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

Halka Klement^*, Brad St. Croix, Chloe Milsom^*, Linda May^*, Qing Guo, Joanne L. Yu^*, Petr Klement^* and Janusz Rak^*¶

From the Henderson Research Centre^* and the Population Health Institute, McMaster University, Hamilton, Ontario, Canada; the Montreal Children’s Hospital Research Institute,^{^¶} McGill University, Montreal, Quebec, Canada; University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic; and the National Cancer Institute at Frederick, Frederick, Maryland

It is rarely considered that age-related common vascular co-morbiditiesmay affect therapeutic outcomes of antiangiogenic therapy incancer. Indeed, the accepted model of human disease consistsof 4- to 8-week-old (young) tumor-bearing, but otherwise healthy,experimental mice, yet human cancers are diagnosed and treatedin later decades of life when atherosclerosis and vascular diseasesare highly prevalent. Here we present evidence that tumor growthand angiogenesis are profoundly altered in mice affected bynatural aging and with genetically induced atherosclerosis (inApoE^–/– mice). Thus, transplantable tumors (Lewislung carcinoma and B16F1) grew at higher rates in young (4 to8 weeks old) ApoE^+/+ and ApoE^–/– nonatheroscleroticsyngeneic recipients than in their old (12 to 18 months old)or atherosclerotic (old/ApoE^–/–) counterparts. Theseage-related changes were paralleled by reduced tumor vascularity,lower expression of tumor endothelial marker 1, increased acutetumor hypoxia, depletion of circulating CD45^–/VEGFR⁺ cells,and impaired endothelial sprouting ex vivo. Exposure of tumor-bearingmice to metronomic therapy with cyclophosphamide exerted antimitoticeffects on tumors in young hosts, but this effect was reducedin atherosclerotic mice. Collectively, our results suggest thatvascular aging and disease may affect tumor progression, angiogenesis,and responses to therapy.