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

Proteoglycans (PGs) are implicated in the growth and progression of malignant tumors. In this study, we examined the concentration and localization of PGs in advanced (stage IV) laryngeal squamous cell carcinoma (LSCC) and compared with human normal larynx (HNL). LSCC and HNL sections were examined immunohistochemically with a panel of antibodies, and tissues extracts were analyzed by biochemical methods including immunoblotting and high performance liquid chromatography (HPLC). The results demonstrated significant destruction of cartilage in LSCC, which was followed by marked decrease of aggrecan and link protein. In contrast to the loss of aggrecan in LSCC, accumulation of versican and decorin was observed in the tumor-associated stroma. Biochemical analyses indicated that aggrecan, versican, decorin and biglycan comprise the vast majority of total PGs in both healthy and cancerous tissue. In LSCC the absolute amounts of KS/CS/DS-containing PGs were dramatically decreased about 18-fold in comparison to HNL. This decrease is due to the loss of aggrecan. Disaccharide analysis of CS/DSPGs from LSCC showed a significant reduction of 6-sulfated Delta-disaccharides (Deltadi-6S) with a parallel increase of 4-sulfated Delta-disaccharides (Deltadi-4S) as compared to HNL. The obtained data clearly demonstrate that tumor progression is closely related to specific alteration of matrix PGs in LSCC. The altered composition of PGs in cartilage, as well as in tumor-associated stroma, is crucial for the biological behaviour of cancer cells in the diseased tissue.
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PMID:Matrix proteoglycans are markedly affected in advanced laryngeal squamous cell carcinoma. 1519 96

ADAMTS1 is an extracellular metalloproteinase known to participate in a variety of biological processes that includes inflammation, angiogenesis, and development of the urogenital system. Many of its functions rely on its catalytic activity, which thus far has been limited to the cleavage of the matrix proteoglycans aggrecan and versican. However, it is likely that other substrates exist. Using a yeast two-hybrid screen, we identified the Kunitz-type inhibitor, tissue factor pathway inhibitor-2 (TFPI-2), as a binding partner of ADAMTS1. The interaction was confirmed by several biochemical and cell-based assays. In addition, our studies revealed alterations in the pattern of TFPI-2-secreted isoforms and in its extracellular location caused by the specific action of ADAMTS1. Interestingly, we found that TFPI-2 is a novel substrate of ADAMTS1. The cleavage removes a protease-sensitive C-terminal region in TFPI-2, altering its binding properties. The proposed role of TFPI-2 as a maintenance factor of extracellular remodeling suggests the indirect function of ADAMTS1 as an additional homeostatic player by its ability to alter the extracellular location of TFPI-2 and, therefore, to disrupt the remodeling machinery, a phenomenon directly associated to pathologies such as atherosclerosis and tumor progression.
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PMID:ADAMTS1 interacts with, cleaves, and modifies the extracellular location of the matrix inhibitor tissue factor pathway inhibitor-2. 1664 Oct 89

Pancreatic carcinoma (PC) is a cancer type with highly malignant growth and dissemination pattern of which the mechanisms are poorly understood. However, the malignant phenotype is closely linked to extracellular matrix (ECM) of which proteoglycans (PGs) and hyaluronan (HA) play a crucial role in the control of tumor progression and metastasis. In this study, we demonstrated that versican and decorin, two different PGs with contradictory roles and functions in the pathobiology of cancer, were the main matrix PGs in PC presenting a great increase 27- and 7-fold, respectively, in comparison to normal pancreas (NP). PC was characterized by the disproportional increase of versican compared to decorin, about 4 to 1, with a concurrent increase of HA, which may be closely associated with the growth and aggressiveness of this carcinoma. Significant specific post-translational modifications were also observed in both versican and decorin regarding the type, hydrodynamic size, sulfation pattern and extent of uronate epimerization of their glycosaminoglycan chains (GAGs). In particular, chondroitin sulphate (CS) was the predominant GAG type in both PC-associated versican and decorin. The CS of PC-decorin was increased 11-fold, compared to NP in which dermatan sulfate (DS) was the predominant GAG type in both PGs. The sulfation pattern of GAG chains was significantly altered in PC, since 6-sulfated disaccharides predominated in both versican and decorin with a marked presence of non-sulfated disaccharides accompanied by lower hydrodynamic sizes of both CS and DS chains compared to NP. In conclusion, all these findings agree with the highly malignant phenotype of this cancer and, thus, more studies need to be addressed on the roles of the post-translational modifications of versican and decorin in the biology of cancer.
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PMID:The greatly increased amounts of accumulated versican and decorin with specific post-translational modifications may be closely associated with the malignant phenotype of pancreatic cancer. 1673 Sep 6

