Mangiferin inhibits chronic stress-induced tumor growth in colorectal liver metastases via WAVE2 signaling pathway

Background: Evidence indicates that chronic stress promotes progression of colorectal liver metastases (CLM). Mangiferin is the active chemical constituent of the rhizomes of Anemarrhena asphodeloides Bunge. Mangiferin (MGF) exerts anti-inflammatory, anti-proliferative, anti-angiogenic, anti-fibrotic and antioxidant effects in a variety of cancers. Its mechanism in chronic stress and tumor growth is still poorly understood. Methods: To investigate the effects of MGF on the CLM and tumor-associated depression, activated hepatic stellate cells (a-HSCs), HT-29 CRC cells, were used in chronic unpredictable mild stress (CUMS) of tumor-bearing models. Potential antidepressant activity was determined by FST, TST, SIT and serum cytokine (IL-6, IL-18 and TNF-α) examination. Downstream signaling molecules were detected by Western blot, immunohistochemistry and fluorescence microscopy. Results: CUMS induced depression behavior and depression-related cytokines and promoted tumor growth in CLM. MGF-treated mice significantly improved chronic stress behaviors by reducing depression-related cytokines. In addition, MGF treatment inhibits WAVE2 signaling pathway, leading to TGF-β1 induced HSC inhibition, thereby reducing depressive behavior and tumor growth in CLM. Conclusion: MGF can alleviate CUMS induced tumor growth and the treatment of CLM patients with MGF may be beneficial.