title: Id1-induced IGF-II and its autocrine/endocrine promotion of esophageal cancer progression and chemoresistance--implications for IGF-II and IGF-IR-targeted therapy.
abstract: OBJECTIVE
  To investigate the autocrine/endocrine role of Id1-induced insulin-like growth factor-II (IGF-II) in esophageal cancer, and evaluate the potential of IGF-II- and IGF-type I receptor (IGF-IR)-targeted therapies.
  
  
  METHODS
  Antibody array-based screening was used to identify differentially secreted growth factors from Id1-overexpressing esophageal cancer cells. In vitro and in vivo assays were performed to confirm the induction of IGF-II by Id1, and to study the autocrine and endocrine effects of IGF-II in promoting esophageal cancer progression. Human esophageal cancer tissue microarray was analyzed for overexpression of IGF-II and its correlation with that of Id1 and phosphorylated AKT (p-AKT). The efficacy of intratumorally injected IGF-II antibody and intraperitoneally injected cixutumumab (fully human monoclonal IGF-IR antibody) was evaluated using in vivo tumor xenograft and experimental metastasis models.
  
  
  RESULTS
  Id1 overexpression induced IGF-II secretion, which promoted cancer cell proliferation, survival, and invasion by activating AKT in an autocrine manner. Overexpression of IGF-II was found in 21 of 35 (60%) esophageal cancer tissues and was associated with upregulation of Id1 and p-AKT. IGF-II secreted by Id1-overexpressing esophageal cancer xenograft could instigate the growth of distant esophageal tumors, as well as promote metastasis of circulating cancer cells. Targeting IGF-II and IGF-IR had significant suppressive effects on tumor growth and metastasis in mice. Cixutumumab treatment enhanced the chemosensitivity of tumor xenografts to fluorouracil and cisplatin.
  
  
  CONCLUSIONS
  The Id1-IGF-II-IGF-IR-AKT signaling cascade plays an important role in esophageal cancer progression. Blockade of IGF-II/IGF-IR signaling has therapeutic potential in the management of esophageal cancer.
authors.affiliation: Authors' Affiliations: Department of Anatomy, Centre for Cancer Research; Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR; Institute of Life and Health Engineering, Jinan University, Guangzhou, China; and ImClone Systems Corporation, a wholly owned subsidiary of Eli Lilly & Co, New York, New YorkAuthors' Affiliations: Department of Anatomy, Centre for Cancer Research; Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR; Institute of Life and Health Engineering, Jinan University, Guangzhou, China; and ImClone Systems Corporation, a wholly owned subsidiary of Eli Lilly & Co, New York, New York.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Authors' Affiliations: Department of Anatomy, Centre for Cancer Research; Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR; Institute of Life and Health Engineering, Jinan University, Guangzhou, China; and ImClone Systems Corporation, a wholly owned subsidiary of Eli Lilly & Co, New York, New YorkAuthors' Affiliations: Department of Anatomy, Centre for Cancer Research; Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR; Institute of Life and Health Engineering, Jinan University, Guangzhou, China; and ImClone Systems Corporation, a wholly owned subsidiary of Eli Lilly & Co, New York, New York.
authors.forename: Sai Wah
authors.initials: SW
authors.lastname: Tsao
authors.affiliation: Authors' Affiliations: Department of Anatomy, Centre for Cancer Research; Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR; Institute of Life and Health Engineering, Jinan University, Guangzhou, China; and ImClone Systems Corporation, a wholly owned subsidiary of Eli Lilly & Co, New York, New YorkAuthors' Affiliations: Department of Anatomy, Centre for Cancer Research; Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR; Institute of Life and Health Engineering, Jinan University, Guangzhou, China; and ImClone Systems Corporation, a wholly owned subsidiary of Eli Lilly & Co, New York, New York.
authors.forename: Kwok Wah
authors.initials: KW
authors.lastname: Chan
authors.affiliation: Authors' Affiliations: Department of Anatomy, Centre for Cancer Research; Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR; Institute of Life and Health Engineering, Jinan University, Guangzhou, China; and ImClone Systems Corporation, a wholly owned subsidiary of Eli Lilly & Co, New York, New York.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Ludwig
authors.affiliation: Authors' Affiliations: Department of Anatomy, Centre for Cancer Research; Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR; Institute of Life and Health Engineering, Jinan University, Guangzhou, China; and ImClone Systems Corporation, a wholly owned subsidiary of Eli Lilly & Co, New York, New York.
authors.forename: Ruslan
authors.initials: R
authors.lastname: Novosyadlyy
authors.affiliation: Authors' Affiliations: Department of Anatomy, Centre for Cancer Research; Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR; Institute of Life and Health Engineering, Jinan University, Guangzhou, China; and ImClone Systems Corporation, a wholly owned subsidiary of Eli Lilly & Co, New York, New York.
authors.forename: Yuk Yin
authors.initials: YY
authors.lastname: Li
authors.affiliation: Authors' Affiliations: Department of Anatomy, Centre for Cancer Research; Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR; Institute of Life and Health Engineering, Jinan University, Guangzhou, China; and ImClone Systems Corporation, a wholly owned subsidiary of Eli Lilly & Co, New York, New York.
authors.forename: Qing Yu
authors.initials: QY
authors.lastname: He
authors.affiliation: Authors' Affiliations: Department of Anatomy, Centre for Cancer Research; Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR; Institute of Life and Health Engineering, Jinan University, Guangzhou, China; and ImClone Systems Corporation, a wholly owned subsidiary of Eli Lilly & Co, New York, New YorkAuthors' Affiliations: Department of Anatomy, Centre for Cancer Research; Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR; Institute of Life and Health Engineering, Jinan University, Guangzhou, China; and ImClone Systems Corporation, a wholly owned subsidiary of Eli Lilly & Co, New York, New York lmcheung@hkucc.hku.hk.
authors.forename: Annie L M
authors.initials: AL
authors.lastname: Cheung
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D019898:Autocrine Communication; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004703:Endocrine System / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil; D051798:Inhibitor of Differentiation Protein 1; D007335:Insulin-Like Growth Factor II; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; C497453:ID1 protein, human; C557414:cixutumumab