Early Cardiac Remodeling Promotes Tumor Growth and Metastasis

Abstract

Background: Recent evidence suggests that cancer and cardiovascular diseases are associated. Chemotherapy drugs are known to result in cardiotoxicity, and studies have shown that heart failure and stress correlate with poor cancer prognosis. However, whether cardiac remodeling in the absence of heart failure is sufficient to promote cancer is unknown. Methods: To investigate the effect of early cardiac remodeling on tumor growth and metastasis colonization, we used transverse aortic constriction (TAC), a model for pressure overload–induced cardiac hypertrophy, and followed it by cancer cell implantation. Results: TAC-operated mice developed larger primary tumors with a higher proliferation rate and displayed more metastatic lesions compared with controls. Serum derived from TAC-operated mice potentiated cancer cell proliferation in vitro, suggesting the existence of secreted tumor-promoting factors. Using RNA-sequencing data, we identified elevated mRNA levels of periostin in the hearts of TAC-operated mice. Periostin levels were also found to be high in the serum after TAC. Depletion of periostin from the serum abrogated the proliferation of cancer cells; conversely, the addition of periostin enhanced cancer cell proliferation in vitro. This is the first study to show that early cardiac remodeling nurtures tumor growth and metastasis and therefore promotes cancer progression. Conclusions: Our study highlights the importance of early diagnosis and treatment of cardiac remodeling because it may attenuate cancer progression and improve cancer outcome.

Common mechanistic pathways in cancer and heart failure. A scientific roadmap on behalf of the Translational Research Committee of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC)

“…The TAC‐operated mice demonstrated bigger tumours, higher proliferation rates, and more metastasis compared to their control. Also, treating cancer cells, in vitro , with serum derived from the TAC‐operated mice stimulated their proliferation 78 . These results validated the concept of secreted factors in the serum that promote tumour growth 4,78 .…”

Evaluation of renal cancer progression in a mouse model of heart failure

“…Furthermore, Avraham et al. [ 6 ] provided evidence that cardiac remodeling induced by transverse aortic constriction (TAC) in mice also enhanced breast and lung cancer growth, again explained by increased expression of secreted factors from the failing heart.…”

A new classification of cardio-oncology syndromes

“…However, three pre-clinical studies with several combinations of HF aetiologies and cancer types have proven the direct connection between the two syndromes. Also, investigators of these studies found that failing hearts can affect tumour growth and severity independent of CVD risk factors [ 50 , 121 , 122 ].…”

“…9 Theoretical depiction of a clinical situation with a patient consistent with more than a single classification. However, the application of our classification system depends on which disease is diagnosed first and on the available data regarding systemic and genetic predisposition and risk factors [ 122 , 123 ] …”