Role of insulin-like growth factor-1R system in colorectal carcinogenesis

https://doi.org/10.1016/j.critrevonc.2007.09.003Get rights and content

Abstract

The insulin-like growth factor (IGF) system is comprised of receptors, ligands (IGF-I and IGF-II), and a family of binding proteins (IGFBPs). It plays an important role in growth and development and in the maintenance of normal homeostasis. We present a review of the current laboratory and epidemiologic evidence that suggests an important role of the IGF system in colorectal carcinogenesis. Due to the complexity of this system, we have focused the review on the role of the IGF-1 receptor and its ligands in colorectal carcinogenesis and the strategies to block this pathway as a potential anti-cancer therapy.

Introduction

The insulin-like growth factor (IGF) system has been shown to play a critical role in growth and development and in the maintenance of normal homeostasis. It is comprised of receptors, ligands (IGF-I and IGF-II) and a family of binding proteins (IGFBPs) (Fig. 1) [1], [2]. IGF-I and IGF-II are single chain polypeptides that share 62% homology with proinsulin. Although liver is the major site of production of IGF-I, which is regulated by growth hormone (GH) levels, it is produced by a number of tissues and exerts paracrine and autocrine effects on cells. Both IGF-I and IGF-II exert their biologic effects through activation of insulin-like growth factor type 1 receptor (IGF-1R). Binding of ligands causes activation of downstream cascades resulting in proliferative, differentiative and anti-apoptotic effects.

We present a review of the current evidence, from laboratory and epidemiologic studies, that suggests an important role of the IGF system in colorectal carcinogenesis. Due to the complexity of the effects and interactions of this system, the focus of this review is on the role of IGF-1R and its ligands, IGF-I and -II, in colorectal carcinogenesis and strategies to block this pathway as potential anti-cancer therapy. Data for this review was identified by searches of MEDLINE and PubMed and references from relevant articles using the search terms “insulin-like growth factor”, “cancer”, and “colorectal cancer”. Abstracts and reports from meetings are included. Only papers published in English between 1980 and 2006 are included.

Section snippets

IGF system and colorectal cancer: emerging evidence

Increased levels of IGF ligands and/or over-expression of IGF receptor have been observed in many cancers and have been shown to affect proliferation, differentiation, migration and apoptosis of cancer cells [1], [3].

Therapeutic strategies (Table 3)

Based on above evidence, the IGF pathway could be an important target for anti-cancer therapies. The strategies to inhibit IGF-1R signaling include IGF-1R monoclonal antibodies, IGF mimetic peptides that inhibit ligand/receptor interaction, tyrosine kinase inhibitors (TKIs), expression of dominant negative IGF-1R mutants, antisense strategies (antisense oligodeoxynucleotides, antisense RNA, IGF-1R specific small interfering RNAs (siRNAs)), IGF-1R specific peptide aptamers, and purified or

Conclusion

The IGF system plays an important role in tumorigenesis and has been shown to be an absolute requirement for the establishment and maintenance of the transformed phenotype [53]. The effect of down-regulating the IGF system is more profound on cells growing in anchorage independent conditions as opposed to cells growing in a monolayer [54]. This may provide relative selectivity for agents that target this pathway for the treatment of cancer. Early clinical trials with agents targeting the IGF

Reviewers

Monica M. Mita, MD, Institute for Drug Development Cancer Therapy and Research Center, 7979 Wurzbach Road, 4th Floor, San Antonio, TX 78229, United States.

Coty HO, MD, Chief, HEME/ONC, University of Texas at Tyler, 1446-206 Parkview Circle, Wilmington, NC 28405, United States.

Conflicts of interest

None.

Acknowledgement

This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, Bethesda, MD, United States.

