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Int J Biol Sci 2017; 13(6):804-814. doi:10.7150/ijbs.19398

Research Paper

Stroma-derived Fibrinogen-like Protein 2 Activates Cancer-associated Fibroblasts to Promote Tumor Growth in Lung Cancer

Ying Zhu1, 2*, Longhui Zhang1, 2*, Haoran Zha1, 2, Fei Yang3, Chunyan Hu1, 2, Lin Chen4, Bo Guo3✉, Bo Zhu1, 2✉

1. Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P. R. China;
2. Chongqing Key Laboratory of Immunotherapy, Chongqing 400037, P. R. China;
3. Department of Pathogenic Biology, Third Military Medical University, Chongqing, 400038, P. R. China;
4. Department of Rehabilitation Medicine, Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, 400042, P. R. China
* These authors contributed equally to this work.

Abstract

Fibrinogen-like protein 2 (Fgl2), a member of the fibrinogen super family, is a pleiotropic cytokine that impacts diverse cellular functions. Previous studies have shown that tumor cell-derived Fgl2 promotes tumorigenesis and metastasis in immune-deficient mice, and it also functions as an immune-suppressive modulator in glioblastoma multiform (GMB). This study aimed to evaluate whether and how tumor stroma-derived Fgl2 affects tumorigenesis and tumor progression. We established the syngeneic transplantable Lewis lung carcinoma (LLC) model in Fgl2-knock-out (Fgl2-KO) mice and we found that deficiency of host Fgl2 is associated with reduced growth of syngeneic LLC tumors. Furthermore, we confirmed that host Fgl2 deficiency significantly decreased the accumulation of myeloid-derived suppressor cells (MDSCs) through down-regulation of chemokine (C-X-C motif) ligand 12 (CXCL12) expression. More importantly, we demonstrated that Fgl2 induced an activated and pro-tumorigenic phenotype of cancer-associated fibroblasts (CAFs) which are the principal source of CXCL12 in the tumor microenvironment (TME). Our results present a novel role of stroma-derived Fgl2 in CAF activation and function, suggesting that Fgl2 is an effective therapeutic target for treating lung cancer.

Keywords: Fgl2, cancer-associated fibroblast, myeloid-derived suppressor cell, lung cancer.

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How to cite this article:
Zhu Y, Zhang L, Zha H, Yang F, Hu C, Chen L, Guo B, Zhu B. Stroma-derived Fibrinogen-like Protein 2 Activates Cancer-associated Fibroblasts to Promote Tumor Growth in Lung Cancer. Int J Biol Sci 2017; 13(6):804-814. doi:10.7150/ijbs.19398. Available from http://www.ijbs.com/v13p0804.htm