Expression of heparanase gene, CD44v6, MMP-7 and<i>nm23</i>protein and their relationship with the invasion and metastasis of gastric carcinomas

Chen, Junqiang; Zhan, Wei; He, Yulong; Peng, Junsheng; Wang, Jianping; Cai, Shirong; Ma, Jingfei

doi:10.3748/wjg.v10.i6.776

Cited by 52 publications

(37 citation statements)

References 32 publications

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“…Heparanase upregulation correlated with reduced postoperative survival of pancreatic, 16 bladder, 17 gastric, 18 cervical 19 and colorectal 20 cancer patients. Similarly, heparanase upregulation correlated with increased lymph node and distant metastases, 17,18,[21][22][23][24][25] providing a strong clinical support for the prometastatic feature of heparanase.…”

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confidence: 80%

“…Fractions (0.2 ml) were eluted with PBS and their radioactivity counted in a l-scintillation counter. Degradation fragments of heparan sulfate side chains generated by heparanase are eluted at 0.5oK av o0.8 (peak II, fractions [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. Nearly intact heparan sulfate proteoglycans are eluted just after the Vo (K av o0.2, peak I, fractions 3-15).…”

Section: Heparanase Activity Assaymentioning

confidence: 99%

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Spatial and temporal heparanase expression in colon mucosa throughout the adenoma-carcinoma sequence

Doviner

Maly

Kaplan³

et al. 2006

Modern Pathology

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Heparanase is a mammalian endo-b-D-glucuronidase that cleaves heparan sulfate side chains at a limited number of sites. Such enzymatic activity is thought to participate in degradation and remodeling of the extracellular matrix and to facilitate cell invasion associated with tumor metastasis, angiogenesis and inflammation. Traditionally, heparanase activity was well correlated with the metastatic potential of a large number of tumor-derived cell types. More recently, heparanase upregulation has been documented in an increasing number of primary human tumors, correlating with poor postoperative survival and increased tumor vascularity. Here, we employed antiheparanase 733 polyclonal antibody that preferentially recognizes the 50 kDa active heparanase subunit over the 65 kDa proenzyme, as well as anti-heparanase 92.4 monoclonal antibody that recognizes both the latent and the active enzyme, to follow heparanase expression, processing and localization throughout the adenoma-carcinoma transition of the colon epithelium. Normal (nondysplastic) mucosa of the large bowel near epithelial neoplasms, as well as areas of mild dysplasia in adenomas, exhibited a strong reactivity with antibody 733 that became even stronger in foci of moderate dysplasia. Interestingly, although reactivity with antibody 733 was markedly reduced in severe dysplasia and in colorectal carcinoma, response to antibody 92.4 exhibited the opposite trend and staining intensities increased in parallel with tumor stage, the highest being in carcinoma cells. Involvement of latent heparanase (detected by 92.4, but not by 733 antibody) in tumor progression was suggested by activation of the Akt/PKB signal transduction pathway upon heparanase overexpression or exogenous addition to HT29 human colon carcinoma cells. These results suggest that heparanase expression is induced during colon carcinogenesis, and that its processing, conformation and localization are tightly regulated during the course of colon adenoma-carcinoma progression. Heparanase is an endoglycosidase that specifically cleaves heparan sulfate side chains of heparan sulfate proteoglycans. 1,2 Heparan sulfate proteoglycans consist of a protein core to which several heparan sulfate side chains are covalently attached. These complex macromolecules are highly abundant in the extracellular matrix and are thought to play an important structural role, contributing to extracellular matrix integrity and insolubility. 3 In addition, heparan sulfate side chains can bind to a variety of biological mediators such as growth factors, cytokines and chemokines, 4,5 thus functioning as a readily available reservoir that can be liberated upon local or systemic cues. Moreover, heparan sulfate proteoglycans on the cell surface participates directly in signal-transduction cascades by potentiating the interaction between certain growth factors and their receptors. 6-9 Heparan sulfate-degrading activity is thus expected to affect several fundamental aspects of cell behavior under normal and clinical settings. 1,2 Tr...

