Minireview: IGF, Insulin, and Cancer.

In recent years, the influence of the IGF system and insulin on cancer growth has been widely studied. Observational human studies have reported increased cancer mortality in those with obesity and type 2 diabetes, which may be attributable to hyperinsulinemia, elevated IGF-I, or potentially both factors. Conversely, those with low insulin, IGF-I and IGF-II levels appear to be relatively protected from cancer development. Initial attention focused on the role of IGF-I in tumor development. The results of these investigations allowed for the development of therapies targeting the IGF-I receptor signaling pathway. However, after in vitro and in vivo studies demonstrating that insulin may also play a significant and independent role in tumorigenesis, insulin is now receiving more attention in this regard. Some studies suggest that targeting insulin receptor signaling may be an important alternative or adjunct to targeting IGF-I receptor signaling. In this minireview, we discuss some of the recent in vitro, animal, and clinical studies that have elaborated our understanding of the influence of IGF and insulin on tumorigenesis. These studies have shed more light on the interaction between insulin and IGF signaling in cancer cells. They have made possible the development of novel targeted therapies and highlighted some of the potential future directions for research and therapeutics.

[1]  E. Surmacz.  Function of the IGF-I Receptor in Breast Cancer , 2004, Journal of Mammary Gland Biology and Neoplasia.

[2]  Michael J Thun,et al.  Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. , 2003, The New England journal of medicine.

[3]  D. Hunter,et al.  Insulin-like growth factor-I, its binding proteins (IGFBP-1 and IGFBP-3), and growth hormone and breast cancer risk in The Nurses Health Study II. , 2006, Endocrine-related cancer.

[4]  Douglas Hanahan,et al.  Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy , 2010, Proceedings of the National Academy of Sciences.

[5]  D. Yee,et al.  Inhibition of Cancer Cell Proliferation and Metastasis by Insulin Receptor Downregulation , 2010, Oncogene.

[6]  A. Costantino,et al.  Insulin Receptor Isoform A, a Newly Recognized, High-Affinity Insulin-Like Growth Factor II Receptor in Fetal and Cancer Cells , 1999, Molecular and Cellular Biology.

[7]  M. Thun,et al.  Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. , 2004, American journal of epidemiology.

[8]  F. Clavel-Chapelon,et al.  Serum levels of IGF‐I, IGFBP‐3 and colorectal cancer risk: results from the EPIC cohort, plus a meta‐analysis of prospective studies , 2010, International journal of cancer.

[9]  S. Koujak,et al.  Compensatory Insulin Receptor (IR) Activation on Inhibition of Insulin-Like Growth Factor-1 Receptor (IGF-1R): Rationale for Cotargeting IGF-1R and IR in Cancer , 2010, Molecular Cancer Therapeutics.

[10]  J. Petrik,et al.  Reversibility and recurrence of IGF-IR-induced mammary tumors , 2009, Oncogene.

[11]  G. Reaven,et al.  Pathophysiology of insulin resistance in human disease. , 1995, Physiological reviews.

[12]  M. De León,et al.  Insulin-like growth factors I and II receptors in the breast cancer survival disparity among African-American women. , 2010, Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society.

[13]  A. Casson,et al.  Loss of imprinting of the insulin-like growth factor II (IGF2) gene in esophageal normal and adenocarcinoma tissues. , 2009, Carcinogenesis.

[14]  Qifeng Yang,et al.  Prognostic significance of IGF-1R expression in patients treated with breast-conserving surgery and radiation therapy. , 2010, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[15]  Matthias Egger,et al.  Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis , 2004, The Lancet.

[16]  Nahum Sonenberg,et al.  Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. , 2006, Cancer research.

[17]  Federica Madia,et al.  Growth Hormone Receptor Deficiency Is Associated with a Major Reduction in Pro-Aging Signaling, Cancer, and Diabetes in Humans , 2011, Science Translational Medicine.

[18]  L. Hennighausen,et al.  Reduced circulating insulin-like growth factor I levels delay the onset of chemically and genetically induced mammary tumors. , 2003, Cancer research.

[19]  K. Zänker,et al.  Diabetogenic glucose and insulin concentrations modulate transcriptom and protein levels involved in tumour cell migration, adhesion and proliferation , 2010, British Journal of Cancer.

[20]  S. Schuetze,et al.  Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma and Ewing's sarcoma: a phase 1 expansion cohort study. , 2010, The Lancet. Oncology.

[21]  L. Hennighausen,et al.  Circulating insulin-like growth factor-I levels regulate colon cancer growth and metastasis. , 2002, Cancer research.

[22]  J. Scott,et al.  Insulin-like growth factor-II gene expression in Wilms' tumour and embryonic tissues , 1985, Nature.

[23]  D. Leroith,et al.  Insulin-Sensitizing Therapy Attenuates Type 2 Diabetes–Mediated Mammary Tumor Progression , 2009, Diabetes.

[24]  A. Thor,et al.  Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro , 2009, Cell cycle.

[25]  D. Leroith,et al.  The role of the growth hormone/insulin-like growth factor axis in tumor growth and progression: Lessons from animal models. , 2005, Cytokine & growth factor reviews.

[26]  W. Tamborlane,et al.  Effect of Diabetes and its Control on Insulin-like Growth Factors in the Young Subject with Type I Diabetes , 1984, Diabetes.

