Epithelial derived CTGF promotes breast tumor progression via inducing EMT and collagen I fibers deposition

// Xiaoping Zhu 1, * , Jing Zhong 1, 2, * , Zhen Zhao 1, 3 , Jianting Sheng 1 , Jiang Wang 1, 4 , Jiyong Liu 1, 5 , Kemi Cui 1 , Jenny Chang 6 , Hong Zhao 1 , Stephen Wong 1, 6 1 Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX, USA 2 Department of Radiology, The Teaching Hospital of Fujian Medical University, Fujian Provincial Cancer Hospital, Fuzhou, China 3 Department of Radiology, Zhongda Hospital, Nanjing, China 4 Department of Orthopedics, Tongji Hospital, Wuhan, China 5 Department of Pharmacy, Changhai Hospital, Shanghai, China 6 Methodist Cancer Center, Houston Methodist Hospital, Houston, TX, USA * These authors have contributed equally to this work Correspondence to: Hong Zhao, e-mail: hzhao@tmhs.org Keywords: connective tissue growth factor (CTGF), epithelial-mesenchymal transition (EMT), collagen I fibers, tumor necrosis factor receptor 1 (TNFR1) pathway, breast cancer Received: April 02, 2015      Accepted: July 17, 2015      Published: July 29, 2015 ABSTRACT Interactions among tumor cells, stromal cells, and extracellular matrix compositions are mediated through cytokines during tumor progression. Our analysis of 132 known cytokines and growth factors in published clinical breast cohorts and our 84 patient-derived xenograft models revealed that the elevated connective tissue growth factor (CTGF) in tumor epithelial cells significantly correlated with poor clinical prognosis and outcomes. CTGF was able to induce tumor cell epithelial-mesenchymal transition (EMT), and promote stroma deposition of collagen I fibers to stimulate tumor growth and metastasis. This process was mediated through CTGF-tumor necrosis factor receptor I (TNFR1)-IκB autocrine signaling. Drug treatments targeting CTGF, TNFR1, and IκB signaling each prohibited the EMT and tumor progression.