphasic: In hyperplasias, dysplasias, and invading cancer fronts, inflammatory mast cells are conscripted to reorganize stromal architecture and hyperactivate angiogenesis; within the cancer core, upregulation of angiogenesis factors in tumor cells apparently renders them self-sufficient at sustaining neovascularization.
 ...
PMID:Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. 1036 56

Previous studies have shown a correlation between the production of certain matrix metalloproteinases (MMPs), especially the gelatinases, by malignant tumors and the progression of these cancers as they invade and metastasize through the extracellular matrix and basement membranes. However, very few of these studies examined this relationship in human oral cancer in vivo, and none addressed the issue of how combinations of the MMPs may further enhance tumor progression. To determine which MMPs are produced in vivo by human oral cancers, we used specific anti-human-MMP antibodies and immunocytochemistry (ICC) methods to examine oral cancer tissue specimens from 20 surgery patients. The ICC data indicated that 72-kDa (72K-GL) and 92-kDa gelatinases (92K-GL) were produced in vivo by discreet clusters of tumor cells and by stromal fibroblasts, vascular endothelial cells (72K-GL), and PMNs (92K-GL). Some stromal fibroblasts near the tumors also appeared to produce fibroblast-type collagenase (FIB-CL), a finding confirmed by Western blot analysis of media conditioned by oral tumor explant cultures. ICC results indicated that 5 of the 20 tumors coincidentally produced all three MMPs. To examine how the two gelatinases and FIB-CL may interact in vitro to degrade fibrillar type I collagen, a major structural component of the extracellular matrix, we used a modified FIB-CL activity assay. Combinations of the gelatinases and FIB-CL were incubated with a 3H-collagen substrate, with the results compared with the combination of stromelysin-1 (SL-1, a superactivator of FIB-CL) and FIB-CL. 92K-GL caused a nine-fold increase in collagenase activity, equivalent to SL-1, while 72K-GL produced a four-fold increase. These results indicate that human oral cancers produce 92K-GL, 72K-GL, and FIB-CL in vivo and that the gelatinases and FIB-CL cooperate to enhance collagen degradation greatly in vitro.
 ...
PMID:92K-GL (MMP-9) and 72K-GL (MMP-2) are produced in vivo by human oral squamous cell carcinomas and can enhance FIB-CL (MMP-1) activity in vitro. 1040 63

Tumor cells interact with stromal cells via soluble or cell-bound factors stimulating the production of matrix metalloproteinases (MMPs), a group of enzymes largely involved in the extracellular matrix (ECM) remodeling in tumor invasion. Among these factors, extracellular matrix metalloproteinase inducer (EMMPRIN) has been shown to stimulate in vitro the fibroblast production of various MMPs such as interstitial collagenase (MMP-1), stromelysin-1 (MMP-3), and gelatinase A (MMP-2). In this study, the EMMPRIN protein was detected by immunohistochemistry prominently in malignant proliferations of the breast and the lung. It was present at the surface of both tumor epithelial and peritumor stromal cells. Because previous studies have reported that stromal cells do not express EMMPRIN mRNAs, it is very likely that EMMPRIN is bound to stromal cells via a specific receptor. Moreover, our observations also demonstrated that the same peritumor stromal cells strongly express MMP-2. Our results show that EMMPRIN is an important factor in tumor progression by causing tumor-associated stromal cells to increase their MMP-2 production, thus facilitating tumor invasion and neoangiogenesis. (J Histochem Cytochem 47: 1575-1580, 1999)
 ...
PMID:Expression of the extracellular matrix metalloproteinase inducer (EMMPRIN) and the matrix metalloproteinase-2 in bronchopulmonary and breast lesions. 1056 41

We have identified a human placenta cDNA coding for a new member of the matrix metalloproteinase (MMP) family. The isolated cDNA encodes a polypeptide of 261 amino acids, the smallest MMP identified to date, which contains several structural features of MMPs including the signal sequence, the prodomain involved in enzyme latency, and the catalytic domain with the zinc-binding site. However, it lacks the hinge region and hemopexin-domain present in most MMPs. According to these structural characteristics, the human MMP described herein has been called matrilysin-2 (MMP-26), because it exclusively shares with matrilysin this minimal domain organization required for secretion, latency, and activity. The amino acid sequence of matrilysin-2 also contains a threonine residue adjacent to the Zn-binding site that has been defined as a specific feature of matrilysin. Chromosomal location of the matrilysin-2 gene showed that it maps to the short arm of chromosome 11, a location distinct to that of other MMP genes. Matrilysin-2 was expressed in Escherichia coli, and, after purification and refolding, the recombinant protein was found to degrade synthetic substrates commonly used for assaying MMPs. Furthermore, this protein hydrolyzed type IV collagen, fibronectin, fibrinogen, and gelatin, which indicated that matrilysin-2 is a potent enzyme with a wide substrate specificity. In addition, it was found that matrilysin-2 is able to activate progelatinase B. Proteolytic activity of matrilysin-2 against all of these substrates was abolished by synthetic inhibitors and by tissue inhibitors of metalloproteinases. Expression analysis revealed that matrilysin-2 is detected not only in placenta and uterus but is widely expressed in malignant tumors from different sources as well as in diverse tumor cell lines. These data together with its broad spectrum of proteolytic activity, suggest that matrilysin-2 may play a role in some of the tissue-remodeling events associated with tumor progression.
 ...
PMID:Matrilysin-2, a new matrix metalloproteinase expressed in human tumors and showing the minimal domain organization required for secretion, latency, and activity. 1098 80

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 malignant melanomas (MMs) 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 MMs, 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.
 ...
PMID:Matrix metalloproteinase expression in malignant melanomas: tumor-extracellular matrix interactions in invasion and metastasis. 1128 31

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 prostatic carcinomas 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 (+), low to high intensity (C to A) staining could be detected for MMP-2, while no immunoreactivity was observed employing MoABs directed against MMP-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 is involved in the neoangiogenic and focal clonal selection and expansion phenomena associated with in situ tumor progression, invasion of the microvasculature, and metastasis.
 ...
PMID:Immunocytochemical detection of matrix metalloproteinase expression in prostate cancer. 1128 32


1 2 3 4 5 6 7 Next >>