Elevated concentrations of hyaluronan are often associated with human breast cancer malignancy. Here, we investigated the roles of hyaluronan in carcinogenesis and cancer progression using the mouse mammary tumor virus (MMTV)-Neu transgenic model of spontaneous breast cancer. Conditional transgenic mice that express murine hyaluronan synthase 2 (Has2) by Cre-mediated recombination were generated and crossed with the MMTV-Neu mice. In expressing Cre recombinase under the control of the MMTV promoter, the bigenic mice bearing Has2 and neu transgenes exhibited a deposition of hyaluronan matrix and aggressive growth of Neu-initiated mammary tumors. Notably, forced expression of Has2 impaired intercellular adhesion machinery and elicited cell survival signals in tumor cells. Concurrent with these alterations of tumor cells, intratumoral stroma and microvessels were markedly induced. To reveal the molecular basis of hyaluronan-mediated neovascularization, various hyaluronan samples were examined for their ability to potentiate in vivo angiogenesis. In Matrigel plug assays, basic fibroblast growth factor-induced neovascularization was elevated in the presence of either hyaluronan oligosaccharides or a hyaluronan aggregate containing versican. Administration of hyaluronan-versican aggregates, but not native hyaluronan alone, promoted stromal cell recruitment concurrently with the infiltration of endothelial cells. Taken together, these results suggest that hyaluronan overproduction accelerates tumor angiogenesis through stromal reaction, notably in the presence of versican.
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PMID:Hyperproduction of hyaluronan in neu-induced mammary tumor accelerates angiogenesis through stromal cell recruitment: possible involvement of versican/PG-M. 1732 91

Larynx is a complicated organ with peculiar properties, having a noticeable impact in vocal and respiratory physiology. In squamous cell laryngeal carcinoma, the extracellular matrix components underwent significant modifications concerning their fine chemical structure. Degradation of aggrecan is observed, whereas versican and decorin amounts are increased. The expression of aggrecan is almost totally ceased in later cancer stages, whereas decorin is expressed in normal and cancerous samples. But its expression is increased in cancer, being related to cancer stage. However, the expression of versican seems to be characteristic of the tumor, since none or traces expression is observed in normal samples. Chondroitin/dermatan sulfate is the major glycosaminoglycan, but its sulfation shows a shift from C6 position of galactosamine in normal samples to C4 in malignancy. Dermatan sulfate represents minor amounts in normal samples but increases in proportion up to one-fourth of total sulfated glycosaminoglycans in malignancy. In addition, an increase in the amounts of hyaluronan is also observed in malignant samples. Accumulated data demonstrate that tumor progression is closely related to the alteration of the expression and biochemical composition of specific extracellular constituents that describes the mild aggressive phenotype of squamous cell laryngeal carcinoma.
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PMID:Biochemical changes of extracellular proteoglycans in squamous cell laryngeal carcinoma. 1866 51

ADAMs and ADAMTSs are multi-domain proteins characterised by the presence of both metalloproteinase and disintegrin-like domains. ADAM proteins are usually type 1 transmembrane proteins, and ADAMTSs are secreted from cells. The dysregulated expression of ADAMs and ADAMTSs has been reported in a wide range of human cancers, where, in many cases, they are implicated as positive regulators of cancer progression. Proteolytically active ADAMs act as ectodomain sheddases, which release extracellular regions of membrane-bound proteins (e.g., adhesion molecules, growth factors, cytokines, chemokines and receptors). Certain ADAMTSs break down extracellular matrix (ECM) proteoglycans (e.g., aggrecan, brevican and versican). Through these actions they are able to sculpt the tumour microenvironment and modulate key processes involved in cancer progression, including cell proliferation, migration and angiogenesis. Members of both groups of protein can also act to inhibit or slow cancer progression: ADAMs can interact with specific integrins to elicit inhibitory effects on cancer dissemination, and certain ADAMTSs possess antiangiogenic activity, which prevents an increase in tumour size. This review covers recent developments in the involvement of ADAM and ADAMTS proteins in human cancer.
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PMID:ADAMs and ADAMTSs in cancer. 1963 55

