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Heart Failure Stimulates Tumor Growth by Circulating Factors.

Heart Failure Stimulates Tumor Growth by Circulating Factors.

Authors :
Meijers WC
Maglione M
Bakker SJL
Oberhuber R
Kieneker LM
de Jong S
Haubner BJ
Nagengast WB
Lyon AR
van der Vegt B
van Veldhuisen DJ
Westenbrink BD
van der Meer P
Silljé HHW
de Boer RA
Source :
Circulation [Circulation] 2018 Aug 14; Vol. 138 (7), pp. 678-691.
Publication Year :
2018

Abstract

Background: Heart failure (HF) survival has improved, and nowadays, many patients with HF die of noncardiac causes, including cancer. Our aim was to investigate whether a causal relationship exists between HF and the development of cancer.<br />Methods: HF was induced by inflicting large anterior myocardial infarction in APC <superscript>min</superscript> mice, which are prone to developing precancerous intestinal tumors, and tumor growth was measured. In addition, to rule out hemodynamic impairment, a heterotopic heart transplantation model was used in which an infarcted or sham-operated heart was transplanted into a recipient mouse while the native heart was left in situ. After 6 weeks, tumor number, volume, and proliferation were quantified. Candidate secreted proteins were selected because they were previously associated both with (colon) tumor growth and with myocardial production in post-myocardial infarction proteomic studies. Myocardial gene expression levels of these selected candidates were analyzed, as well as their proliferative effects on HT-29 (colon cancer) cells. We validated these candidates by measuring them in plasma of healthy subjects and patients with HF. Finally, we associated the relation between cardiac specific and inflammatory biomarkers and new-onset cancer in a large, prospective general population cohort.<br />Results: The presence of failing hearts, both native and heterotopically transplanted, resulted in significantly increased intestinal tumor load of 2.4-fold in APC <superscript>min</superscript> mice (all P<0.0001). The severity of left ventricular dysfunction and fibrotic scar strongly correlated with tumor growth ( P=0.002 and P=0.016, respectively). We identified several proteins (including serpinA3 and A1, fibronectin, ceruloplasmin, and paraoxonase 1) that were elevated in human patients with chronic HF (n=101) compared with healthy subjects (n=180; P<0.001). Functionally, serpinA3 resulted in marked proliferation effects in human colon cancer (HT-29) cells, associated with Akt-S6 phosphorylation. Finally, elevated cardiac and inflammation biomarkers in apparently healthy humans (n=8319) were predictive of new-onset cancer (n=1124) independently of risk factors for cancer (age, smoking status, and body mass index).<br />Conclusions: We demonstrate that the presence of HF is associated with enhanced tumor growth and that this is independent of hemodynamic impairment and could be caused by cardiac excreted factors. A diagnosis of HF may therefore be considered a risk factor for incident cancer.

Details

Language :
English
ISSN :
1524-4539
Volume :
138
Issue :
7
Database :
MEDLINE
Journal :
Circulation
Publication Type :
Academic Journal
Accession number :
29459363
Full Text :
https://doi.org/10.1161/CIRCULATIONAHA.117.030816