PMID- 24599933 OWN - NLM STAT- MEDLINE DCOM- 20150209 LR - 20220420 IS - 1557-3265 (Electronic) IS - 1078-0432 (Linking) VI - 20 IP - 10 DP - 2014 May 15 TI - Id1-induced IGF-II and its autocrine/endocrine promotion of esophageal cancer progression and chemoresistance--implications for IGF-II and IGF-IR-targeted therapy. PG - 2651-62 LID - 10.1158/1078-0432.CCR-13-2735 [doi] AB - PURPOSE: 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. EXPERIMENTAL DESIGN: 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. CI - (c)2014 American Association for Cancer Research. FAU - Li, Bin AU - Li B AD - 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. FAU - Tsao, Sai Wah AU - Tsao SW AD - 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. FAU - Chan, Kwok Wah AU - Chan KW AD - 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. FAU - Ludwig, Dale L AU - Ludwig DL AD - 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. FAU - Novosyadlyy, Ruslan AU - Novosyadlyy R AD - 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. FAU - Li, Yuk Yin AU - Li YY AD - 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. FAU - He, Qing Yu AU - He QY AD - 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. FAU - Cheung, Annie L M AU - Cheung AL AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140305 PL - United States TA - Clin Cancer Res JT - Clinical cancer research : an official journal of the American Association for Cancer Research JID - 9502500 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antibodies, Neutralizing) RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (ID1 protein, human) RN - 0 (Inhibitor of Differentiation Protein 1) RN - 2285XW22DR (cixutumumab) RN - 67763-97-7 (Insulin-Like Growth Factor II) RN - EC 2.7.10.1 (Receptor, IGF Type 1) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - U3P01618RT (Fluorouracil) SB - IM MH - Animals MH - Antibodies, Monoclonal/pharmacology MH - Antibodies, Monoclonal, Humanized MH - Antibodies, Neutralizing/immunology/pharmacology MH - Antimetabolites, Antineoplastic/pharmacology MH - Autocrine Communication MH - Blotting, Western MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Drug Resistance, Neoplasm/drug effects MH - Endocrine System/metabolism MH - Esophageal Neoplasms/drug therapy/*metabolism/pathology MH - Fluorouracil/pharmacology MH - Humans MH - Inhibitor of Differentiation Protein 1/genetics/*metabolism MH - Insulin-Like Growth Factor II/genetics/immunology/*metabolism MH - Lung Neoplasms/metabolism/prevention & control/secondary MH - Mice MH - Mice, Nude MH - Phosphatidylinositol 3-Kinases/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - RNA Interference MH - Receptor, IGF Type 1/antagonists & inhibitors/genetics/*metabolism MH - Signal Transduction/drug effects MH - Tumor Burden/drug effects MH - Xenograft Model Antitumor Assays EDAT- 2014/03/07 06:00 MHDA- 2015/02/11 06:00 CRDT- 2014/03/07 06:00 PHST- 2014/03/07 06:00 [entrez] PHST- 2014/03/07 06:00 [pubmed] PHST- 2015/02/11 06:00 [medline] AID - 1078-0432.CCR-13-2735 [pii] AID - 10.1158/1078-0432.CCR-13-2735 [doi] PST - ppublish SO - Clin Cancer Res. 2014 May 15;20(10):2651-62. doi: 10.1158/1078-0432.CCR-13-2735. Epub 2014 Mar 5.