title: Infiltrating neutrophils promote renal cell carcinoma progression via VEGFa/HIF2α and estrogen receptor β signals.
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.
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, New York, USA.|Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Song
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Chiuan-Ren
authors.initials: CR
authors.lastname: Yeh
authors.affiliation: Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Dalin
authors.initials: D
authors.lastname: He
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, New York, USA.|Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Xie
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: See-Tong
authors.initials: ST
authors.lastname: Pang
authors.affiliation: Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Luke Sien-Shih
authors.initials: LS
authors.lastname: Chang
authors.affiliation: Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Yeh
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D047629:Estrogen Receptor beta / Q000378:metabolism*; D005260:Female; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D014162:Transfection; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D047629:Estrogen Receptor beta; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C467484:VEGFA protein, human
keywords: ERβ; RCC; VEGFa and HIF pathways; neutrophils; tumor microenvironment