Atherosclerosis and Vascular Aging as Modifiers of Tumor Progression, Angiogenesis, and Responsiveness to Therapy

It is rarely considered that age-related common vascular co-morbidities may affect therapeutic outcomes of antiangiogenic therapy in cancer. Indeed, the accepted model of human disease consists of 4- to 8-week-old (young) tumor-bearing, but otherwise healthy, experimental mice, yet human cancers are diagnosed and treated in later decades of life when atherosclerosis and vascular diseases are highly prevalent. Here we present evidence that tumor growth and angiogenesis are profoundly altered in mice affected by natural aging and with genetically induced atherosclerosis (in ApoE−/− mice). Thus, transplantable tumors (Lewis lung carcinoma and B16F1) grew at higher rates in young (4 to 8 weeks old) ApoE+/+ and ApoE−/− nonatherosclerotic syngeneic recipients than in their old (12 to 18 months old) or atherosclerotic (old/ApoE−/−) counterparts. These age-related changes were paralleled by reduced tumor vascularity, lower expression of tumor endothelial marker 1, increased acute tumor hypoxia, depletion of circulating CD45−/VEGFR+ cells, and impaired endothelial sprouting ex vivo. Exposure of tumor-bearing mice to metronomic therapy with cyclophosphamide exerted antimitotic effects on tumors in young hosts, but this effect was reduced in atherosclerotic mice. Collectively, our results suggest that vascular aging and disease may affect tumor progression, angiogenesis, and responses to therapy.