Tumours modulate the systemic vascular response to anti-angiogenic therapy

Area of Science:

• Oncology
• Toxicology
• Vascular Biology

Background:

• Drug candidate toxicologic evaluation typically uses healthy animals, limiting understanding in diseased hosts.
• Vascular modulating agents (VMAs) in oncology can have 'off-target' effects, necessitating better prediction of clinical outcomes.
• Tumor growth alters host endocrine tissue vasculature, influenced by cytokines, growth factors, and myeloid-derived suppressor cells.

Purpose of the Study:

• To investigate tumor-host interactions in response to vascular modulating agents (VMAs).
• To understand how tumor growth influences VMA-induced toxicity in endocrine tissues.
• To explore the role of specific signaling pathways in mediating resistance to VMA toxicity.

Main Methods:

• Utilized Calu-6 xenograft model in mice.
• Administered vascular modulating agents (VMAs) to assess toxicity.
• Analyzed vascular changes in host endocrine tissues.
• Investigated the role of basic fibroblast growth factor (bFGF) and the autotaxin-lysophosphatic acid axis.

Main Results:

• Calu-6 xenograft growth conferred resistance to VMA-induced vascular rarefaction in peripheral endocrine tissues.
• This resistance has potential functional implications, particularly with mixed tyrosine kinase inhibition.
• Findings suggest a role for both tumor- and host-derived basic fibroblast growth factor (bFGF).
• Upregulation of the intra-tumoral autotaxin-lysophosphatic acid signaling axis was observed.

Conclusions:

• Tumor-host interactions significantly modulate VMA toxicity.
• The Calu-6 model provides a platform to study resistance mechanisms to VMA-induced toxicity.
• Targeting bFGF and the autotaxin-lysophosphatic acid axis may offer strategies to predict or mitigate adverse drug effects in cancer patients.