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Published on: February 20, 2019
Ageing-related responses to antiangiogenic effects of sunitinib in atherosclerosis-prone mice
Brian Meehan1, Delphine Garnier1, Alexander Dombrovsky1
1Montreal Children's Hospital, RI MUHC, McGill University, Montreal, Quebec, Canada.
Abstract:
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.
Insights
Sunitinib more effectively inhibits tumor growth in aged mice with atherosclerosis, altering the tumor microenvironment. Age and atherosclerosis impact antiangiogenic therapy effectiveness in cancer.
Area of Science:
- Oncology
- Vascular Biology
- Aging Research
Background:
- Antiangiogenic therapies are crucial in cancer treatment but are influenced by age-related vascular comorbidities like atherosclerosis.
- Current mouse models often fail to replicate the complex vascular environment of aged patients with atherosclerosis.
- Atherosclerosis significantly impacts the efficacy of antiangiogenic drugs, a factor often overlooked in preclinical studies.
Purpose of the Study:
- To investigate the age-dependent effects of sunitinib, an antiangiogenic inhibitor, on tumor growth and the tumor microenvironment.
- To evaluate the role of atherosclerosis in modulating the response to sunitinib in a Lewis Lung Carcinoma (LLC) model.
- To understand how aging and atherosclerosis influence the tumor microenvironment's response to antiangiogenic therapy.
Main Methods:
- Utilized atherosclerosis-prone ApoE-/- mice, both young and aged, with syngeneic LLC tumors.
- Administered sunitinib and assessed its impact on global tumor growth.
- Analyzed tumor microenvironment characteristics including hypoxia, microvascular density (MVD), pericyte coverage, soluble VEGFR2 levels, immune cell infiltration (CD45+, CD163+), and inflammatory pathway activation (phospho-STAT3).
Main Results:
- Sunitinib demonstrated greater inhibition of tumor growth in aged mice compared to young mice.
- Aged mice treated with sunitinib exhibited increased tumor hypoxia, reduced MVD, and lower pericyte coverage.
- Sunitinib modulated immune cell infiltration and inflammatory pathways in an age-dependent manner, with distinct effects on M2-like macrophages and STAT3 activation.
Conclusions:
- Age and atherosclerosis significantly alter the tumor microenvironment's response to sunitinib.
- These age- and atherosclerosis-related modifications may influence the overall effectiveness of sunitinib and potentially other antiangiogenic therapies in cancer patients.
- Preclinical models should incorporate age-related comorbidities to better predict therapeutic outcomes.
