Tumours modulate the systemic vascular response to anti‐angiogenic therapy

Abstract

Toxicologic evaluation of new drug candidates routinely utilizes healthy animals. In oncology, there remains a limited understanding of the effects of novel test candidates in a diseased host. For vascular modulating agents (VMAs), an increased understanding of preclinical tumour-host interaction, and its potential to exacerbate or alleviate 'off-target' effects of anti-angiogenic administration, could aid in the prediction of adverse clinical outcomes in a defined cancer patient. We have previously reported that the implantation and growth of a range of human-and mouse-derived tumours leads to structural vascular and, potentially, functional signalling changes within host mouse endocrine tissues, indicating possible roles for tumour-and hostderived cytokines/growth factors and the liberation of myeloid-derived suppressor cells in this phenomenon. Here, we further demonstrate that the growth of the Calu-6 xenograft is associated with a resistance to VMA-induced mouse peripheral endocrine vascular rarefaction (toxicity), with potential functional impact, notably with respect to mixed tyrosine kinase inhibition. The pathogenesis of these findings indicates a potential role for both tumour-and host-derived basic fibroblast growth factor (bFGF), with associated upregulation in the intra-tumoural autotaxinlysophosphatic acid signalling axis.