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Microvascular density and hypoxia-inducible factor pathway in pancreatic endocrine tumours: negative correlation of microvascular density and VEGF expression with tumour progression.

Couvelard A, O'Toole D, Turley H, Leek R, Sauvanet A, Degott C, Ruszniewski P, Belghiti J, Harris AL, Gatter K, Pezzella F - Br. J. Cancer (2005)

Bottom Line: Poorly differentiated carcinomas were associated with nuclear HIF-1alpha and membranous CA9 expression.Low MVD (P = 0.0001) and membranous CA9 expression (P = 0.0004) were associated with a poorer survival.As they progress, VEGF expression is lost and MVD significantly decreases.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Hôpital Beaujon, 100 Boulevard du Général Leclerc, 92110 Clichy, France. anne.couvelard@bjn.ap-hop-paris.fr

ABSTRACT
Tumour-associated angiogenesis is partly regulated by the hypoxia-inducible factor (HIF) pathway. Endocrine tumours are highly vascularised and the molecular mechanisms of their angiogenesis are not fully delineated. The aim of this study is to evaluate angiogenesis and expression of HIF-related molecules in a series of patients with pancreatic endocrine tumours (PETs). The expression of vascular endothelial growth factor (VEGF), HIF-1alpha, HIF-2alpha and carbonic anhydrase 9 (CA9) was examined by immunohistochemistry in 45 patients with PETs and compared to microvascular density (MVD), endothelial proliferation, tumour stage and survival. Microvascular density was very high in PETs and associated with a low endothelial index of proliferation. Microvascular density was significantly higher in benign PETs than in PETs of uncertain prognosis, well-differentiated and poorly differentiated carcinomas (mean values: 535, 436, 252 and 45 vessels mm(-2), respectively, P < 0.0001). Well-differentiated tumours had high cytoplasmic VEGF and HIF-1alpha expression. Poorly differentiated carcinomas were associated with nuclear HIF-1alpha and membranous CA9 expression. Low MVD (P = 0.0001) and membranous CA9 expression (P = 0.0004) were associated with a poorer survival. Contrary to other types of cancer, PETs are highly vascularised, but poorly angiogenic tumours. As they progress, VEGF expression is lost and MVD significantly decreases. The regulation of HIF signalling appears to be specific in pancreatic endocrine tumours.

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Box plot of VEGF cytoplasmic score stratified according to the WHO classification. Differences between groups were statistically significant (P=0.03).
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fig2: Box plot of VEGF cytoplasmic score stratified according to the WHO classification. Differences between groups were statistically significant (P=0.03).

Mentions: VEGF expression correlated negatively with WHO disease stage (Figures 1A, B and 2). Five of eight patients (62%) with negative staining for VEGF had WHO-stage 4, five out of 18 (28%) WHO-stage 3 and two out of 19 (11%) WHO-stage 1–2. The VEGF score was significantly higher in tumours with a low index of proliferation or mitosis count, no necrosis, no fibrotic focus and a high microvascular density (although this did not reach significant levels; P=0.06). No difference in VEGF expression was observed in endocrine tumours associated with VHL or not (see values in Table 2). There was no association between VEGF expression and survival.


Microvascular density and hypoxia-inducible factor pathway in pancreatic endocrine tumours: negative correlation of microvascular density and VEGF expression with tumour progression.

Couvelard A, O'Toole D, Turley H, Leek R, Sauvanet A, Degott C, Ruszniewski P, Belghiti J, Harris AL, Gatter K, Pezzella F - Br. J. Cancer (2005)

Box plot of VEGF cytoplasmic score stratified according to the WHO classification. Differences between groups were statistically significant (P=0.03).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2361752&req=5

fig2: Box plot of VEGF cytoplasmic score stratified according to the WHO classification. Differences between groups were statistically significant (P=0.03).
Mentions: VEGF expression correlated negatively with WHO disease stage (Figures 1A, B and 2). Five of eight patients (62%) with negative staining for VEGF had WHO-stage 4, five out of 18 (28%) WHO-stage 3 and two out of 19 (11%) WHO-stage 1–2. The VEGF score was significantly higher in tumours with a low index of proliferation or mitosis count, no necrosis, no fibrotic focus and a high microvascular density (although this did not reach significant levels; P=0.06). No difference in VEGF expression was observed in endocrine tumours associated with VHL or not (see values in Table 2). There was no association between VEGF expression and survival.

Bottom Line: Poorly differentiated carcinomas were associated with nuclear HIF-1alpha and membranous CA9 expression.Low MVD (P = 0.0001) and membranous CA9 expression (P = 0.0004) were associated with a poorer survival.As they progress, VEGF expression is lost and MVD significantly decreases.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Hôpital Beaujon, 100 Boulevard du Général Leclerc, 92110 Clichy, France. anne.couvelard@bjn.ap-hop-paris.fr

ABSTRACT
Tumour-associated angiogenesis is partly regulated by the hypoxia-inducible factor (HIF) pathway. Endocrine tumours are highly vascularised and the molecular mechanisms of their angiogenesis are not fully delineated. The aim of this study is to evaluate angiogenesis and expression of HIF-related molecules in a series of patients with pancreatic endocrine tumours (PETs). The expression of vascular endothelial growth factor (VEGF), HIF-1alpha, HIF-2alpha and carbonic anhydrase 9 (CA9) was examined by immunohistochemistry in 45 patients with PETs and compared to microvascular density (MVD), endothelial proliferation, tumour stage and survival. Microvascular density was very high in PETs and associated with a low endothelial index of proliferation. Microvascular density was significantly higher in benign PETs than in PETs of uncertain prognosis, well-differentiated and poorly differentiated carcinomas (mean values: 535, 436, 252 and 45 vessels mm(-2), respectively, P < 0.0001). Well-differentiated tumours had high cytoplasmic VEGF and HIF-1alpha expression. Poorly differentiated carcinomas were associated with nuclear HIF-1alpha and membranous CA9 expression. Low MVD (P = 0.0001) and membranous CA9 expression (P = 0.0004) were associated with a poorer survival. Contrary to other types of cancer, PETs are highly vascularised, but poorly angiogenic tumours. As they progress, VEGF expression is lost and MVD significantly decreases. The regulation of HIF signalling appears to be specific in pancreatic endocrine tumours.

Show MeSH
Related in: MedlinePlus