Ageing-related responses to antiangiogenic effects of sunitinib in atherosclerosis-prone mice

• The antitumor effect of sunitinib in mice is age-dependent.
• Atherosclerotic mice can be used as a model of vascular ageing relevant to cancer.
• Vascular ageing impacts tumor microenvironment.
• Ageing impacts tumor microenvironmental responses to antiangiogenic therapy.

Antiangiogenic therapies in cancer exert their effects in the context of age-related comorbidities, which affect the entirety of the vascular system. Among those conditions, the impact of atherosclerosis is especially prevalent, but poorly understood, and not reflected in mouse models routinely used for testing antiangiogenic therapeutics. Our earlier work suggested that these obstacles can be overcome with the use of atherosclerosis-prone ApoE−/− mice harbouring syngeneic transplantable Lewis Lung Carcinoma (LLC). Here we report that, sunitinib, the clinically approved, antiangiogenic inhibitor impedes global tumor growth to a greater extent in aged then in young mice. This activity was coupled with changes in the tumor microenvironment, which in aged mice was characterized by pronounced hypoxia, reduction in microvascular density (MVD) and lower pericyte coverage, relative to young controls. We also detected soluble VEGR2 in plasma of sunitinib treated mice. Interestingly, sunitinib modulated tumor infiltration with bone marrow-derived cells (CD45+), recruitment of M2-like macrophages (CD163+) and activation of inflammatory pathways (phospho-STAT3) in a manner that was age-dependent. We suggest that age and atherosclerosis may alter the effects of sunitinib on the tumor microenvironment, and that these considerations may also apply more broadly to other forms of antiangiogenic treatment in cancer.