title: Urokinase plasminogen activator secreted by cancer-associated fibroblasts induces tumor progression via PI3K/AKT and ERK signaling in esophageal squamous cell carcinoma.
abstract: Cancer-associated fibroblasts (CAFs) are believed to influence tumor behavior and clinical outcomes. We previously showed that conditioned medium (CM) from CAFs induces proliferation and motility of esophageal squamous cell carcinoma (ESCC) cells. Here, we investigated the molecular mechanisms by which the CAF-secreted proteins induce ESCC development and progression. Using antibody arrays, we identified urokinase plasminogen activator (uPA) as one of the main proteins whose release was increased in CAFs compared to normal fibroblasts (NFs). Immunohistochemical analysis of pathological sections showed that uPA-positive cells were localized at the boundaries of tumor and stroma tissues, in stroma between tumor nests, and within the tumors. Increased stromal uPA levels (132/146 cases) correlated with tumor invasion (p < 0.05) and overall survival of ESCC patients (p < 0.05). In vitro assays showed that uPA promotes ESCC cell proliferation, migration, and invasion via PI3K/AKT and ERK signaling pathways. In vivo, anti-uPA antibody suppressed tumor growth in ESCC xenografts. These results suggest that uPA released from stroma, and especially from CAFs, might be a predictive marker for ESCC diagnosis and prognosis, as well as an effective therapeutic target.
authors.affiliation: Institute of Biomedicine & Department of Cell Biology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, China.
authors.forename: Baoqing
authors.initials: B
authors.lastname: Tian
authors.affiliation: Institute of Biomedicine & Department of Cell Biology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, China.
authors.forename: Xiaojia
authors.initials: X
authors.lastname: Chen
authors.affiliation: Institute of Biomedicine & Department of Cell Biology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, China.
authors.forename: Huihua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Institute of Biomedicine & Department of Cell Biology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Li
authors.affiliation: Cancer Center of Guangzhou Medical University, Guangzhou, China.
authors.forename: Jiakang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute of Biomedicine & Department of Cell Biology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.affiliation: Department of Clinical Oncology, University of Hong Kong, Hong Kong, China.
authors.forename: Li-Yi
authors.initials: LY
authors.lastname: Zhang
authors.affiliation: Shenzhen Key Laboratory of translational Medicine of Tumor and Cancer Research Centre, School of Medicine, Shenzhen University, Shenzhen, China.
authors.forename: Li
authors.initials: L
authors.lastname: Fu
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Biomedicine & Department of Cell Biology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, China.
authors.forename: Changjun
authors.initials: C
authors.lastname: Nie
authors.affiliation: Institute of Biomedicine & Department of Cell Biology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Institute of Biomedicine & Department of Cell Biology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Tan
authors.affiliation: Institute of Biomedicine & Department of Cell Biology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Clinical Oncology, University of Hong Kong, Hong Kong, China.|Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Guan
authors.affiliation: Institute of Biomedicine & Department of Cell Biology, Jinan University, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, China.
authors.forename: An
authors.initials: A
authors.lastname: Hong
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008875:Middle Aged; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D014568:Urokinase-Type Plasminogen Activator
keywords: CAFs; ERK; ESCC; PI3K/AKT; uPA