Tumors modulate fenestrated vascular beds and host endocrine status

Abstract

Allograft and xenograft transplantation into a mouse host is frequently utilized to study cancer biology, tumor behavior, and response to treatment. Preclinical studies employing these models often focus solely upon the intra-tumoral effects of a given treatment, without consideration of systemic toxicity or tumor-host interaction, nor whether this latter relationship could modulate the toxicologic response to therapy.Here it is demonstrated that the implantation and growth of a range of human-and mouse-derived cell lines leads to structural vascular and, potentially, functional changes within peripheral endocrine tissues, a process that could conceivably ameliorate the severity of anti-angiogenic-induced fenestrated vessel attenuation.Observations suggest a multifactorial process, which may involve host-and tumorderived cytokines/growth factors, and the liberation of myeloid-derived suppressor cells. Further investigation revealed a structurally comparable response to the administration of exogenous estrogen. These findings, in addition to providing insight into the development of clinical anti-angiogenic "adaptation," may be of significance within the "cancer-cachexia" and cancer-related anemia syndromes in man.

Tumours modulate the systemic vascular response to anti‐angiogenic therapy

“…However, there appeared to be an increase in the density of vascular profiles, and in the extent of vascular (sinusoidal) branching/anastomoses, within the adrenal cortex, amongst a number of tumour‐bearing animals, when compared with non‐tumour‐bearing counterparts. This was similar to previous observations made when examining this tissue from xenograft‐implanted mice (Hargreaves et al, 2021). Animals administered high‐dose AZ10167514, in particular, also displayed a notable decrease in vascular (sinusoidal) branching/anastomoses within the adrenal cortex, in both non‐tumour‐bearing and tumour‐bearing individuals (Figure 1).…”

“…Finally, as previously described and also observed here (Hargreaves et al, 2021), there was an apparent increase in adrenal cortical vascularity amongst vehicle control Calu‐6 tumour‐bearing animals, when compared with the cohort of comparative vehicle control non‐tumour‐bearing animals.…”

“…We previously demonstrated that the implantation and growth of a range of mouse‐ and human‐derived allografts/xenografts leads not only to structural vascular changes within the peripheral host endocrine tissues but also imparts potential functional consequence. We noted that histogenetically diverse subtypes of tumour appeared stratified in their ability to influence peripheral endocrine vascularity and indicated a potential role in these observations for tumour‐ and host‐derived cytokines/growth factors, and the liberation of MDSCs (Hargreaves et al, 2021).…”

“…We further recently demonstrated 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 (MDSCs) in this phenomenon (Hargreaves et al, 2021). This work sought to evaluate these observations, with respect to their potential effect upon, and/or association with, the induction of VMA-induced peripheral endocrine vascular rarefaction (toxicity) in the mouse.…”

“…We further recently demonstrated 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 (MDSCs) in this phenomenon (Hargreaves et al, 2021).…”