Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of proteases in the tumor cell invasion process is multifaceted. Members of the matrix metalloproteinase (MMP) family have been implicated in primary and metastatic tumor growth, angiogenesis, and degradation of extracellular matrix (ECM) components. Differentiating between the up-regulation of MMP production and the presence of activated MMPs can be difficult but may well dictate which MMPs are critical to invasion. Because the hydrolysis of collagens is one of the committed steps in ECM turnover, we have investigated selective MMP action on collagenous substrates as a means to evaluate active MMPs. Two triple-helical peptide (THP) models of the MMP-9 cleavage site in type V collagen, alpha1(V)436-450 THP and alpha1(V)436-447 fTHP, were hydrolyzed by MMP-2 and MMP-9 at the Gly-Val bond, analogous to the bond cleaved by MMP-9 in the corresponding native collagen. Kinetic analyses showed k(cat)/K(m) values of 14,002 and 5,449 s(-1)m(-1) for MMP-2 and -9 hydrolysis of alpha1(V)436-447 fTHP, respectively. These values, along with individual k(cat) and K(m) values, are comparable with collagen hydrolysis by MMP-2 and -9. Neither THP was hydrolyzed by MMP-1, -3, -13, or -14. alpha1(V)436-447 fTHP and a general fluorogenic THP were used to screen for triple-helical peptidase activity in alpha(2)beta(1) integrin-stimulated melanoma cells. Binding of the alpha(2)beta(1) integrin resulted in the production of substantial triple-helical peptidase activity, the majority (>95%) of which was non-MMP-2/-9. THPs were found to provide highly selective substrates for members of the MMP family and can be used to evaluate active MMP production in cellular systems.
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PMID:Selective hydrolysis of triple-helical substrates by matrix metalloproteinase-2 and -9. 1264 91

The tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) has been recognized as a multifunctional protein. The role of TIMPs in cancer remains the subject of conflicting reports with an antitumor activity or a tumor growth stimulation activity by several mechanisms. The aim of our study is to investigate the effect of ectopic TIMP-1 overexpression on the primary transplanted tumor growth. We employed transgenic mice overexpressing the human TIMP-1 (hTIMP-1) in the liver under control of the albumin promoter/enhancer (TIMP-Tg-mice) and producing high serum levels of TIMP-1. We used the transplantable Ehrlich tumor cells in the current study. The allograft study revealed that the tumor growth in the TIMP-Tg-mice was more significantly inhibited than control (Cont) mice by associated suppression of neovascularization in the tumor. The in vitro studies showed that the recombinant TIMP-1 (rTIMP-1) did not affect the proliferation of the endothelial cells (ECs) and tumor cells, suggesting that the tumor suppressive effect of TIMP-1 was not due to cytotoxicity. TIMP-1 significantly inhibited EC tubular formation in vitro. Furthermore, TIMP-1 treatment did not affect the levels of matrix metalloproteinase (MMP)-2 and MMP-9 mRNA in the Ehrlich tumor cells in vitro, although these expressions in the tumor were markedly suppressed in the TIMP-Tg-mice, compared to the Cont-mice at the end of the experiment. These results suggested that the ectopically overexpressed TIMP-1 inhibited the tumor growth by angiogenesis suppression.
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PMID:Tissue inhibitor of metalloproteinases-1 (TIMP-1) inhibits tumor growth and angiogenesis in the TIMP-1 transgenic mouse model. 1270 67

Matrix metalloproteinases (MMPs) are believed to play a pivotal role in malignant behavior of cancer cells such as rapid tumor growth, invasion, and metastasis by degrading extracellular matrix (ECM). Different types of synthetic inhibitors against MMPs (MMPIs) were developed as candidates for anti-cancer therapeutics and so far clinical trials had led to no significant success. However, this does not diminish the importance of MMPs in the malignancy of cells. Details about MMPs, specifically when and how they take part in the development of cancer are necessary for more advanced application of MMPIs. In this paper, we summarize recent knowledge about membrane-type 1 matrix metalloproteinase (MT1-MMP) which is expressed on cancer cell surface as an invasion-promoting proteinase. By localizing at the leading edge of invasive cancer cells, MT1-MMP degrades components of the tissue barriers. One of the major targets is type I collagen, the most abundant ECM component. Although MT1-MMP itself cannot degrade type IV collagen in the basement membrane, it binds to and activates proMMP-2, one of the type IV collagenases. However, degradation of the ECM is not the sole function of MT1-MMP. MT1-MMP also regulates cell-ECM interaction by processing cell adhesion molecules such as CD44 and integrin alphav chain, and eventually promotes cell migration as well. In addition to the transcriptional regulation, invasion-promoting activity of the MT1-MMP is also strictly monitored at the post-translational level. Precise knowledge about the regulation will give us insight to develop new methods for treating invasive cancer patients.
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PMID:Membrane-type 1 matrix metalloproteinase: a key enzyme for tumor invasion. 1270 53

