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Clin Cancer Res. 2014 May 15;20(10):2651-62. doi: 10.1158/1078-0432.CCR-13-2735. Epub 2014 Mar 5.

Id1-induced IGF-II and its autocrine/endocrine promotion of esophageal cancer progression and chemoresistance--implications for IGF-II and IGF-IR-targeted therapy.

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  • 1Authors' 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.
  • 2Authors' 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.
  • 3Authors' 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.

Abstract

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.

©2014 American Association for Cancer Research.

PMID:
24599933
[PubMed - indexed for MEDLINE]
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