Proteoglycans are ubiquitous components of the extracellular matrix and cell surface, and may mediate tumor progression and metastasis. The aim of this study was to evaluate the expression of syndecan-1 and versican in epithelial ovarian cancer. We immunohistochemically evaluated the expression of syndecan-1 and versican in 111 patients with epithelial ovarian cancer, and analyzed the correlation of this expression with various observed clinicopathological features, including patient outcome. There is a significant correlation between primary and metastatic sites with respect to syndecan-1 and versican expression. Epithelial syndecan-1 expression was significantly lower in patients with advanced disease. Epithelial versican expression was significantly higher in patients with early disease, especially in clear cell adenocarcinoma patients. Stromal syndecan-1 and versican expression was significantly higher in patients with advanced disease. Multivariate analysis showed that negative epithelial syndecan-1 expression was an independent prognostic factor for progression-free survival. Stromal syndecan-1 and versican co-expression was of borderline significance for progression-free and overall survival. Loss of epithelial syndecan-1 expression and induction of stromal syndecan-1 and versican expression may be associated with tumor progression in epithelial ovarian cancer. Syndecan-1 and versican expression status can serve as an indicator of prognosis in patients with epithelial ovarian cancer.
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PMID:Clinical significance of syndecan-1 and versican expression in human epithelial ovarian cancer. 2020 74

Cervical carcinoma is the second most frequent cancer type in women worldwide. Both inflammatory cells and stromal cells are important for tumor progression. Stromal cells produce growth factors and extracellular matrix and provide an adequate environment for angiogenesis. Versican, a member of the extracellular matrix, has been shown to have a role in tumor progression. The aim of this study was to investigate versican expression, and its association with tumor-infiltrating inflammatory cell subsets and with clinicopathological parameters in human cervical cancers. We have studied the expression of versican in 149 cervical cancers using immunohistochemistry and mRNA in situ hybridization. Versican was predominantly expressed in the stroma (myofibroblasts). Using quantitative real-time-PCR, V0 was found to be the most prominent isoform. High stromal versican expression was significantly associated with a low number of tumor-infiltrating T cells (P=0.018) and particularly a low number of CD8-positive T cells (cytotoxic T cells; P=0.002). Stromal versican expression was significantly higher in patients with an infiltration depth >14 mm (P=0.004) and in patients with parametrial invasion (P=0.044). Stromal versican expression was not associated with survival. Our results suggest that versican expression in the stromal compartment of cervical cancers results in reduced numbers of intraepithelial CD8-positive T cells and enhanced local invasion.
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PMID:Versican expression is associated with tumor-infiltrating CD8-positive T cells and infiltration depth in cervical cancer. 2072 14

The expression of proteoglycans (PGs), essential macromolecules of the tumor microenvironment, is markedly altered during malignant transformation and tumor progression. Synthesis of stromal PGs is affected by factors secreted by cancer cells and the unique tumor-modified extracellular matrix may either facilitate or counteract the growth of solid tumors. The emerging theme is that this dual activity has intrinsic tissue specificity. Matrix-accumulated PGs, such as versican, perlecan and small leucine-rich PGs, affect cancer cell signaling, growth and survival, cell adhesion, migration and angiogenesis. Furthermore, expression of cell-surface-associated PGs, such as syndecans and glypicans, is also modulated in both tumor and stromal cells. Cell-surface-associated PGs bind various factors that are involved in cell signaling, thereby affecting cell proliferation, adhesion and motility. An important mechanism of action is offered by a proteolytic processing of cell-surface PGs known as ectodomain shedding of syndecans; this facilitates cancer and endothelial cell motility, protects matrix proteases and provides a chemotactic gradient of mitogens. However, syndecans on stromal cells may be important for stromal cell/cancer cell interplay and may promote stromal cell proliferation, migration and angiogenesis. Finally, abnormal PG expression in cancer and stromal cells may serve as a biomarker for tumor progression and patient survival. Enhanced understanding of the regulation of PG metabolism and the involvement of PGs in cancer may offer a novel approach to cancer therapy by targeting the tumor microenvironment. In this minireview, the implication of PGs in cancer development and progression, as well as their pharmacological targeting in malignancy, are presented and discussed.
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PMID:Proteoglycans in health and disease: novel roles for proteoglycans in malignancy and their pharmacological targeting. 2084 May 87

There is increasing evidence to suggest that extracellular matrix (ECM) components play an active role in tumor progression and are an important determinant for the growth and progression of solid tumors. Tumor cells interfere with the normal programming of ECM biosynthesis and can extensively modify the structure and composition of the matrix. In ovarian cancer alterations in the extracellular environment are critical for tumor initiation and progression and intra-peritoneal dissemination. ECM molecules including versican and hyaluronan (HA) which interacts with the HA receptor, CD44, have been shown to play critical roles in ovarian cancer metastasis. This review focuses on versican, HA, and CD44 and their potential as therapeutic targets for ovarian cancer.
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PMID:Role of versican, hyaluronan and CD44 in ovarian cancer metastasis. 2154 Oct 39


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