Enhanced expression of thrombospondin-1 and hypovascularity in human cholangiocarcinoma

Kawahara, Nobuaki; Ono, Masahiro; Taguchi, Kenichi; Okamoto, Masahiro; Shimada, Mitsuo; Takenaka, Katsuto; Hayashi, Kenshi; Mosher, DF; Sugimachi, Keizō; Tsuneyoshi, Masazumi; Kuwano, Michihiko

doi:10.1002/hep.510280610

Cited by 79 publications

(60 citation statements)

References 18 publications

(28 reference statements)

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“…On initial inspection, our results may seem contradictory to Maeda et al (4,26) because we found that the expression of TSP-1 in colorectal liver metastases was negatively prognostic. However, on closer analysis, the differences may be explained by the site of expression of TSP-1.…”

Section: Discussioncontrasting

confidence: 98%

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Expression of Thrombospondin-1 in Resected Colorectal Liver Metastases Predicts Poor Prognosis

Sutton¹,

O’Byrne²,

Goddard³

et al. 2005

Clinical Cancer Research

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Purpose: The aim of this study was to examine the expression and prognostic relevance of thrombospondin-1 (TSP-1) in tumor biopsies taken from a consecutive series of liver resections done at the University Hospitals of Leicester and the Royal Liverpool Hospital. Experimental Design: Patients having undergone a liver resection for colorectal liver metastases at our institutions between 1993 and 1999 inclusive were eligible. Inclusion criteria were curative intent, sufficient tumor biopsy, and patient follow-up data. One hundred eighty-two patients were considered in this study. Standard immunohistochemical techniques were used to study the expression of TSP-1 in 5-Am tumor sections from paraffin-embedded tissue blocks. TSP-1 was correlated with survival using the Kaplan-Meier method and log-rank test for univariate analysis and the Cox proportional hazard model for multivariate analysis. Results: One hundred eighty-two patients (male, n = 122 and female, n = 60) ages between 25 and 81 years (mean, 61 years) were included. TSP-1 was expressed around blood vessels (n = 45, 25%) or in the stroma (n = 59, 33%). No expression was detected in the remaining tumors. TSP-1 significantly correlated with poor survival on univariate (P = 0.01 for perivascular expression and P = 0.03 for stromal expression) and multivariate analysis (P = 0.01 for perivascular expression). Conclusion: TSP-1 is a negatively prognostic factor for survival in resected colorectal liver metastases.Thrombospondin-1 (TSP-1) is a multidomain glycoprotein that modulates platelet aggregation, wound healing, protease activity, and cellular functions such as adhesion, motility, and growth (1). However, the precise function of TSP-1 in the growth of tumors is not straightforward. Evidence suggests that different fragments of the large TSP-1 molecule may individually facilitate different and opposing tumor-modulating properties, such as proangiogenic and antiangiogenic activity (2) and promotion/inhibition of tumor cell migration (3).In colorectal cancer, TSP-1 has been shown to have both an antiangiogenic effect (4, 5) and conversely be associated with venous invasion and tumor progression (6). However, expression of TSP-1 has been associated with increased disease-free survival rates: 84% 5-year survival in primary colorectal tumors expressing TSP-1 compared with 55% in TSP-1-negative tumors in one study (4) and 91% survival versus 44% in TSP-1-negative tumors in another study (5). Studies in breast cancer have described reduced TSP-1 levels in association with more aggressive tumors (3). It is noteworthy that these figures pertain to studies carried out in primary tumors. The aim of this study was to examine the expression and prognostic relevance of TSP-1 in resected colorectal liver metastases.

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Section: Discussioncontrasting

confidence: 98%

“…Tumors with high VEGF and low TSP-1 had higher microvessel counts and by multivariate analysis worse prognosis with a 73% recurrence rate. Similarly, in hepatocellular carcinoma, high levels of TSP-1 and low levels of VEGF equated with low microvessel density (26).…”

Section: Discussionmentioning

confidence: 96%

Expression of Thrombospondin-1 in Resected Colorectal Liver Metastases Predicts Poor Prognosis

Sutton¹,

O’Byrne²,

Goddard³

et al. 2005

Clinical Cancer Research

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“…A number of studies have shown a relationship between VEGF expression, or angiogenesis and p53 mutation in human tumors. Some studies showed a positive correlative relationship (25,26), but others did not (27,28). However, no study has yet examined the relationship between p53 overexpression and angiopoietin expression in HCC.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of VEGF and Angiopoietin 2: A Key to High Vascularity of Hepatocellular Carcinoma?

