6M, tif) Supplementary Figure Legend: Click here for supplemental data(20K, doc) Acknowledgments We thank Dr Steven Gallinger and Dr Ming Tsao for their help establishing the primary pancreatic cancer xenografts, and past and present members of the Hedley Lab, particularly Drs Nhu-An Pham and Diana selleck chem Birle for their helpful comments. Joao Magalhaes was responsible for the pathological examination of the primary xenografts, and we thank him, and James Ho May Cheung, and Trudey Nicklee for their excellent technical help with the immunohistochemistry staining and digital image analysis. Grant support: National Cancer Institute of Canada/Canadian Cancer Society. Notes Supplementary Information accompanies the paper on British Journal of Cancer website (http://www.nature.

com/bjc)
The formation of new blood vessels, angiogenesis, is a complex and tightly regulated process governed by the action of endogenous pro- and anti-angiogenic factors [1]. The members of the vascular endothelial growth factor (VEGF) family represent prototypical inducers of blood and lymph vessel formation. However, despite our growing knowledge of the molecular cues involved in shaping a new vasculature, the regulation of physiological and pathological blood vessel formation by VEGFs is still not completely understood. The VEGF family is comprised of five members that bind and activate three receptor tyrosine kinases (VEGFR-1, -2 and -3) with different specificity [2]. Haploinsufficiency of Vegfa in mice provides an illustrative example of the importance of VEGF-A signaling through VEGFR-1 and -2 for proper endothelial cell function [3], [4].

Placental growth factor (PlGF) binds exclusively to VEGFR-1, and targeting of PlGF inhibits angiogenesis in various pathological settings, including tumor growth [5]. Furthermore, through binding to VEGFR-3 on lymphatic endothelial cells, VEGF-C and -D predominantly regulate lymphangiogenesis [6], even though VEGFR-3 expression by tumor blood vessels has also been reported [7]. VEGF-B specifically binds and activates VEGFR-1, either alone or in conjunction with the co-recpetor neuropilin-1. However, the function of VEGF-B signaling in the context of pathological angiogenesis remains elusive [8]. VEGF-B was first identified as an endothelial cell mitogen highly expressed in heart and skeletal muscle [9].

Consequently, transgenic expression of VEGF-B through adenoviral delivery readily induces angiogenesis in the myocardium [10]. However, VEGF-B deficient mice do not display any overt vascular abnormalities in the unchallenged heart vasculature, even though an impaired recovery from cardiac ischemia is suggestive of Dacomitinib an underlying vascular dysfunction [11], [12]. Moreover, ectopic expression of VEGF-B in skeletal muscle does not induce angiogenesis [10].