Abstract
Increasing evidence suggests the existence of shared pathophysiological mechanisms between cardiovascular diseases (CVD) and cancer. Historically, the association between these two disease entities has been prescribed to shared risk factors such as smoking, diabetes, obesity, etc. However, recent publications have, for the first time, provided evidence of a causal link between CVD, specifically heart failure (HF), and increased cancer growth. These new observations have led to the hypothesis that CVD may trigger or promote cancer growth.
At present, the precise mechanism leading to enhanced cancer growth in the presence of HF is unknown. Secretion of factors by the failing heart has been suggested as a potential mechanism, in which the endothelium might emerge as a central player. Although a specific factor secreted by the endothelium has not yet been identified, we hypothesize that neuregulin-1 (NRG-1) could be an endothelial factor linking HF and cancer. NRG-1, up-regulated in various CVD including HF, is involved in the promotion of cardiac regeneration and repair. In addition, NRG-1 is a ligand for the epidermal growth factor receptors (ERBB) 3 and 4, which form dimers with ERBB2. ERBB2 and 3 are known proto-oncogenes involved in multiple cancers including breast and colon cancer. Currently, phase III clinical trials with NRG-1 as a potential treatment for HF are ongoing. Therefore, induction of tumor growth as a result of NRG-1 treatment is potentially a major safety issue during these clinical trials. Our objective is to unravel the role of endothelial secreted NRG-1 as a potential link between HF and cancer enhancement.
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