et al. 2003

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Hepatocellular carcinoma (HCC) is becoming one of the most common malignant tumors worldwide and is characterized by a high vascularity. Angiogenesis, formation of new microvessels, is critical for the growth and progression of various human solid tumors. Vascular endothelial growth factor (VEGF) and angiopoietins (Ang1 and Ang2) are endothelial cell-specific vasculogenic and angiogenic growth factors, but their expression and roles in HCC have not been extensively explored. The aim of this study was to determine the expression and cellular localization of VEGF, Ang1, and Ang2 in specimens of resected human HCC using in situ hybridization and immunohistochemical staining and to examine their relationship to microvessel density (MVD) and tumor size. We also investigated whether mutation of p53 protein might affect the expression of the above angiogenic growth factors. VEGF and Ang2 were strongly expressed and localized predominantly to cancer cells, whereas Ang1 was detected in supportive cells of large blood vessels, stromal cells, endothelial cells, and tumor cells. Expression of the VEGF protein and the Ang2 (but not Ang1) mRNA were strongly correlated with MVD (P < .05, P ‫؍‬ .001) and tumor size (P < .05). There was also a strong correlation between VEGF protein and Ang2 mRNA expression (P < .001). However, no significant correlation was found between overexpression of p53 and the expression of VEGF, angiopoietins, or MVD. These findings suggest that overproduction of the angiogenic growth factors VEGF and Ang2 by HCC cells may increase vascularity and tumor growth in a paracrine manner. Our findings also suggest that interaction between VEGF and Ang2 may play a critical role in tumor angiogenesis in HCC.

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“…Increased VEGF expression has been reported to be associated with a significant vascularization of human intrahepatic cholangiocarcinomas, as assessed by microvessel density [135,136] . In comparison, hypovascularity of cholangiocarcinoma may be related to a downregulation of VEGF together with an up-regulation of the angiogenesis inhibitor thrombospondin-1 [136,141,142] , although further studies are needed to validate the likelihood of this being a primary mechanism underlying the limited angiogenesis observed in cases of intrahepatic cholangiocarcinoma.…”

Section: Vegfmentioning

confidence: 99%

Role of ErbB family receptor tyrosine kinases in intrahepatic cholangiocarcinoma

Sirica¹

2008

WJG

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Aberrant expression and signaling of epidermal growth factor receptor (ErbB) family receptor tyrosine kinases, most notably that of ErbB2 and ErbB1, have been implicated in the molecular pathogenesis of intrahepatic cholangiocarcinoma. Constitutive overexpression of ErbB2 and/or ErbB1 in malignant cholangiocytes has raised interest in the possibility that agents which selectively target these receptors could potentially be effective in cholangiocarcinoma therapy. However, current experience with such ErbBdirected therapies have at best produced only modest responses in patients with biliary tract cancers. This review provides a comprehensive and critical analysis of both preclinical and clinical studies aimed at assessing the role of altered ErbB2 and/or ErbB1 expression, genetic modifications, and dysregulated signaling on cholangiocarcinoma development and progression. Specific limitations in experimental approaches that have been used to assess human cholangiocarcinoma specimens for ErbB2 and/or ErbB1 overexpression and gene amplification are discussed. In addition, current rodent models of intrahepatic cholangiocarcinogenesis associated with constitutive ErbB2 overexpression are reviewed. Select interactive relationships between ErbB2 or ErbB1 with other relevant molecular signaling pathways associated with intrahepatic cholangiocarcinoma development and progression are also detailed, including those linking ErbB receptors to bile acid, cyclooxygenase-2, i n t e r l e u k i n -6 / g p 1 3 0 , t ra n s m e m b ra n e m u c i n s , hepatocyte growth factor/Met, and vascular endothelial growth factor signaling. Lastly, various factors that can limit therapeutic efficacy of ErbB-targeted agents against cholangiocarcinoma are considered.

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Enhanced expression of thrombospondin-1 and hypovascularity in human cholangiocarcinoma

Abstract: Physiological angiogenesis results from the balance of angiogenesis activators and inhibitors.

Cited by 79 publications

References 18 publications

Expression of Thrombospondin-1 in Resected Colorectal Liver Metastases Predicts Poor Prognosis

Expression of Thrombospondin-1 in Resected Colorectal Liver Metastases Predicts Poor Prognosis

Overexpression of VEGF and Angiopoietin 2: A Key to High Vascularity of Hepatocellular Carcinoma?

Role of ErbB family receptor tyrosine kinases in intrahepatic cholangiocarcinoma

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