Interleukin-8 Mediates Resistance to Antiangiogenic Agent Sunitinib in Renal Cell Carcinoma

被引：339

作者：

Huang, Dan ^{[1
]}

Ding, Yan ^{[1
]}

Zhou, Ming ^{[3
]}

Rini, Brian I. ^{[4
]}

Petillo, David ^{[1
]}

Qian, Chao-Nan ^{[1
,5
]}

Kahnoski, Richard ^{[6
]}

Futreal, P. Andrew ^{[7
]}

Furge, Kyle A. ^{[2
]}

Teh, Bin Tean ^{[1
]}

机构：

[1] Van Andel Res Inst, Canc Genet Lab, Grand Rapids, MI 49503 USA

[2] Van Andel Res Inst, Lab Computat Biol, Grand Rapids, MI 49503 USA

[3] Cleveland Clin, Dept Anat Pathol, Cleveland, OH 44106 USA

[4] Cleveland Clin, Dept Solid Tumor Oncol & Urol, Cleveland, OH 44106 USA

[5] Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol S China, Guangzhou 510275, Guangdong, Peoples R China

[6] Spectrum Hlth, Dept Urol, Grand Rapids, MI USA

[7] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton, England

来源：

CANCER RESEARCH | 2010年 / 70卷 / 03期

基金：

英国惠康基金;

关键词：

ENDOTHELIAL GROWTH-FACTOR; TARGETED THERAPY; INTERFERON-ALPHA; ANGIOGENESIS; INHIBITION; MECHANISMS; PATHWAY; MALATE;

D O I：

10.1158/0008-5472.CAN-09-3965

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The broad spectrum kinase inhibitor sunitinib is a first-line therapy for advanced clear cell renal cell carcinoma (ccRCC), a deadly form of kidney cancer. Unfortunately, most patients develop sunitinib resistance and progressive disease after about 1 year of treatment. In this study, we evaluated the mechanisms of resistance to sunitinib to identify the potential tactics to overcome it. Xenograft models were generated that mimicked clinical resistance to sunitinib. Higher microvessel density was found in sunitinib-resistant tumors, indicating that an escape from antiangiogenesis occurred. Notably, escape coincided with increased secretion of interleukin-8 (IL-8) from tumors into the plasma, and coadministration of an IL-8 neutralizing antibody resensitized tumors to sunitinib treatment. In patients who were refractory to sunitinib treatment, IL-8 expression was elevated in ccRCC tumors, supporting the concept that IL-8 levels might predict clinical response to sunitinib. Our results reveal IL-8 as an important contributor to sunitinib resistance in ccRCC and a candidate therapeutic target to reverse acquired or intrinsic resistance to sunitinib in this malignancy. Cancer Res; 70(3); 1063-71. (C)2010 AACR.

引用

页码：1063 / 1071

页数：9

共 25 条

[1] Modes of resistance to anti-angiogenic therapy [J].

Bergers, Gabriele ;

Hanahan, Douglas .

NATURE REVIEWS CANCER, 2008, 8 (08) :592-603

[2] The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis [J].

Brat, DJ ;

Bellail, AC ;

Van Meir, EG .

NEURO-ONCOLOGY, 2005, 7 (02) :122-133

[3] Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors [J].

Casanovas, O ;

Hicklin, DJ ;

Bergers, G ;

Hanahan, D .

CANCER CELL, 2005, 8 (04) :299-309

[4] von Hippel-Lindau gene status and response to vascular endothelial growth factor targeted therapy for metastatic clear cell renal cell carcinoma [J].

Choueiri, Toni K. ;

Vaziri, Susan A. J. ;

Jaeger, Erich ;

Elson, Paul ;

Wood, Laura ;

Bhalla, Ish Prasad ;

Small, Eric J. ;

Weinberg, Vivian ;

Sein, Nancy ;

Simko, Jeff ;

Golshayan, Ali-Reza ;

Sercia, Linda ;

Zhou, Ming ;

Waldman, Frederic M. ;

Rini, Brian I. ;

Bukowski, Ronald M. ;

Ganapathi, Ram .

JOURNAL OF UROLOGY, 2008, 180 (03) :860-865

[5] Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy [J].

Ebos, John M. L. ;

Lee, Christina R. ;

Christensen, James G. ;

Mutsaers, Anthony J. ;

Kerbel, Robert S. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (43) :17069-17074

[6] Pathways Mediating Resistance to Vascular Endothelial Growth Factor - Targeted Therapy [J].

Ellis, Lee M. ;

Hicklin, Daniel J. .

CLINICAL CANCER RESEARCH, 2008, 14 (20) :6371-6375

[7] VEGF-targeted therapy: mechanisms of anti-tumour activity [J].

Ellis, Lee M. ;

Hicklin, Daniel J. .

NATURE REVIEWS CANCER, 2008, 8 (08) :579-591

[8] Molecular basis for sunitinib efficacy and future clinical development [J].

Faivre, Sandrine ;

Demetri, George ;

Sargent, William ;

Raymond, Eric .

NATURE REVIEWS DRUG DISCOVERY, 2007, 6 (09) :734-745

[9] Interleukin-8 is a paracrine inducer of fibroblast growth factor 2, a stromal and epithelial growth factor in benign prostatic hyperplasia [J].

Giri, D ;

Ittmann, M .

AMERICAN JOURNAL OF PATHOLOGY, 2001, 159 (01) :139-147

[10] Patterns of somatic mutation in human cancer genomes [J].

Greenman, Christopher ;

Stephens, Philip ;

Smith, Raffaella ;

Dalgliesh, Gillian L. ;

Hunter, Christopher ;

Bignell, Graham ;

Davies, Helen ;

Teague, Jon ;

Butler, Adam ;

Edkins, Sarah ;

O'Meara, Sarah ;

Vastrik, Imre ;

Schmidt, Esther E. ;

Avis, Tim ;

Barthorpe, Syd ;

Bhamra, Gurpreet ;

Buck, Gemma ;

Choudhury, Bhudipa ;

Clements, Jody ;

Cole, Jennifer ;

Dicks, Ed ;

Forbes, Simon ;

Gray, Kris ;

Halliday, Kelly ;

Harrison, Rachel ;

Hills, Katy ;

Hinton, Jon ;

Jenkinson, Andy ;

Jones, David ;

Menzies, Andy ;

Mironenko, Tatiana ;

Perry, Janet ;

Raine, Keiran ;

Richardson, Dave ;

Shepherd, Rebecca ;

Small, Alexandra ;

Tofts, Calli ;

Varian, Jennifer ;

Webb, Tony ;

West, Sofie ;

Widaa, Sara ;

Yates, Andy ;

Cahill, Daniel P. ;

Louis, David N. ;

Goldstraw, Peter ;

Nicholson, Andrew G. ;

Brasseur, Francis ;

Looijenga, Leendert ;

Weber, Barbara L. ;

Chiew, Yoke-Eng .

NATURE, 2007, 446 (7132) :153-158

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