title: Autophagy is involved in TGF-β1-induced protective mechanisms and formation of cancer-associated fibroblasts phenotype in tumor microenvironment.
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.
authors.affiliation: Pharmacy College, Jinan University, Guangzhou 510632, China.
authors.forename: Fang-Lan
authors.initials: FL
authors.lastname: Liu
authors.affiliation: Pharmacy College, Jinan University, Guangzhou 510632, China.
authors.forename: En-Pan
authors.initials: EP
authors.lastname: Mo
authors.affiliation: Pharmacy College, Jinan University, Guangzhou 510632, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Pharmacy College, Sun Yat-Sen University, Guangzhou 510405, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Du
authors.affiliation: Pharmacy College, Sun Yat-Sen University, Guangzhou 510405, China.
authors.forename: Hong-Sheng
authors.initials: HS
authors.lastname: Wang
authors.affiliation: Pharmacy College, Jinan University, Guangzhou 510632, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Pharmacy College, Jinan University, Guangzhou 510632, China.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kurihara
authors.affiliation: Pharmacy College, Jinan University, Guangzhou 510632, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Pharmacy College, Jinan University, Guangzhou 510632, China.
authors.forename: Shao-Hui
authors.initials: SH
authors.lastname: Cai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D041681:NIH 3T3 Cells; D010641:Phenotype; D020011:Protective Agents / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020011:Protective Agents; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1
keywords: TGF-β1; autophagy; cancer-associated fibroblasts; mitochondria; tumor microenvironment