Oral squamous cell carcinoma (OSCC) is one of the most common head and neck cancers. OSCC generally has a poor prognosis due to its tendency towards local invasion and subsequent metastasis, which is mediated by multiple proteolytic enzymes and angiogenesis. The purpose of this study was to evaluate the anti-cancer effects of genistein, a soybean product known to be an effective natural anti-angiogenic agent, with respect to tumor growth, angiogenesis and in vitro invasion in an OSCC model. Northern blot analysis for vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and matrix metalloproteinase-2 (MMP-2), in vitro invasion assay and gelatin zymography were carried out for HSC-3 cells treated with genistein (27.3 microg/ml). In the animal experiment, genistein (0.5 mg/kg) was injected into tumor (HSC-3)-bearing mice (male balb/c/nu). The tumor growth rate and metastasis to lymph node or lung were compared and the microvessel density (CD31) was subsequently analyzed by immunohistochemistry. The genistein-treated group showed a down-regulation in VEGF mRNA expression, but not in bFGF and MMP-2 mRNA expression. Genistein reduced in vitro invasion through the artificial basement membrane and gelatin zymography also showed a reduced gelatinolytic activity in the genistein-treated group. In the genistein-treated mice, a significantly lower CD31 immunoreactivity was found. However, the tumor growth and metastatic behavior in the experimental group and the control group were similar and there were no significant differences. These results suggest the possible use of genistein as an anti-cancer agent in oral squamous cell carcinoma. However, it appears from the present study that anti-angiogenic therapy consisting of a single application of genistein may not provide a satisfactory treatment for OSCC. As a result, further research is recommended to confirm that genistein may be employed as an adjunct treatment modality for OSCC.
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PMID:Anti-cancer effect of genistein in oral squamous cell carcinoma with respect to angiogenesis and in vitro invasion. 1270

The matrix metalloproteinases (MMPs) constitute a multigene family of over 23 secreted and cell-surface associated enzymes that cleave or degrade various pericellular substrates. In addition to virtually all extracellular matrix (ECM) compounds, their targets include other proteinases, chemotactic molecules, latent growth factors, growth factor-binding proteins and cell surface molecules. The MMP activity is controlled by the physiological tissue inhibitors of MMPs (TIMPs). There is much evidence that MMPs and their inhibitors play a key role during extracellular remodeling in physiological situations and in cancer progression. They have other functions that promoting tumor invasion. Indeed, they regulate early stages of tumor progression such as tumor growth and angiogenesis. Membrane type MMPs (MT-MMPs) constitute a new subset of cell surface-associated MMPs. The present review will focus on MT1-MMP which plays a major role at least, in the ECM remodeling, directly by degrading several of its components, and indirectly by activating pro-MMP2. As our knowledge on the field of MT1-MMP biology has grown, the unforeseen complexities of this enzyme and its interaction with its inhibitor TIMP-2 have emerged, often revealing unexpected mechanisms of action.
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PMID:Membrane type-1 matrix metalloproteinase and TIMP-2 in tumor angiogenesis. 1271 42

The endothelin A receptor (ET(A)R) autocrine pathway is overexpressed in many malignancies, including ovarian carcinoma. In this tumor, engagement of ET(A)R triggers tumor growth, survival, neoangiogenesis, and invasion. To evaluate whether ET(A)R represents a new target in cancer treatment, we examine in vitro and in vivo the effect of the selective ET(A)R antagonist ABT-627 (atrasentan), a small p.o. bioavailable molecule, in mono- and combination therapy with taxane. ABT-627 effectively inhibits cell proliferation, vascular endothelial growth factor (VEGF) secretion of ovarian carcinoma cell lines, and primary cultures. ET(A)R blockade also results in the sensitization to paclitaxel-induced apoptosis. In ovarian carcinoma xenografts, in which the ET-1/ET(A)R autocrine pathway is overexpressed, tumor growth was significantly inhibited in ABT-627-treated mice compared with control. The therapeutic efficacy of ABT-627 was associated with a significant reduction in microvessel density, expression of VEGF, and matrix metalloproteinase-2, and increased the percentage of apoptotic tumor cells. Combined treatment of ABT-627 with paclitaxel produced additive antitumor, apoptotic, and antiangiogenic effects. These findings demonstrate that the small molecule ABT-627 is a candidate for clinical testing as an antitumor agent in ovarian cancer patients, especially in combination with taxane therapy. Interruption of ET(A)R signaling therefore, represents, a promising therapeutic strategy in ovarian carcinoma.
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PMID:Therapeutic targeting of the endothelin a receptor in human ovarian carcinoma. 1275 Feb 65

