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Heart Failure Stimulates Tumor Growth by Circulating Factors.
Heart Failure Stimulates Tumor Growth by Circulating Factors.
- 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.
- Subjects :
- Adenomatous Polyps epidemiology
Adenomatous Polyps genetics
Adenomatous Polyps pathology
Adult
Aged
Animals
Anterior Wall Myocardial Infarction epidemiology
Anterior Wall Myocardial Infarction physiopathology
Case-Control Studies
Disease Models, Animal
Female
Genes, APC
HT29 Cells
Heart Failure epidemiology
Heart Failure physiopathology
Humans
Inflammation Mediators blood
Intestinal Neoplasms epidemiology
Intestinal Neoplasms genetics
Intestinal Neoplasms pathology
Intestinal Polyps epidemiology
Intestinal Polyps genetics
Intestinal Polyps pathology
Male
Mice, Inbred C57BL
Mice, Transgenic
Middle Aged
Prognosis
Risk Assessment
Risk Factors
Signal Transduction
Time Factors
Ventricular Remodeling
Adenomatous Polyps blood
Anterior Wall Myocardial Infarction blood
Cell Proliferation
Heart Failure blood
Intercellular Signaling Peptides and Proteins blood
Intestinal Neoplasms blood
Intestinal Polyps blood
Tumor Burden
Subjects
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