The role of smoking in cancer-associated cardiovascular disease

Background: While the individual impacts of smoking on cancer and CVD are well-documented, the complex interplay between cancer, smoking, and CVD remains poorly understood. Our unpublished studies in mice and humans indicate cancer directly accelerates intraplaque angiogenesis and atherosclerotic plaque vulnerability, presumably mediated by cancer secreted angiogenic cytokine – TNF-α. Additionally, we previously demonstrated that nicotine promotes atherogenesis by directly stimulating intraplaque angiogenesis. Interestingly, recent epidemiology studies have shown that cancer survivors who smoke have an increased risk of developing cardiovascular events. However, it remains unclear whether this elevated risk is solely due to the direct impact of smoking on CVD or whether there is a synergistic effect between smoking and cancer in promoting CVD.

Hypothesis: Smoking synergizes with cancer to promote atherosclerotic plaque vulnerability via heightened angiogenesis.

Methods: We will randomize atheroprone mice implanted with a wide range of tumors (or matching placebo) to cigarette smoke exposure (or non-smoking control). Plaque characteristics will be measured by histological staining. In vitro Matrigel assays and in vivo Matrigel plug implantation and femoral artery ligation models will be used to test the molecular mechanisms underlying heightened angiogenesis.

Anticipated results: Tumor-bearing mice who smoke will develop larger and more vulnerable plaques, driven by increases in neovascularization and intraplaque hemorrhage. The molecular mechanisms responsible for the synergistic amplification in angiogenesis are expected to involve the upregulation of nAChR and TNF-α expression and activation of VEGF via NF-ĸB.

Conclusion: Our work will provide critical insights into the mechanisms by which smoking exacerbates cancer-associated CVD, potentially identifying novel therapeutic targets to mitigate cardiovascular risks in cancer patients who smoke.