Background: Insulin-like growth factor 2 (IGF2) is a protein hormone known to regulate cell proliferation, growth, migration, differentiation and survival. The gene is parentally imprinted in the sense that transcripts are almost exclusively derived from the paternal allele. Loss of imprinting of the IGF2 gene is a recurrent observation in growth disorders that combine overgrowth with a variety of malignant tumours. Moreover, IGF2 has been proposed to play a role in the development of a variety of seemingly unrelated cancers that play an important role in geriatric medicine, e.g. breast cancer, colon cancer and lung cancer. Finally, IGF2 has been implicated in cardiovascular disease, since, for example, IGF2 has been shown to influence the size of atherosclerotic lesions. Objective: To summarize current knowledge about IGF2, its interactions with binding proteins and receptors and connections with key diseases. Methods: The contents of this paper were based on reviews of existing literature within the field. Results: There is a substantial amount of research linking IGF2 to growth disorders, cancer and to a much lesser degree cardiovascular disease. Some of the studies on IGF2 and tumour growth have yielded conflicting results, for instance regarding its effect on apoptosis. Conclusion: Today, our knowledge on how IGF2 is composed and interacts with receptors has come a long way. However, there is comparatively little information on how IGF2 affects tumour growth and cardiovascular diseases such as atherosclerosis. Thus, further research will be needed to elucidate the impact of IGF2 on key diseases.

Keywords:
Growth factors, Gene expression, Cancer, Cardiovascular disease
1.
Salmon WDJ, Daughaday WH: A hormonally controlled serum factor which stimulates sulphate incorporation by cartilage in vitro. J Lab Clin Med 1957;49:825-836.
2.
Rinderknecht E, Humbel RE: The amino acid sequence of human insulin like growth factor I and its structural homology with pro-insulin. J Biol Chem 1978;253:2769-2776.
3.
Rinderknecht E, Humbel RE: Primary structure of insulin like growth factor II. FEBS Lett 1978;89:283-286.
4.
Engström W, Shokrai A, Otte K, Granérus M, Gessbo A, Bierke P, Madej A, Sjölund M, Ward A: Transcriptional regulation and biological significance of the insulin like growth factor II gene. Cell Prolif 1998;31:173-189.
5.
Sara VR, Hall K, Misaki M, Fryklund L, Christensen N, Wetterberg L: Ontogenesis of somatomedins and insulin receptors in the human fetus. J Clin Invest 1983;71:1084-1094.
6.
Clemmons DR: Insulin-like growth factor binding proteins and their role in controlling IGF actions. Cytokine Growth Factor Rev 1997;8:45-62.
7.
de Chiara T, Robertson E, Efstradiatis A: Parental imprinting of the mouse insulin like growth factor II gene. Cell 1992;64:849-859.
8.
Qiu Q, Jiang JY, Bell M, Tsang, BK, Gruslin A: Activation of endoproteolytic processing of insulin-like growth factor-II in fetal, early postnatal, and pregnant rats and persistence of circulating levels in postnatal life. Endocrinology 2007;148:4803-4811.
9.
EntrezGene. NCBI database. ID 3481.
10.
Alvino CL, Ong SC, McNeil KA, Delaine C, Booker GW, Wallace JC, Forbes BE: Understanding the mechanism of insulin and insulin-like growth factor (IGF) receptor activation by IGF II. PLoS One 2011;6:e27488.
11.
Hassan AB: Keys to the hidden treasures of the mannose 6-phosphate/insulin-like growth factor 2 receptor. Am J Pathol 2003;162:3-6.
12.
Brown J, Esnouf RM, Jones MA, Linnell J, Harlos K, Hassan AB, Jones EY: Structure of a functional IGF-2R fragment determined from the anomalous scattering of sulfur. EMBO J 2002;21:1054-1062.
13.
Brown J, Jones E, Forbes BE: Interactions of IGF II with the IGF-2R/cation independent mannose-6-phosphate receptor mechanism and biological outcomes. Vitam Horm 2009;80:699-719.
14.
Ward A: Beckwith-Wiedemann syndrome and Wilms' tumour. Mol Hum Reprod 1997;3:157-168.
15.
Cheng I, Stram D, Burtt NP, Gianniny L, Garcia RR, Pooler L, Henderson BE, Le Marchand L, Haiman CA: IGF2R missense single-nucleotide polymorphisms and breast cancer risk. The multiethnic cohort study. Cancer Epidemiol Biomarkers Prev 2009;18:1922-1924.
16.
Lönn S, Rothman N, Shapiro WR, Fine HA, Selker RG, Black PM, Loeffler JS, Hutchison AA, Inskip PD: Genetic variation in insulin like growth factors and brain tumor risk. Neuro Oncol 2008;10:553-559.
17.
