title: STAT3-mediated IGF-2 secretion in the tumour microenvironment elicits innate resistance to anti-IGF-1R antibody.
abstract: Drug resistance is a major impediment in medical oncology. Recent studies have emphasized the importance of the tumour microenvironment (TME) to innate resistance, to molecularly targeted therapies. In this study, we investigate the role of TME in resistance to cixutumumab, an anti-IGF-1R monoclonal antibody that has shown limited clinical efficacy. We show that treatment with cixutumumab accelerates tumour infiltration of stromal cells and metastatic tumour growth, and decreases overall survival of mice. Cixutumumab treatment stimulates STAT3-dependent transcriptional upregulation of IGF-2 in cancer cells and recruitment of macrophages and fibroblasts via paracrine IGF-2/IGF-2R activation, resulting in the stroma-derived CXCL8 production, and thus angiogenic and metastatic environment. Silencing IGF-2 or STAT3 expression in cancer cells or IGF-2R or CXCL8 expression in stromal cells significantly inhibits the cancer-stroma communication and vascular endothelial cells' angiogenic activities. These findings suggest that blocking the STAT3/IGF-2/IGF-2R intercellular signalling loop may overcome the adverse consequences of anti-IGF-1R monoclonal antibody-based therapies.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151 742, Korea.
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Lee
authors.affiliation: National Cancer Center, Goyang-si, Gyeonggi-do 410 769, Korea.
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Kang
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151 742, Korea.
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Boo
authors.affiliation: College of Pharmacy, Inje University, Gimhae, Gyeongnam 621 749, Korea.
authors.forename: Su-Jung
authors.initials: SJ
authors.lastname: Hwang
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151 742, Korea.
authors.forename: Sungyoul
authors.initials: S
authors.lastname: Hong
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151 742, Korea.
authors.forename: Su-Chan
authors.initials: SC
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151 742, Korea.
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Park
authors.affiliation: Department of Nuclear Medicine, Cancer Imaging Center, Seoul National University Hospital, Seoul 110 744, Korea.
authors.forename: Tae-Moon
authors.initials: TM
authors.lastname: Chung
authors.affiliation: Department of Nuclear Medicine, Cancer Imaging Center, Seoul National University Hospital, Seoul 110 744, Korea.
authors.forename: Hyewon
authors.identifier: http://orcid.org/0000-0003-1006-2689
authors.initials: H
authors.lastname: Youn
authors.affiliation: Department of Obstetrics and Gynecology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul 156 707, Korea.|Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 110 744, Korea.
authors.forename: Seung
authors.initials: S
authors.lastname: Mi Lee
authors.affiliation: Department of Obstetrics and Gynecology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul 156 707, Korea.|Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 110 744, Korea.
authors.forename: Byoung
authors.initials: B
authors.lastname: Jae Kim
authors.affiliation: Department of Nuclear Medicine, Cancer Imaging Center, Seoul National University Hospital, Seoul 110 744, Korea.
authors.forename: June-Key
authors.initials: JK
authors.lastname: Chung
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151 742, Korea.
authors.forename: Yeonseok
authors.initials: Y
authors.lastname: Chung
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: William N
authors.initials: WN
authors.lastname: William
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151 742, Korea.|The Center for Anti-Cancer CDx, N-Bio, Seoul National University, Seoul 151 742, Korea.
authors.forename: Young
authors.initials: Y
authors.lastname: Kee Shin
authors.affiliation: College of Pharmacy, Inje University, Gimhae, Gyeongnam 621 749, Korea.
authors.forename: Hyo-Jong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Gachon University, Inchon 406 840, Korea.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Oh
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151 742, Korea.
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Lee
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D045744:Cell Line, Tumor; D065150:Cellular Reprogramming; D019008:Drug Resistance, Neoplasm; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D019899:Paracrine Communication; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016209:Interleukin-8; D017527:Receptor, IGF Type 2; D050796:STAT3 Transcription Factor; C557414:cixutumumab; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1