Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The lysosomal cysteine proteinases cathepsins B and L are known to play an important role in the invasive growth of tumor cells, but their association with angiogenesis has been less well studied. The aim of this study was to determine the possible role of endothelial cell-associated cathepsins B and L in induced capillary growth in the aorta ring model of angiogenesis. Specific inhibitors of cysteine proteinases did not inhibit capillary growth in aorta ring culture and only slightly inhibited the degradation of surrounding collagen. In contrast, strong inhibition of both processes by the matrix metalloproteinase inhibitor BB-94 was observed, indicating the importance of endogenous MMP production in angiogenesis. In support of this finding, we demonstrated a significant increase in endogenous endothelial mRNA of MMP2, but not of cathepsins B and L, in proliferating primary human dermal microvascular endothelial cells (HMVEC-d) in culture. However, MMP2 mRNA expression was increased only when the cells were embedded in collagen but not when they were grown on plastic, regardless of the addition of the growth factors VEGF or bFGF. Moreover, on plastic the impairment of MMP2 induction by growth factors was observed. The differential effect of growth factors implies the crosstalk with integrin signaling as a consequence of binding to the different matrix. This study suggests that endothelial cell-associated cathepsins B and L are not involved in the invasive growth of capillaries from existing blood vessels and that the presence of collagen is necessary for MMP2 expression in endothelial cells.
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PMID:Comparison of expression of cathepsins B and L and MMP2 in endothelial cells and in capillary sprouting in collagen gel. 1525 44

A mouse model involving the human papillomavirus type-16 oncogenes develops cervical cancers by lesional stages analogous to those in humans. In this study the angiogenic phenotype was characterized, revealing intense angiogenesis in high-grade cervical intraepithelial neoplasias (CIN-3) and carcinomas. MMP-9, a proangiogenic protease implicated in mobilization of VEGF, appeared in the stroma concomitant with the angiogenic switch, expressed by infiltrating macrophages, similar to what has been observed in humans. Preclinical trials sought to target MMP-9 and angiogenesis with a prototypical MMP inhibitor and with a bisphosphonate, zoledronic acid (ZA), revealing both to be antiangiogenic, producing effects comparable to a Mmp9 gene KO in impairing angiogenic switching, progression of premalignant lesions, and tumor growth. ZA therapy increased neoplastic epithelial and endothelial cell apoptosis without affecting hyperproliferation, indicating that ZA was not antimitotic. The analyses implicated cellular and molecular targets of ZA's actions: ZA suppressed MMP-9 expression by infiltrating macrophages and inhibited metalloprotease activity, reducing association of VEGF with its receptor on angiogenic endothelial cells. Given its track record in clinical use with limited toxicity, ZA holds promise as an "unconventional" MMP-9 inhibitor for antiangiogenic therapy of cervical cancer and potentially for additional cancers and other diseases where MMP-9 expression by infiltrating macrophages is evident.
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PMID:An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. 1534 80

Epithelial ovarian cancer is the leading cause of death from gynaecologic malignancies in western countries. In the clinical day treatment decision of the physician (e. g. surgery, chemotherapy) based on individual prognostic factors of the patient with ovarian cancer. The tumor stage at time of diagnosis and the postoperative residual tumor mass are prognostic factors and are unequivocally related to overall survival. Other prognostic factors are identified mostly in small series and are discussed in the literature controversially. This article discussing the value of conventional prognostic factors, as stage, postoperative tumor mass, age, lymph node status, ascites) and newer molecular biological factors, as Her-2-status, PAI-1, MMP, VEGF and CD24.
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PMID:[Conventional and experimental prognostic factors in ovarian cancer]. 1547 50

Despite novel therapies in lung cancer treatment the 5-year survival rate still remains poor. Furthermore, screening concepts for early diagnosis, based on conventional sputum cytology and chest radiography, have so far not demonstrated an impact on decreasing lung-cancer mortality. More specific molecular markers allow new insights in the process of lung carcinogenesis. Furthermore they raise the hope that they provide new tools for early diagnosis and screening of high-risk individuals, determination of prognosis, and identification of innovative treatments. In this review, these perspectives of molecular targets in lung cancer will be discussed and summarised. Angiogenesis-stimulating factors (VEGF, FGF, MMP, etc.), parameters concerning tumour cell proliferation and apoptosis (EGFR, p53, K-ras, rb, bcl-2, etc.) are well known. Several of these genetic factors have already been investigated, but no single parameter has yet gained a sufficient selectivity regarding prognostic significance or therapeutic efficacy. New aspects in the complex tumour-stroma interaction and the interactive, cross-talking signal transduction pathways and recently developed functional genomic approaches, such as DNA microarrays and proteomics might lead to further progress in biological staging models and treatment concepts.
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PMID:Molecular oncology--perspectives in lung cancer. 1555 1

