Abstract Body: Background: Patients and survivors with colorectal cancer (CRC) have increased risk of developing atherosclerotic cardiovascular disease (CVD). Previous epidemiological studies indicate that obesity and hypercholesterolemia, canonical drivers of atherosclerosis, increase incidence and progression of CRC through both metabolic and tumor immune cell reprogramming. Mechanisms of disease crosstalk between CRC and CVD, however, are not defined.
Hypothesis: CRC potentiates atherosclerosis through metabolic and immune cell reprogramming.
Methods: 4-week-old cancer-free C57BL/6J and spontaneous CRC tumor-forming APC^Min(+/-) mice received intra-orbital injections of AAV8-D377Y-mPCSK9 and were placed on high fat diet for 12 weeks to induce atherogenesis. Aortic sinus and whole aorta were stained with Oil Red O and Sudan IV respectively for plaque burden analysis. High risk plaque features such as fibrous cap thickness and macrophage infiltration were quantified. Intestines were stained with methylene blue for tumor burden quantification and plasma was collected for unbiased metabolomics.
Results: Compared to cancer-free mice, APC^Min(+/-) mice have significantly increased plaque burden in the aortic sinus (36.9% ± 8.1 vs 45.95 ± 9.4, p<0.05) and descending aorta (5.3% ± 1.6 vs 9% ± 3, p<0.05). APC^Min(+/-) mice have thicker fibrous caps (1.4 mm ± 0.63 vs 2.42 mm ± 0.73, p<0.05) and increased macrophage infiltration by CD68+ cell count.
Metabolomics revealed the most significant increase in xanthine, hypoxanthine, and purine degradation products in the plasma of APC^Min(+/-) compared to control mice.
Conclusion: The spontaneous model of CRC has increased total plaque burden compared to cancer-free controls. Plaque from these mice also presented with a thicker fibrous cap and increased macrophage infiltration. The lack of necrotic core, rupture, or other high-risk features and thicker fibrous cap suggests that these plaques were in the early stages of formation. However, in the presence of CRC, plaques were larger, more mature, and with higher lipid content when compared to cancer-free controls. Serum metabolomics revealed increased purine degradation byproducts of xanthine oxidoreductase (XOR). Ongoing work focuses on repeating plaque assessment and metabolomics using a metastatic model of CRC. Future directions will also focus on circulating myeloid cell characterization and treatment studies with XOR inhibitors in these dual disease models.