Abstract
The study of vascular modulation has received a great deal of attention in recent years, as knowledge has increased around the role of angiogenesis within disease contexts such as cancer. Allograft and xenograft transplantation into a mouse host is frequently utilised to study tumour-associated angiogenesis and the response to anti-angiogenic treatments. Pre-clinical studies employing these models often focus solely upon the intra-tumoural effects of a given treatment, without consideration of systemic toxicity or tumour-host interaction, nor whether this latter relationship could modulate the toxicologic response to therapy. In addition, techniques used to quantify “off-target” drug-induced vascular regression, a process translating into a number of dose-limiting clinical sequelae, have attained relatively modest advancement in the pre-clinical setting.
Here, the generation of a novel structural biomarker, which can be incorporated into a number of contemporary image analysis platforms and used to compare tumour versus systemic host tissue vascularity, is demonstrated. By contrasting the measurements obtained, the pre-clinical efficacy of vascular-modulating chemotherapies can be evaluated in light of the predicted therapeutic window (Hargreaves et al., 2017).
It is further demonstrated that the implantation and growth of a range of human- and mouse-derived cell lines leads not only to structural vascular and potential functional changes within peripheral endocrine tissues, but also ameliorates the severity of anti-angiogenic-induced fenestrated vessel attenuation. Observations suggest a multi-factorial process, variably involving host- and tumour-derived growth factors/cytokines and the liberation of myeloid-derived suppressor cells. These findings may be of significance in the development of clinical anti-angiogenic “adaptation” and within the “cancer-cachexia” syndrome in man (Hargreaves et al., 2021).
Finally, it is shown that the growth of the Calu-6 xenograft is associated with a resistance to Vascular-Modulating Agent-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 Fibroblast Growth Factor, with associated upregulation in the intra-tumoural autotaxin-lysophosphatic acid signalling axis (Hargreaves et al., 2022).