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Updated: Oct 3, 2025
Monitoring Functionality and Morphology of Vasculature Recruited by Factors Secreted by Fast-growing Tumor-generating Cells
Published on: November 23, 2014
Tumours modulate the systemic vascular response to anti-angiogenic therapy
Adam Hargreaves1,2, Simon T Barry3, Alison Bigley4
1PathCelerate Ltd., Macclesfield, UK.
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.
Insights
New cancer drug candidates require testing in diseased hosts. This study shows a Calu-6 tumor xenograft resists vascular modulating agent toxicity, revealing insights into tumor-host interactions and potential adverse clinical outcomes.
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.
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