Infiltrating neutrophils promote renal cell carcinoma progression via VEGFa/HIF2α and estrogen receptor β signals

// Wenbin Song 1,2,* , Chiuan-Ren Yeh 1,* , Dalin He 2,* , Yong Wang 1 , Hongjun Xie 1,2 , See-Tong Pang 1 , Luke Sien-Shih Chang 2 , Lei Li 2 and Shuyuan Yeh 1 1 George Whipple Lab for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, New York, USA 2 Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China * These authors Contributed equally to this work Correspondence to: Lei Li, email: // Shuyuan Yeh, email: // Keywords : tumor microenvironment, RCC, Neutrophils, ERβ, VEGFa and HIF pathways Received : November 24, 2014 Accepted : April 02, 2015 Published : June 15, 2015 Abstract Neutrophils make up a significant portion of the infiltrated immune cells found in the tumor microenvironment. Here we found more infiltrated neutrophils in human renal cell carcinoma (RCC) lesions than adjacent benign areas. In vitro RCC studies showed that neutrophils (HL-60N cells) infiltrated toward RCC cells and subsequently enhanced RCC cell migration and invasion. Co-culture of RCC cells with HL-60N cells up-regulated ERβ, VEGFa and HIF2α mRNA levels. ERβ signals increased RCC cell migration via induction of the VEGFa/HIF2α pathway. Treatment of HIF inhibitor or rapamycin, or knockdown of ERβ in RCC cells reversed HL-60N-promoted RCC migration . In vivo data using orthotopically xenografted RCC mouse model confirmed that infiltrated neutrophils promoted RCC migration via modulating the expressions of ERβ, VEGFa and HIF2α signal pathways. Together, our studies revealed that neutrophils are favorably recruited to the RCC cells to promote the RCC migration and invasion. Targeting the infiltrating RCC tumor microenvironment with anti-estrogen or rapamycin may be a potential therapy to suppress RCC progression.