Tissue level, activation and cellular localisation of TGF-β1 and association with survival in gastric cancer patients

Hawinkels, Lukas J.A.C.; Verspaget, Hein W.; Duijn, Wim van; Zon, J. M. Van Der; Zuidwijk, Kim; Kubben, F. J. G. M.; Verheijen, J.H.; Hommes, Daan W.; Lamers, C. B. H. W.; Sier, Cornelis F.M.

doi:10.1038/sj.bjc.6603877

Cited by 82 publications

(78 citation statements)

References 43 publications

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“…These findings were also associated with a poor prognosis for the patients. 45 Similar observations have been made in ovarian and colon carcinomas. 46,47 A strong local upregulation of the PA-system mediated through uPAR could in turn not only activate other proteases but also be important stimulators of cell proliferation and angiogenesis.…”

Section: Discussionsupporting

confidence: 71%

Prognosis in adenocarcinomas of lower oesophagus, gastro‐oesophageal junction and cardia evaluated by uPAR‐immunohistochemistry

Lærum

Øvrebø

Skarstein

et al. 2011

Intl Journal of Cancer

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Adenocarcinomas of lower oesophagus, gastro‐oesophageal junction and cardia in humans are highly invasive tumours with poor prognosis. The localisation of urokinase‐type plasminogen activator receptor (uPAR) was determined in 66 patients; 60 with adenocarcinomas and six cases with Barrett's oesophagus. uPAR was expressed in nearly all cases of invasive adenocarcinomas by populations of cancer cells, macrophages and myofibroblasts at both the invasion front and the tumour core. In areas with high‐grade dysplasia or with Barrett's metaplasia adjacent to the tumour tissue, no uPAR‐immunoreactivity was found. High local expression of uPAR, therefore, appears to be a characteristic marker for invasive behaviour in this tumour, suggesting that uPAR's contribution to matrix degradation during invasive growth is a late event in carcinogenesis. Using a scoring system for semiquantitative estimation of uPAR‐positivity on immmunohistochemically stained specimens, a significant association was found between poor overall survival and high uPAR‐score for cancer cells in the tumour core and for macrophages peripherally at the tumour invasion zone. In multivariate analysis, these two uPAR‐scores were confirmed as highly significant prognostic parameters independent of Tumour, Node, Metastasis (TNM)‐stage and World Health Organization (WHO) classification. The proteolytic action of these malignant and nonmalignant accessory cells thus seemed to follow two main patterns: one dominated by uPAR positive cancer cells and one by uPAR‐positive macrophages. Scoring of uPAR‐positivity might be a useful parameter for onset of invasion and prognosis in these adenocarcinomas.

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Section: Discussionsupporting

confidence: 71%

Prognosis in adenocarcinomas of lower oesophagus, gastro‐oesophageal junction and cardia evaluated by uPAR‐immunohistochemistry

Lærum

Øvrebø

Skarstein

et al. 2011

Intl Journal of Cancer

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show abstract

“…A-77 significantly inhibited the invasiveness of cancer cells with or without TGFh. Because gastric cancer cells produce TGFh1 (33,34), A-77 might decrease the autocrine manner of invasion ability for gastric cancer cells. The pathologic findings of the peritoneal nodules showed diffuse infiltration of cancer cells with the fibrous stroma on a control mouse.…”

Section: Discussionmentioning

confidence: 99%

A Novel Transforming Growth Factor β Receptor Kinase Inhibitor, A-77, Prevents the Peritoneal Dissemination of Scirrhous Gastric Carcinoma

Kawajiri

Yashiro

Shinto

et al. 2008

Clinical Cancer Research

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Purpose: Transforming growth factor h receptor (TGFh-R) is reported to correlate with the malignant potential of scirrhous gastric carcinoma. The aim of the current study is to clarify the possibility of molecular target therapy with a TGFh-R inhibitor, A-77, for the treatment of peritoneal dissemination of scirrhous gastric cancer. Experimental Design: Three scirrhous gastric cancer cell lines and two fibroblasts were used. For in vivo experiments, the A-77 was administered i.p. to mouse models of peritoneal dissemination. The influences of A-77 on the adhesion ability, invasion ability, and the expression of adhesion molecules were examined in vitro.Results: The A-77 administration resulted in a significantly (P < 0.01) better prognosis for the mice with peritoneal dissemination (median survival time, 51 days), compared with the control (median survival time, 25 days). A-77 therefore significantly (P < 0.01) decreased the weight and number of metastatic nodes. The adhesive ability and invasion ability of cancer cells were significantly decreased by A-77. A-77 decreased the expression of a 2 , a 3 , and a 5 integrins in gastric cancer cells. The histologic findings showed the degree of fibrosis to be less in the tumors treated by A-77. A-77 decreased the growth of fibroblast and invasion-stimulating activity of fibroblasts on cancer cells. Conclusion:TheTGFh-R inhibitor, A-77, decreased the expression of integrins in cancer cells and the proliferation of fibroblasts, which resulted in the decreased adhesive and invasive abilities of scirrhous gastric cancer cells to peritoneum. A-77 is thus considered to be useful for the inhibition of peritoneal dissemination of scirrhous gastric carcinoma.

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“…To determine tissue localization of endoglin, immunohistochemistry was performed as previously described (23). Representative photomicrographs were taken with a Nikon Eclipse E900 microscope equipped with a Nikon DXM1200 digital camera.…”

Section: Methodsmentioning

confidence: 99%

Matrix Metalloproteinase-14 (MT1-MMP)–Mediated Endoglin Shedding Inhibits Tumor Angiogenesis

et al. 2010

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Endoglin is a transforming growth factor-β coreceptor with a crucial role in angiogenesis. A soluble form of endoglin is present in the circulation, but the role of soluble endoglin (sEndoglin) is poorly understood. In addition, the endoglin shedding mechanism is not known. Therefore, we examined the role of sEndoglin in tumor angiogenesis and the mechanism by which the extracellular domain of endoglin is released from the membrane. In colorectal cancer specimens, we observed high endothelial endoglin protein expression, accompanied with slightly lower sEndoglin levels in the circulation, compared with healthy controls. In vitro analysis using endothelial sprouting assays revealed that sEndoglin reduced spontaneous and vascular endothelial growth factorinduced endothelial sprouting. Human umbilical vascular endothelial cells were found to secrete high levels of sEndoglin. Endoglin shedding was inhibited by matrix metalloproteinase (MMP) inhibitors and MMP

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Tissue level, activation and cellular localisation of TGF-β1 and association with survival in gastric cancer patients

Cited by 82 publications

References 43 publications

Prognosis in adenocarcinomas of lower oesophagus, gastro‐oesophageal junction and cardia evaluated by uPAR‐immunohistochemistry

Prognosis in adenocarcinomas of lower oesophagus, gastro‐oesophageal junction and cardia evaluated by uPAR‐immunohistochemistry

A Novel Transforming Growth Factor β Receptor Kinase Inhibitor, A-77, Prevents the Peritoneal Dissemination of Scirrhous Gastric Carcinoma

Matrix Metalloproteinase-14 (MT1-MMP)–Mediated Endoglin Shedding Inhibits Tumor Angiogenesis

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