Irreversible cardiac remodeling promotes cancer progression via secreted factors in ATF3 transgenic mouse model

Abstract

Abstract Cardiac hypertrophy and cancer are the leading cause of deaths worldwide. While heart failure and cancer have been considered separate diseases, it is becoming evident that they are highly connected and affect each other's outcome. Recent studies using mouse models mimicking myocardial infraction and aortic stenosis were shown to promote cancer progression. These two mouse models involve major irreversible surgeries. Here, we employed a transgenic mouse model for heart hypertrophy and examined the crosstalk between the hypertrophied heart and cancer progression. Heart hypertrophy was induced by adult ATF3 expression in cardiomyocytes followed by either PyMT, breast cancer cells or Lewis lung carcinoma (LLC) cells implantation. PyMT and LLC tumors grow larger in size and display increased cell proliferation in ATF3-transgenic mice as compared with control mice. In addition, pulmonary experimental metastasis assay revealed augmented number and size of metastasis lesions in the lungs. Subsequently, we identified five putative cardiac secreted factors that are highly expressed in the hearts derived from ATF3-transgenic that may be involved in tumor progression. These include Fibronectin, CP, serpin3, CTgF and PSTN. Next, we addressed whether the cause or the effect are necessary to promote tumor growth. Towards this end, ATF3 expression was turned-off after cardiac hypertrophy development followed by cancer cell implantation. The tumor promotion phenotype as well as enhancement of metastatic seeding in these mice was fully preserved, suggesting the generation of an irreversible viscous cycle that lead to cancer progression. Significantly, the expression of Fibronectin and CTgF was dampened in the presence of doxycycline, thus exclude their putative role in mediating the tumor promotion and metastatic seeding phenotypes. Collectively, heart hypertrophy and cancer diseases communicate via secreted factors that result in cancer promotion and disease deterioration. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Israel Science Foundation