The recent landmark Phase III clinical trial with a VEGF-specific antibody suggests that antiangiogenic therapy must be combined with cytotoxic therapy for the treatment of solid tumors. However, there are no guidelines for optimal scheduling of these therapies. Here we show that VEGFR2 blockade creates a "normalization window"--a period during which combined radiation therapy gives the best outcome. This window is characterized by an increase in tumor oxygenation, which is known to enhance radiation response. During the normalization window, but not before or after it, VEGFR2 blockade increases pericyte coverage of brain tumor vessels via upregulation of Ang1 and degrades their pathologically thick basement membrane via MMP activation.
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PMID:Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. 1560 55

Bone metabolism is regulated not only by the nutrition supplied by vessel but also by the signals from the cells in vascular tissues. Identification of such signaling molecules has been the major issue in the field of research on the relationship between bone and vasculatures. This review touches on the recent findings on the expression and functions of such signaling molecules including VEGF, MMP and non-collagenous bone matrix proteins.
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PMID:[Bone metabolism and angiogenesis]. 1577 33

The present article refers to the mechanism of angiogenesis, a phenomenon which in certain cases is normal, however it usually accompanies the formation of solid cancerous tumors. During the process of angiogenesis, migration, differentiation and proliferation of endothelial cells occurs. In some pathological cases, the most important of which is cancer, the mechanism of angiogenesis is reinforced. It has been observed that a tumor cannot grow without the formation of new blood vessels in the surrounding tissues, which account for blood supply to the tumor. The process of angiogenesis is regulated by chemical signals of the organism, which function as an "angiogenesis switch" regulating the formation of new vasculature. A variety of anti-angiogenic agents which lead to angiogenesis inhibition are found in the clinical trial phase. Among these agents are: i) molecules which inhibit the action of Vascular Endothelial Growth Factors, VEGF, ii) molecules which obstruct migration, differentiation and proliferation of endothelial cells, via their binding to receptors of the alpha(nu)beta(3) integrins and iii) inhibitors of metalloproteinases (MMP). Certain molecules of the above mentioned categories, labeled with radionuclides which emit gamma- radiation or beta- particles or positrons, have been proposed and are being evaluated as possible radiopharmaceuticals, for the visualization of receptors involved in the mechanism of angiogenesis, aiming at the scintigraphic detection of primary or metastatic cancer at an early stage and possibly, aiming at its inhibition/treatment. Regarding the study of angiogenesis the following have been described: a. antibodies targeting VEGF, labeled with radionuclides emitting beta- and/or gamma-radiation, which can be applied for the diagnosis and possibly, for the treatment of cancer, b. peptide derivatives which contain the amino-acid sequence RGD (Arg-Gly-Asp) and compete for the alpha(nu)beta(3) integrins, with the proteins of the stroma. It has been found that these radiolabeled derivatives localize in tumors and can be used for the visualization and, possibly, for the tumor eradication of primary and metastatic cancer.
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PMID:[Angiogenesis in cancer and its detection with radiolabeled biomolecules]. 1588 45

Current treatments are generally ineffective once breast cancer has metastasized; median survival is reduced to 2-3 yr. Previous research studies demonstrating potent synergistic antitumor activity of lysine, proline, ascorbic acid, and epigallocatechin gallate prompted us to investigate the in vivo inhibitory effect of a nutrient mixture containing lysine, proline, arginine, ascorbic acid, and epigallocatechin gallate (NM) on the growth of human cancer xenografts in female athymic nude mice. Five to six week old female mice were inoculated with 3x106 breast cancer cells MDA-MB-231. After injection, the mice were randomly divided into two groups A and B; group A was fed a regular diet and group B with the regular diet supplemented with 0.5% of the nutrient mixture (NM). Four weeks later, the mice were sacrificed, and their tumors were excised, weighed, and processed for histology. We also tested the effect of NM in vitro on estrogen-receptor positive (ER+) MCF-7 and estrogen-receptor negative (ER-) MDA-MB-231 breast cancer cell lines by measuring: cell proliferation by MTT assay, expression of MMPs by gelatinase zymography, invasion through Matrigel, and VEGF by ELISA. MCF-7 cells were also treated with estradiol to study enhanced invasion and expression of MMPs and VEGF. Results showed that NM inhibited the growth and reduced the size of tumors in female nude mice by 27%. Furthermore, histological evaluation revealed increased mitotic index, MMP-9 and VEGF secretion, and PAS material (mucin) in the control group tissues. In vitro studies showed NM inhibited MDA-MB-231 cell growth by 34% at 500 microg/mL and MCF-7 cell growth by 18% at 1000 microg/mL. Invasion of MDA-MB-231 through Matrigel was inhibited by 50%, 60%, and 95% by 10, 50, and 100 microg/mL of NM, respectively. The results of this study demonstrated that the nutrient mixture tested significantly suppressed tumor growth of breast cancer cells in female athymic nude mice and significantly inhibited MMP expression, angiogenesis, and invasion in breast cancer cells, in vitro, offering promise for therapeutic use in the treatment of breast cancer.
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PMID:In vitro and in vivo antitumorigenic activity of a mixture of lysine, proline, ascorbic acid, and green tea extract on human breast cancer lines MDA-MB-231 and MCF-7. 1596 75

