VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic β cell carcinogenesis

Abstract

In the RIP1-Tag2 mouse model of pancreatic islet carcinoma, angiogenesis is switched on in a discrete premalignant stage of tumor development, persisting thereafter. Signaling through VEGF receptor tyrosine kinases is a well-established component of angiogenic regulation. We show that five VEGF ligand genes are expressed in normal islets and throughout islet tumorigenesis. To begin dissecting their contributions, we produced an islet beta cell specific knockout of VEGF-A, resulting in islets with reduced vascularity but largely normal physiology. In RIP1-Tag2 mice wherein most oncogene-expressing cells had deleted the VEGF-A gene, both angiogenic switching and tumor growth were severely disrupted, as was the neovasculature. Thus, VEGF-A is crucial for angiogenesis in a prototypical model of carcinogenesis, whose loss is not readily compensated.

Mechanisms of adverse effects of anti-VEGF therapy for cancer

“…Facilitation of glucose handling is paradoxical, because loss of capillaries in pancreatic islets would be expected to impair glucose sensing. It also contrasts with observations of defective glucose sensing found after targeted disruption of VEGF signalling in pancreatic islets of genetically altered mice (Inoue et al, 2002;Lammert et al, 2003). Therefore, improved glucose handling after systemic inhibition of VEGF signalling probably involves mechanisms other than reduction in islet vascularisation.…”

“…Inhibition of VEGF signalling in adult mice for 1 -3 weeks resulted in regression of more than half of the capillaries in the thyroid (Kamba et al, 2006). Fenestrated capillaries also regressed in the pituitary, adrenal cortex, and pancreatic islets (Inoue et al, 2002;Lammert et al, 2003;Kamba et al, 2006). Inhibition of VEGF receptor signalling for 3 weeks was accompanied by elevation of blood TSH ( Figure 3G), presumably from impairment of the thyroidhypothalamic feedback loop (Kamba et al, 2006).…”

Impact of whole body irradiation and vascular endothelial growth factor-A on increased beta cell mass after bone marrow transplantation in a mouse model of diabetes induced by streptozotocin

“…Previously we found that VEGF-A produced by beta cells was an essential factor for islet vascularisation [27,28]. To investigate the role of VEGF-A in beta cells, we used RIP-CRE:VEGF fl/fl mice in which the gene encoding VEGF-A (Vegfa) is disrupted in the beta cells and their control mice, VEGF fl/fl [CRE − ] mice [27].…”

“…In the present study, the increase in islet mass by BMT or low-dose irradiation was associated with increased islet vascularisation. Previously we showed that production of VEGF-A by beta cells is an essential factor for islet vacularisation [27,28]. In contrast, low-dose irradiation reportedly promotes VEGF-A release from mast cells that migrate to various tissues [33].…”

“…Green fluorescent protein (GFP) transgenic mice, in which enhanced GFP production was under the control of the cytomegalovirus enhancer and the chicken β-actin promoter, were generously provided by M. Okabe (Osaka University, Osaka, Japan) [24]. The generation and characterisation of RIP-CRE transgenic mice [25] and vascular endothelial growth factor (VEGF fl/fl ) mice (VEGF fl/fl [CRE − ] mice) [26] has been reported previously [27,28].…”