Dr. Shivaani Kummar received her medical degree from Lady Hardinge Medical College, New Delhi, India and her Internal Medicine Residency training from Emory University, Atlanta, Georgia. Upon completion of her fellowship training in Medical Oncology and Hematology from the National Institutes of Health, Bethesda, MD, she joined Yale Cancer Center, Yale University, New Haven, Connecticut as an Assistant Professor in Medical Oncology. She worked closely with the Department of Pharmacology, Yale

References (57)

  • M.N. Pollak et al.

    Insulin-like growth factors and neoplasia

    Nat Rev Cancer

    (2004)
  • R. Durai et al.

    The role of the insulin-like growth factor system in colorectal cancer: review of current knowledge

    Int J Colorectal Dis

    (2005)
  • P.M. Jehle et al.

    Differential autocrine regulation of intestine epithelial cell proliferation and differentiation by insulin-like growth factor (IGF) system components

    Horm Metab Res

    (1999)
  • Y. Wu et al.

    Circulating insulin-like growth factor-I levels regulate colon cancer growth and metastasis

    Cancer Res

    (2002)
  • Y. Akagi et al.

    Regulation of vascular endothelial growth factor expression in human colon cancer by insulin-like growth factor-I

    Cancer Res

    (1998)
  • F. Andre et al.

    Integrins and E-cadherin cooperate with IGF-I to induce migration of epithelial colonic cells

    Int J Cancer

    (1999)
  • F. Garrouste et al.

    Prevention of cytokine-induced apoptosis by insulin-like growth factor-I is independent of cell adhesion molecules in HT29-D4 colon carcinoma cells-evidence for a NF-kappaB-dependent survival mechanism

    Cell Death Differ

    (2002)
  • A. Di Popolo et al.

    IGF-II/IGF-I receptor pathway up-regulates COX-2 mRNA expression and PGE2 synthesis in Caco-2 human colon carcinoma cells

    Oncogene

    (2000)
  • M.M. Weber et al.

    Overexpression of the insulin-like growth factor I receptor in human colon carcinomas

    Cancer

    (2002)
  • M. Nakamura et al.

    Low levels of insulin-like growth factor type 1 receptor expression at cancer cell membrane predict liver metastasis in Dukes’ C human colorectal cancers

    Clin Cancer Res

    (2004)
  • L. Zhang et al.

    Gene expression profiles in normal and cancer cells

    Science

    (1997)
  • K. Nosho et al.

    Interplay of insulin-like growth factor-II, insulin-like growth factor-I, insulin-like growth factor-I receptor, COX-2, and matrix metalloproteinase-7, play key roles in the early stage of colorectal carcinogenesis

    Clin Cancer Res

    (2004)
  • P.J. Jenkins et al.

    Acromegaly, colonic polyps and carcinoma

    Clin Endocrinol (Oxf)

    (1997)
  • A.G. Renehan et al.

    The prevalence and characteristics of colorectal neoplasia in acromegaly

    J Clin Endocrinol Metab

    (2000)
  • D. Baris et al.

    Acromegaly and cancer risk: a cohort study in Sweden and Denmark

    Cancer Causes Control

    (2002)
  • S.M. Orme et al.

    Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group

    J Clin Endocrinol Metab

    (1998)
  • A.C. Paterson et al.

    More about: prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3

    J Natl Cancer Inst

    (2000)
  • J. Ma et al.

    Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3

    J Natl Cancer Inst

    (1999)
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    Dr. Shivaani Kummar received her medical degree from Lady Hardinge Medical College, New Delhi, India and her Internal Medicine Residency training from Emory University, Atlanta, Georgia. Upon completion of her fellowship training in Medical Oncology and Hematology from the National Institutes of Health, Bethesda, MD, she joined Yale Cancer Center, Yale University, New Haven, Connecticut as an Assistant Professor in Medical Oncology. She worked closely with the Department of Pharmacology, Yale University to facilitate bringing new agents to clinical trials. At present, she is a Staff Clinician, Medical Oncology Branch, National Cancer Institute and works on early drug development in oncology.

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