[27]  M. Tang,et al.  Insulin-like Growth Factor 1 Stimulates KCl Cotransport, Which Is Necessary for Invasion and Proliferation of Cervical Cancer and Ovarian Cancer Cells* , 2004, Journal of Biological Chemistry.

[28]  E. Barrett-Connor,et al.  Insulin-like growth factor-I and cancer mortality in older men. , 2010, The Journal of clinical endocrinology and metabolism.

[29]  E. Gale,et al.  The influence of glucose-lowering therapies on cancer risk in type 2 diabetes , 2009, Diabetologia.

[30]  C. Chou,et al.  Clinical implications of insulin-like growth factor 1 system in early-stage cervical cancer , 2008, British Journal of Cancer.

[31]  A. Berchuck,et al.  Frequent IGF2/H19 Domain Epigenetic Alterations and Elevated IGF2 Expression in Epithelial Ovarian Cancer , 2006, Molecular Cancer Research.

[32]  G. Colditz,et al.  Expression of IGF1R in normal breast tissue and subsequent risk of breast cancer , 2010, Breast Cancer Research and Treatment.

[33]  H. Werner,et al.  Long-acting insulin analogues elicit atypical signalling events mediated by the insulin receptor and insulin-like growth factor-I receptor , 2010, Diabetologia.

[34]  L. Hemkens,et al.  Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study , 2009, Diabetologia.

[35]  M. Tabrizi,et al.  Dual IGF-I/II-neutralizing antibody MEDI-573 potently inhibits IGF signaling and tumor growth. , 2011, Cancer research.

[36]  D. Yee,et al.  Down-regulation of type I insulin-like growth factor receptor increases sensitivity of breast cancer cells to insulin. , 2007, Cancer research.

[37]  D. Coppola,et al.  Effect of a null mutation of the insulin-like growth factor I receptor gene on growth and transformation of mouse embryo fibroblasts , 1994, Molecular and cellular biology.

[38]  B. Ch.  Insulin and Diabetes-In Retrospect and in Prospect: The Banting Memorial Lecture, 1945. , 1945 .

[39]  F. Huang,et al.  Insulin receptor (IR) pathway hyperactivity in IGF-IR null cells and suppression of downstream growth signaling using the dual IGF-IR/IR inhibitor, BMS-754807. , 2010, Endocrinology.

[40]  J. French,et al.  Dietary restriction reduces insulin-like growth factor I levels, which modulates apoptosis, cell proliferation, and tumor progression in p53-deficient mice. , 1997, Cancer research.

[41]  P. Glazer,et al.  Insulin-like growth factor-I receptor overexpression mediates cellular radioresistance and local breast cancer recurrence after lumpectomy and radiation. , 1997, Cancer research.

[42]  Laura Sciacca,et al.  Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. , 2009, Endocrine reviews.

[43]  L. Schäffer,et al.  Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. , 2000, Diabetes.

[44]  Z. Laron,et al.  Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies. , 2011, European journal of endocrinology.

[45]  R. Weksberg,et al.  Relaxation of imprinting of human insulin-like growth factor II gene, IGF2, in sporadic breast carcinomas. , 1997, Biochemical and biophysical research communications.

[46]  M. De León,et al.  Differential insulin-like growth factor II (IGF-II) expression: A potential role for breast cancer survival disparity. , 2010, Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society.

[47]  H. Orskov,et al.  Free insulin-like growth factors in human obesity. , 1995, Metabolism: clinical and experimental.

[48]  D. Johnston,et al.  Paracrine overexpression of insulin-like growth factor-1 enhances mammary tumorigenesis in vivo. , 2008, The American journal of pathology.

[49]  D. Leroith,et al.  Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes. , 2010, Cancer research.

[50]  D. Leroith,et al.  The role of the IGF system in cancer growth and metastasis: overview and recent insights. , 2007, Endocrine reviews.

[51]  R. Brand,et al.  Elevated insulin receptor content in human breast cancer. , 1990, The Journal of clinical investigation.

[52]  Andrew W Roddam,et al.  Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies , 2010, The Lancet. Oncology.

[53]  S. Ezzat,et al.  Acromegaly: Re-thinking the cancer risk , 2008, Reviews in Endocrine and Metabolic Disorders.

[54]  Han You,et al.  Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways. , 2006, Genes & development.

[55]  R. Weksberg,et al.  Disruption of insulin–like growth factor 2 imprinting in Beckwith–Wiedemann syndrome , 1993, Nature genetics.

[56]  P. Donnan,et al.  New Users of Metformin Are at Low Risk of Incident Cancer , 2009, Diabetes Care.

[57]  A. Klibanski,et al.  Serum insulin-like growth factor-binding protein-3 levels in the diagnosis of acromegaly. , 1995, The Journal of clinical endocrinology and metabolism.

[58]  G. Loughran,et al.  Gene expression profiles in cells transformed by overexpression of the IGF-I receptor , 2005, Oncogene.

[59]  J. Deslypere,et al.  Fasting serum insulin in relation to components of the metabolic syndrome in European healthy men: the European Fat Distribution Study. , 1995, Metabolism: clinical and experimental.

[60]  Y. Wong,et al.  Sex hormone‐induced prostatic carcinogenesis in the Noble rat: The role of insulin‐like growth factor‐1 (IGF‐1) and vascular endothelial growth factor (VEGF) in the development of prostate cancer , 1998, The Prostate.