Tumours modulate the systemic vascular response to anti-angiogenic therapy

J Appl Toxicol. 2022 Aug;42(8):1371-1384. doi: 10.1002/jat.4301. Epub 2022 Mar 2.

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 host-derived 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 autotaxin-lysophosphatic acid signalling axis.

Keywords: Calu-6; anti-angiogenic; autotaxin-lysophosphatic acid signaling; endocrine; fibroblast growth factor; tumour-host; vascular modulation; vascular toxicity; xenograft.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Humans
  • Mice
  • Neoplasms* / drug therapy
  • Neovascularization, Pathologic* / drug therapy