Oncofoetal insulin receptor isoform A marks the tumour endothelium; an underestimated pathway during tumour angiogenesis and angiostatic treatment

摘要

Background In a genomic screen for determinants of the tumour vasculature, we identified insulin receptor (INSR) to mark the tumour endothelium. As a functional role for insulin/INSR in cancer has been suggested and markers of the tumour endothelium may be attractive therapeutic targets, we investigated the role of INSR in angiogenesis. Methods In a genomic screen for determinants of the tumour vasculature we identified insulin receptor to mark the tumour endothelium. Results The current report demonstrates the following: (i) the heavy overexpression of INSR on angiogenic vasculature in human tumours and the correlation to short survival, (ii) that INSR expression in the tumour vasculature is mainly representing the short oncofoetal and non-metabolic isoform INSR-A, (iii) the angiogenic activity of insulin on endothelial cells (EC) in vitro and in vivo, (iv) suppression of proliferation and sprouting of EC in vitro after antibody targeting or siRNA knockdown, and (v) inhibition of in vivo angiogenesis in the chicken chorioallantoic membrane (CAM) by anti-INSR antibodies. We additionally show, using preclinical mouse as well as patient data, that treatment with the inhibitor sunitinib significantly reduces the expression of INSR-A. Conclusions The current study underscores the oncogenic impact of INSR and suggests that targeting the INSR-A isoform should be considered in therapeutic settings.