Autophagy is involved in TGF-β1-induced protective mechanisms and formation of cancer-associated fibroblasts phenotype in tumor microenvironment

// Fang-Lan Liu 1 , En-Pan Mo 1 , Liu Yang 1 , Jun Du 2 , Hong-Sheng Wang 2 , Huan Zhang 1 , Hiroshi Kurihara 1 , Jun Xu 1 , Shao-Hui Cai 1 1 Pharmacy College, Jinan University, Guangzhou 510632, China 2 Pharmacy College, Sun Yat-Sen University, Guangzhou 510405, China Correspondence to: Shao-Hui Cai, e-mail: csh5689@sina.com Jun Xu, e-mail: goldstar_8209@163.com Keywords: autophagy, TGF-β1, tumor microenvironment, mitochondria, cancer-associated fibroblasts Received: July 06, 2015     Accepted: December 02, 2015     Published: December 21, 2015 ABSTRACT Transforming growth factor-β1 (TGF-β1) present in tumor microenvironment acts in a coordinated fashion to either suppress or promote tumor development. However, the molecular mechanisms underlying the effects of TGF-β1 on tumor microenvironment are not well understood. Our clinical data showed a positive association between TGF-β1 expression and cancer-associated fibroblasts (CAFs) in tumor microenvironment of breast cancer patients. Thus we employed starved NIH3T3 fibroblasts in vitro and 4T1 cells mixed with NIH3T3 fibroblasts xenograft model in vivo to simulate nutritional deprivation of tumor microenvironment to explore the effects of TGF-β1. We demonstrated that TGF-β1 protected NIH3T3 fibroblasts from Star-induced growth inhibition, mitochondrial damage and cell apoptosis. Interestingly, TGF-β1 induced the formation of CAFs phenotype in starvation (Star)-treated NIH3T3 fibroblasts and xenografted Balb/c mice, which promoted breast cancer tumor growth. In both models, autophagy agonist rapamycin increased TGF-β1-induced protective effects and formation of CAFs phenotypes, while autophagy inhibitor 3-methyladenine, Atg5 knockdown or TGF-β type I receptor kinase inhibitor LY-2157299 blocked TGF-β1 induced these effects. Taken together, our results indicated that TGF-β/Smad autophagy was involved in TGF-β1-induced protective effects and formation of CAFs phenotype in tumor microenvironment, which may be used as therapy targets in breast cancer.