We demonstrate a physiological role for tumstatin, a cleavage fragment of the alpha3 chain of type IV collagen (Col IValpha3), which is present in the circulation. Mice with a genetic deletion of Col IValpha3 show accelerated tumor growth associated with enhanced pathological angiogenesis, while angiogenesis associated with development and tissue repair are unaffected. Supplementing Col IValpha3-deficient mice with recombinant tumstatin to a normal physiological concentration abolishes the increased rate of tumor growth. The suppressive effects of tumstatin require alphaVbeta3 integrin expressed on pathological, but not on physiological, angiogenic blood vessels. Mice deficient in matrix metalloproteinase-9, which cleaves tumstatin efficiently from Col IValpha3, have decreased circulating tumstatin and accelerated growth of tumor. These results indicate that MMP-generated fragments of basement membrane collagen can have endogenous function as integrin-mediated suppressors of pathologic angiogenesis and tumor growth.
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PMID:Physiological levels of tumstatin, a fragment of collagen IV alpha3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via alphaV beta3 integrin. 1284 77

Progress in molecular pharmacology has demonstrated each anticancer drug to have a unique molecular target. Recent drug development has focused on compounds that specifically inhibit and/or modify tumor-specific molecular biological changes (target-based drug development). These compounds are generally classified as either small molecules or macromolecules. With the exception of antibodies, the majority of recently developed target-based drugs are small molecules. Assessing the effects of these compounds on their targets would probably help researchers to predict the antitumor effects of these anticancer drugs; however, actually assessing this hypothesis, even in preclinical models, is difficult. Most preclinical experiments attempt to show tumor growth inhibition or shrinkage, leading to a longer survival period or higher cure rate. Few experiments have examined the correlation between antitumor activity and the effect of a compound on its target. In phase I clinical trials of target-based drugs, the determination of maximum tolerated dose is not enough; the effect of the drug on its target should also be evaluated. Recently, dose-escalation strategies based on the effects of drugs on their targets have been proposed, even though an appropriate target effect is necessary but not sufficient to demonstrate clinical efficacy. Compounds that are not specifically directed against molecular targets on or within tumor cells, but against blood vessels, matrix, etc., usually do not cause tumor shrinkage. These compounds include angiogenesis inhibitors and matrix metalloproteinase inhibitors and are usually used in combination with other treatments at the start of clinical trials. Whether the methodology of clinical trials is sensitive enough to detect the subtle effects of these compounds remains uncertain. The effects of experimental drugs on their targets are rarely examined in clinical trials. Few data from translational studies are available and data obtained using surrogate tissues do not necessarily reflect the effects of the drugs on in situ tumors. Parameters such as time to progression, changes in tumor markers, and growth rates often vary significantly and are regarded as soft endpoints. Phase III trials evaluating survival benefit require extensive resources, including a large number of patients, a sophisticated data center, and well-trained study groups. The problems and future prospects of novel anticancer drug development are discussed.
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PMID:Strategy for the development of novel anticancer drugs. 1285 52

The name matricryptin was proposed by Davis et al. (2000) for enzymatic fragments of extracellular matrix containing exposed matricryptic sites. The exposure of these sites occurred after structural or conformational modifications. Matricryptins derived from non fibrillar collagens (IV, VIII, XV and XVIII) and from matrix metalloproteinase-2 inhibit angiogenesis and tumor growth. Proteolysis of SPARC releases several peptides which exert opposite effects on angiogenesis. Matricryptins derived from glycosaminoglycans also participate in the control of angiogenesis.
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PMID:[Matricryptins derived from non fibrillar collagens, MMP-2 and SPARC are involved in the control of angiogenesis]. 1286 65

Angiogenesis is essential for tumor growth and metastasis. Because endothelial cells are genetically stable, they rarely acquire resistance to anticancer modalities, and could, thus, be a suitable target for radiation therapy. Heavy ion radiation therapy has attracted attention as an effective modality for cancer therapy because of its highly lethal effects, but the effects of heavy ion irradiation on in vitro cell function associated with angiogenesis have not been reported. Our study found that in vitro angiogenesis was inhibited by high linear energy transfer carbon ion irradiation even at sublethal dose (0.1 Gy). ECV304 and HUVEC human umbilical vascular endothelial cells were irradiated with 290 MeV carbon ion beams of approximately 110 keV/ micro m or 4 MV X-ray of approximately 1 keV/ micro m. Their adhesiveness and migration to vitronectin or osteopontin were inhibited, and capillary-like tube structures in three-dimensional culture were destroyed after carbon ion irradiation concomitant with the inhibition of matrix metalloproteinase-2 activity, down-regulation of alphaVbeta3 integrin, which is one of the adhesion molecules, slight up-regulation of membrane type1- matrix metalloproteinase, and significant up-regulation of tissue inhibitor of metalloproteinase-2. On the other hand, sublethal X-ray irradiation promoted migration of endothelial cells, and the capillary-like tube structure in three-dimensional culture progressed even after 16 Gy irradiation. These results provide an implication that heavy ion beam therapy could be superior to conventional photon beam therapy in preventive effects on in vitro angiogenesis even at sublethal dose, and might inhibit angiogenesis in vivo.
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PMID:Heavy ion irradiation inhibits in vitro angiogenesis even at sublethal dose. 1287 34


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