Degradation of extracellular matrix (ECM) is a hallmark of tumor invasion, metastasis and angiogenesis. Based on the Rath multitargeted approach to cancer using natural substances to control ECM stability and enhancing its strength, we developed a novel formulation (NM) of lysine, proline, ascorbic acid and green tea extract that has shown significant anti-cancer activity against a number of cancer cell lines. The aim of the present study was to determine whether NM exhibits anti-angiogenic and anti-metastatic effects using in vitro and in vivo experimental models. Angiogenesis was measured using a chorioallantoic membrane (CAM) assay in chick embryos and bFGF-induced vessel growth in C57BL/6J female mice. To determine the in vivo effect of NM on the tumor xenograft growth, male nude mice were inoculated with 3 x 10(6) MNNG-HOS cells. Control mice were fed a mouse chow diet, while the test group was fed a mouse chow diet supplemented with 0.5% NM for 4 weeks. In vitro studies on cell proliferation (MTT assay), MMP expression (zymography) and Matrigel invasion were conducted on human osteosarcoma U2OS, maintained in McCoy medium, supplemented with 10% FBS, penicillin and streptomycin in 24-well tissue culture plates and tested with NM at 0, 10, 50, 100, 500, and 1000 microg/ml in triplicate at each dose. NM at 250 microg/ml caused a significant (p<0.05) reduction in bFGF-induced angiogenesis in CAM. NM inhibited tumor growth of osteosarcoma MNNG-HOS cell xenografts in nude mice by 53%; furthermore, tumors in NM-treated mice were less vascular and expressed lower levels of VEGF and MMP-9 immunohistochemically than tumors in the control group. In addition, NM exhibited a dose-dependent inhibition of osteosarcoma U2OS cell proliferation (up to 60% at 1000 microg/ml), MMP-2 and -9 expression (with virtual total inhibition at 500 microg/ml NM), and invasion through Matrigel (with total inhibition at 100 microg/ml NM). Moreover, NM decreased U2OS cell expression of VEGF, angiopoietin-2, bFGF, PDGF and TGFbeta-1. These results together with our earlier findings suggest that NM is a relatively non-toxic formulation, which inhibits growth, invasion, metastasis, and angiogenesis of tumor cells.
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PMID:Inhibitory effect of a mixture containing ascorbic acid, lysine, proline and green tea extract on critical parameters in angiogenesis. 1614 36

Pancreatic cancer is one of the most lethal tumours of the gastrointestinal tract. The ability to predict which patients would benefit most from surgical intervention and/or chemotherapy would be a great clinical asset. Considerable research has focused on identifying molecular events in pancreatic carcinogenesis, and their correlation with clinicopathological variables of pancreatic tumours and survival. This systematic review examined evidence from published manuscripts looking at molecular markers in pancreatic cancer and their correlation with tumour stage and grade, response to chemotherapy and long-term survival. A literature search was undertaken using PubMed and MEDLINE search engines, using the keywords p53, p21, p16, p27, SMAD4, K-ras, cyclin D1, Bax, Bcl-2, EGFR, EGF, c-erbB2, HB-EGF, TGFbeta, FGF, MMP, uPA, cathepsin, heparanase, E-cadherin, laminins, integrins, TMSF, CD44, cytokines, angiogenesis, VEGF, IL-8, beta-catenin, DNA microarray, and gene profiling. A bewildering number of biomarkers are currently under evaluation. For the most part, the evidence regarding their application as prognostic indicators is conflicting. The advent of gene microarray and mass spectrometric protein profiling offers the potential to examine many different biomarkers simultaneously. This 'protein/gene signature' could revolutionise work in this field and allow researchers to develop accurate and reproducible predictions of survival based on protein or gene profiles.
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PMID:Molecular prognostic markers in pancreatic cancer: a systematic review. 1614 90


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