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confidence: 80%

Section: Heparanase Activity Assaymentioning

confidence: 99%

Spatial and temporal heparanase expression in colon mucosa throughout the adenoma-carcinoma sequence

Doviner

Maly

Kaplan³

et al. 2006

Modern Pathology

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“…Gastric cancer patients with the AG/GG genotype were significantly more often Hp-positive, which might indicate an enhanced susceptibility for this bacterium. The presence of Hp is associated with the development of gastric cancer and stimulation of MMP-7 production by Hp in human gastric epithelial cells has previously been suggested as a possible mechanism predisposing towards gastric neoplasia (Wroblewski et al, 2003;Chen et al, 2004). Tissue inhibitor of metalloproteinase-2 is involved in the regulation of MMP-2 activity (Howard et al, 1991;Wang et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Clinical impact of MMP and TIMP gene polymorphisms in gastric cancer

et al. 2006

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Gastric cancers express enhanced levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Single-nucleotide polymorphisms (SNPs) in MMP and TIMP genes may be associated with disease susceptibility and might also affect their antigen expression. We studied the genotype distribution and allele frequencies of SNPs of MMP-2, -7, -8 and -9 and TIMP-1 and -2 in gastric cancer patients in relation to tumour progression, patient survival and tissue antigen expression. The genotype distribution and allele frequencies were similar in gastric cancer patients and controls, except for MMP-7 À181A4G . In addition, the genotype distribution of MMP-7 À181A4G was associated with Helicobacter pylori status (w 2 7.8, P ¼ 0.005) and tumour-related survival of the patients. Single-nucleotide polymorphism TIMP-2 303C4T correlated significantly with the WHO classification (w 2 5.9, P ¼ 0.03) and also strongly with tumour-related survival (log rank 11.74, P ¼ 0.0006). Single-nucleotide polymorphisms of MMP-2, -8, -9 and TIMP-1 were not associated with tumour-related survival. Only the gene promoter MMP-2 À1306C4T polymorphism correlated significantly with the protein level within the tumours. First-order dendrogram cluster analysis combined with Cox analysis identified the MMP-7 À181A4G and TIMP-2 303C4T polymorphism combination to have a major impact on patients survival outcome. We conclude that MMP-related SNPs, especially MMP-7 À181A4G and TIMP-2 303C4T , may be helpful in identifying gastric cancer patients with a poor clinical outcome.

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“…Altered DNA copy number status or expression of several genes, such as CD44, p27 kip1 , Bax, VEGF, nm23, TNFRSF6B and several matrix metalloproteinases (MMPs), is associated with lymph node metastasis in gastric cancer [7][8][9][10][11][12][13][14][15][16][17]. In addition, genomewide mRNA expression analyses have been performed in order to determine genetic signatures correlated with lymph node status in gastric cancer patients [18,19].…”

Section: Introductionmentioning

confidence: 99%

Losses of Chromosome 5q and 14q Are Associated with Favorable Clinical Outcome of Patients with Gastric Cancer

et al. 2012

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Purpose. To improve the clinical outcome of patients with gastric cancer, intensified combination strategies are currently in clinical development, including combinations of more extensive surgery, (neo)adjuvant chemotherapy, and radiotherapy. The present study used DNA copy number profiling to identify subgroups of patients with different clinical outcomes. We hypothesize that, by identification of subgroups, individual treatment strategies can be selected to improve clinical outcome and to reduce unnecessary treatment toxicity for patients with gastric cancer.Experimental Design. DNA from 206 gastric cancer patients was isolated and analyzed by genomewide array comparative genomic hybridization. DNA copy number profiles were correlated with lymph node status and patient survival. In addition, heat shock protein 90 (HSP90) expression was analyzed and correlated with survival in 230 gastric cancer patients.Results. Frequent (>20%) DNA copy number gains and losses were observed on several chromosomal regions. Losses on 5q11.2-q31.3 and 14q32.11-q32.33 (14% of patients) were correlated with good clinical outcome in univariate and multivariate analyses, with a median diseasefree survival interval of 9.2 years. In addition, loss of expression of HSP90, located on chromosome 14q32.2, was correlated with better patient survival. Conclusion. Genomewide DNA copy number profiling allowed the identification of a subgroup of gastric cancer patients, marked by losses on chromosomes 5q11.2-q31.3 and 14q32.11-q32.33 or low HSP90 protein expression, with an excellent clinical outcome after surgery alone. We hypothesize that this subgroup of patients most likely will not benefit from (neo)adjuvant systemic treatment and/or radiotherapy, whereas anti-HSP90 therapy may have clinical potential in patients with HSP90-expressing gastric cancer, pending validation in an independent dataset. The Oncologist 2012;17:653-662

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Expression of heparanase gene, CD44v6, MMP-7 andnm23protein and their relationship with the invasion and metastasis of gastric carcinomas

Cited by 52 publications

References 32 publications

Spatial and temporal heparanase expression in colon mucosa throughout the adenoma-carcinoma sequence

Spatial and temporal heparanase expression in colon mucosa throughout the adenoma-carcinoma sequence

Clinical impact of MMP and TIMP gene polymorphisms in gastric cancer

Losses of Chromosome 5q and 14q Are Associated with Favorable Clinical Outcome of Patients with Gastric Cancer

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