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.
Highlights
Tumor microenvironment has emerged as an important target for cancer therapy
To investigate the relationship between transforming growth factor-β1 (TGF-β1) and cancer-associated fibroblasts (CAFs) in tumor microenvironment, we detected the expression of TGF-β and CAFs maker α-smooth muscle actin (α-SMA) in normal breast tissue and tumor tissues obtained from patients with clinical stage I–IV breast cancer
Western blotting analysis showed that TGF-β1 induced CAFs features in Star-treated NIH3T3 fibroblasts, which was characterized with positive expression of α-SMA and fibroblast activation protein-α (FAP-α) (Figure 2C)
Summary
Tumor microenvironment has emerged as an important target for cancer therapy. For most solid tumors, carcinomas, their microenvironment consists of the tumor cells themselves, endothelial cells, immune cells and fibroblasts contribute to tumorigenesis by secretion of cytokines and/or direct cell-cell contact [1]. CAFs are a subpopulation of fibroblasts found in the tumor microenvironment [3], They are myofibroblasts, or activated fibroblasts in the tumor stroma, mostly characterized by the expression of activated fibroblast markers, such as α-smooth muscle actin (α-SMA) and fibroblast activation protein-α (FAP-α) [4]. It is widely assumed that myofibroblasts may develop from NIH3T3 fibroblasts, as both cell types show more similarities than differences including the expression of cytoskeleton proteins like FAP-α and α-SMA [5]. Emerging study indicates that transforming growth factor-β1 (TGF-β1), a multifunctional cytokine www.impactjournals.com/oncotarget that regulates the growth, differentiation and migration of various types of cells [10], has been recognized as the most potent inducer for the transformation of fibroblasts to CAFs [11]. Mechanisms for CAFs activation by TGF-β in tumor microenvironment are not well understood
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