ZYG11A Is Expressed in Epithelial Ovarian Cancer and Correlates With Low Grade Disease

The insulin-like growth factors (IGF) are important players in the development of gynecological malignancies, including epithelial ovarian cancer (EOC). The identification of biomarkers that can help in the diagnosis and scoring of EOC patients is of fundamental importance in clinical oncology. We have recently identified the ZYG11A gene as a new candidate target of IGF1 action. The aim of the present study was to evaluate the expression of ZYG11A in EOC patients and to correlate its pattern of expression with histological grade and pathological stage. Furthermore, and in view of previous analyses showing an interplay between ZYG11A, p53 and the IGF1 receptor (IGF1R), we assessed a potential coordinated expression of these proteins in EOC. In addition, zyg11a expression was assessed in ovaries and uteri of growth hormone receptor (GHR) knock-out mice. Tissue microarray analysis was conducted on 36 patients with EOC and expression of ZYG11A, IGF1R and p53 was assessed by immunohistochemistry. Expression levels were correlated with clinical parameters. qPCR was employed to assess zyg11a mRNA levels in mice tissues. Our analyses provide evidence of reduced ZYG11A expression in high grade tumors, consistent with a putative tumor suppressor role. In addition, an inverse correlation between ZYG11A and p53 levels in individual tumors was noticed. Taken together, our data justify further exploration of the role of ZYG11A as a novel biomarker in EOC

Cardioprotection and Suppression of Fibrosis by Diverse Cancer and Non-Cancer Cell Lines in a Murine Model of Duchenne Muscular Dystrophy

The dynamic relationship between heart failure and cancer poses a dual challenge. While cardiac remodeling can promote cancer growth and metastasis, tumor development can ameliorate cardiac dysfunction and suppress fibrosis. However, the precise mechanism through which cancer influences the heart and fibrosis is yet to be uncovered. To further explore the interaction between heart failure and cancer, we used the MDX mouse model, which suffers from cardiac fibrosis and cardiac dysfunction. A previous study from our lab demonstrated that tumor growth improves cardiac dysfunction and dampens fibrosis in the heart and diaphragm muscles of MDX mice. We used breast Polyoma middle T (PyMT) and Lewis lung carcinoma (LLC) cancer cell lines that developed into large tumors. To explore whether the aggressiveness of the cancer cell line is crucial for the beneficial phenotype, we employed a PyMT breast cancer cell line lacking integrin β1, representing a less aggressive cell line compared to the original PyMT cells. In addition, we examined immortalized and primary MEF cells. The injection of integrin β1 KO PyMT cancer cells and Mouse Embryo Fibroblasts cells (MEF) resulted in the improvement of cardiac function and decreased fibrosis in the heart, diaphragm, and skeletal muscles of MDX mice. Collectively, our data demonstrate that the cancer line aggressiveness as well as primary MEF cells are sufficient to impose the beneficial phenotype. These discoveries present potential novel clinical therapeutic approaches with beneficial outcome for patients with fibrotic diseases and cardiac dysfunction that do not require tumor growth

Tumor Growth Ameliorates Cardiac Dysfunction and Suppresses Fibrosis in a Mouse Model for Duchenne Muscular Dystrophy

The interplay between heart failure and cancer represents a double-edged sword. Whereas cardiac remodeling promotes cancer progression, tumor growth suppresses cardiac hypertrophy and reduces fibrosis deposition. Whether these two opposing interactions are connected awaits to be determined. In addition, it is not known whether cancer affects solely the heart, or if other organs are affected as well. To explore the dual interaction between heart failure and cancer, we studied the human genetic disease Duchenne Muscular Dystrophy (DMD) using the MDX mouse model. We analyzed fibrosis and cardiac function as well as molecular parameters by multiple methods in the heart, diaphragm, lungs, skeletal muscles, and tumors derived from MDX and control mice. Surprisingly, cardiac dysfunction in MDX mice failed to promote murine cancer cell growth. In contrast, tumor-bearing MDX mice displayed reduced fibrosis in the heart and skeletal and diaphragm muscles, resulting in improved cardiac function. The latter is at least partially mediated via M2 macrophage recruitment to the heart and diaphragm muscles. Collectively, our data support the notion that the effect of heart failure on tumor promotion is independent of the improved cardiac function in tumor-bearing mice. Reduced fibrosis in tumor-bearing MDX mice stems from the suppression of new fibrosis synthesis and the removal of existing fibrosis. These findings offer potential therapeutic strategies for DMD patients, fibrotic diseases, and cardiac dysfunction