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

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-1a, HIF-2a 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 À2, respectively, Po0.0001). Well-differentiated tumours had high cytoplasmic VEGF and HIF-1a expression. Poorly differentiated carcinomas were associated with nuclear HIF-1a and membranous CA9 expression. Low MVD (P ¼ 0.0001) and membranous CA9 expression (P ¼ 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.

Molecular markers associated with response to chemotherapy in gastro-entero-pancreatic neuroendocrine tumors

“…Both HIF-1a and CA9 significantly correlated with poorly differentiated and G 2 /G 3 tumors. Recent data from our group revealed both HIF-1a and CA9 as poor prognostic markers in pancreatic GEP (Couvelard et al 2005(Couvelard et al , 2008, and here, we show that these markers are also applicable in predicting survival to GEP from intestinal origin. Interestingly, the MMR protein, hLMH1, was associated with an aggressive phenotype in our cohort of patients, and was also associated with a response to treatment with in patients receiving systemic chemotherapy (PZ0.03) as has been described in other solid tumors (Kitajima et al 2003, Ide et al 2008, Honecker et al 2009).…”

“…In a non-small cell lung cancer model, chemoresistance to doxorubicin has been partially mediated via enhancement of HIF-1a-mediated angiogenesis (Mi et al 2008). We have recently demonstrated that HIF-regulatory proteins are highly expressed in pancreatic GEP, and are correlated with tumor metastases, recurrence, and prognosis (Couvelard et al 2005(Couvelard et al , 2008. Mismatch repair deficiency proteins (hLMH1 and heat shock proteins) have been associated with drug resistance to doxorubicin and cisplatin: hLMH1 was correlated with an aggressive phenotype in gastric cancers (Kitajima et al 2003), and has been associated with resistance to chemotherapy in germ cell tumors (Honecker et al 2009) and poor response to adjuvant 5-FU in patients with CRC (Ide et al 2008).…”

High levels of carbonic anhydrase IX in tumour tissue and plasma are biomarkers of poor prognostic in patients with non-small cell lung cancer

“…It was also related to poorly differentiated tumours (P ¼ 0.0001), as already shown in different types of tumours (Couvelard et al, 2005;Trastour et al, 2007). These findings may reflect the existence of alternative regulatory modes of HIF-1a.…”

Placental growth factor supports neuroendocrine tumor growth and predicts disease prognosis in patients

“…The therapeutic concept of antiangiogenesis has created much interest in tumor-type specific angioregulatory growth factors. Studies conducted in NETs found that VEGF-A, the prototype angiogenic factor in cancer, is highly expressed in intestinal NETs (Terris et al 1998) but was found less abundant in pNETs, inversely correlated to microvascular density, and did not convey prognostic information in pNETs (Terris et al 1998, Marion-Audibert et al 2003, Couvelard et al 2005. Here, we find that PlGF, a member of the VEGF family, is prominently induced in the stroma of pNETs.…”