Abstract 15638: Proinflammatory and Proangiogenic State Promotes Malignant Melanoma Progression in Mouse Model of HFpEF

Abstract

Epidemiological studies have shown that the incidence of various cancers, such as malignant melanoma is higher in patients with heart failure (both HFrEF and HFpEF) than in age-matched population, but the underlying mechanisms remain unknown. We hypothesized that in HFpEF a chronic systemic inflammation promotes malignant melanoma progression. To test this hypothesis orthotopic melanoma xenograft model was employed in a mouse model of HFpEF. Mice with uninephrectomy, aldosterone infusion (UNX-Aldo) with osmotic minipump (Alzet, 0.30 μg/h), and high salt ingestion (1% in drinking water) develop left ventricle diastolic dysfunction as indicated by a significantly (p<0.05) reduced E/A ratio (E=early, A=late mitral inflow peak velocities), increased E/e’ ratio, isovolumic relaxation time and E wave deceleration time, with no change in the ejection fraction. Mouse melanoma B16F10 cells labelled with firefly luciferase was injected in the mouse ear of UNX-Aldo and control mice. Using in vivo bioluminescence imaging we found a significantly augmented tumor growths in the UNX-Aldo mice. UNX-Aldo mice display a robust increase in several serum inflammatory mediators, cytokines and chemokines, such as IL-1, IL-6, TNF, IFN-γ, MCP-1, CD14, CCL12, CXCL13/16, as well as decreases in anti-inflammatory cytokines, such as IL-10, as measured in a Proteome Profiler cytokine array. In addition, UNX-Aldo mice had increased level of multiple angiogenic growth factors, such as IGFBP-1 and GM-CSF. Flow cytometry analysis also revealed and elevated number of tumor-associated, CD11b+F480-Ly6G+CXCL1+ neutrophils in the grafted tumors in UNX-Aldo mice. Collectively, our results indicate that pro-inflammatory and proangiogenic state in experimental HFpEF exacerbates melanoma tumor growth.