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.
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