Savage SA, Woodson K, Walk E, Modi W, Liao J, Douglass C, Hoover RN, Chanock SJ: Analysis of genes critical for growth regulation identifies insulin like growth factor receptor variations with possible functional significance as risk factors for osteosarcoma. Cancer Epidemiol Biomarkers Prev 2007;16:1667-1674.
18.
Favelyukis S, Till JH, Hubbard SR, Miller WT: Structure and autoregulation of the insulin-like growth factor 1 receptor kinase. Nat Struct Mol Biol 2001;8:1058-1063.
19.
Belfiore A, Frasca F, Pandini G, Sciacca L, Vigneri L: Insulin receptor isoforms and insulin receptor/insulin like growth factor receptor hybrids in physiology and disease. Endocr Rev 2009;30:586-623.
20.
Chao W, D'Amore PA: IGF2: epigenetic regulation and role in development and disease. Cytokine Growth Factor Rev 2008;19:111-120.
21.
Pollak MN: Insulin-like growth factors and neoplasia. Novartis Found Symp 2004;262:84-98, discussion 98-107, 265-268.
22.
Senthil D, Choudhury GG, Abboud HE, Sonenberg N, Kasinath BS: Regulation of protein synthesis by IGF-I in proximal tubular epithelial cells. Am J Physiol Renal Physiol 2002;283:F1226-F1236.
23.
Zheng H, Worral C, Stern H, Issad T, Seregard S, Girnita A, Girnita L: Selective recruitment of G-protein coupled receptor kinases controls signalling of the insulin like growth factor 1 receptor. Proc Natl Acad Sci USA 2012;109:7055-7060.
24.
López-Bermejo A, Buckway CK, Devi, GR, Hwa V, Plymate SR, Oh Y, Rosenfeld RG: Characterization of insulin-like growth factor-binding protein-related proteins (IGFBP-rPs) 1, 2, and 3 in human prostate epithelial cells: potential roles for IGFBP-rP1 and 2 in senescence of the prostatic epithelium. Endocrinology 2000;141:4072-4080.
25.
Granérus M, Johannisson A, Ekblom P, Engström W: Insulin-like growth factors I and II induce cell death in Wilms's tumour cells. Mol Pathol 2001;54:30-35.
26.
Choufani S, Shuman C, Weksberg R: Beckwith-Wiedemann syndrome. Am J Med Genet C Semin Med Genet 2010;154C:343-354.
27.
Cerrato F, Sparago A, Verde G, De Crescenzo A, Citro V, Cubellis MV, Rinaldi MM, Boccuto L, Neri G, Magnani C, D'Angelo P, Collini P, Perotti, D, Sebastio G, Maher E, Riccio A: Different mechanisms cause imprinting defects at the IGF2/H19 locus in Beckwith-Wiedemann syndrome and Wilms' tumour. Hum Mol Genet 2008;17:1427-1435.
28.
Samani AA, Yakar S, LeRoith D, Brodt A: The role of the IGF system in cancer growth and metastasis. Overview and recent insights. Endocr Rev 2007;28:20-44.
29.
Lahm H, Amstad P, Wyniger J, Yilmaz A, Fischer JR, Schreyer M, Givel JC: Blockade of the insulin like growth factor I receptor inhibits growth of human colorectal cancer cells. Evidence of a functional IGF II mediated autocrine loop. Int J Cancer 1994;58:452-459.
30.
Cheng Y, Idrees K, Shattock R, Khan S, Zeng Z, Brennan C, Paty P, Barany F: Loss of imprinting and marked gene elevation are two forms of aberrant IGF2 expression in colorectal cancer. Int J Cancer 2010;127:568-577.
31.
Gao Y, Katki H, Graubard B, Pollack M, Martin M, Tao Y, Schoen RE, Church T, Hayes RB, Greene MH, Berndt SI: Serum IGF1, IGF2 and IGFBP3 and risk of advanced colorectal carcinoma. Int J Cancer 2011;131:E105-E113.
32.
Colao A: The GH-IGF-1 axis and the cardiovascular system: clinical implications. Clin Endocrinol (Oxf) 2008;69:347-358.
33.
Rodriguez S, Gaunt TR, O´Dell SD, Chen XH, Gu D, Hawe E, Miller GJ, Humphries SE, Day IN: Haplotypic analysis of the IGF2-INS-TH gene cluster in relation to cardiovascular risk traits. Hum Mol Genet 2004;13:715-725.
34.
Zaina S, Pettersson L, Thomsen AB, Chai CM, Qi Z, Thyberg J, Nilsson J: Shortened life span, bradycardia and hypotension in mice with targeted expression of an IGF2 transgene in smooth muscle cells. Endocrinology 2003;144:2695-2703.
35.
Zainia S, Pettersson L, Ahrén B, Brånén L, Hassan AB, Lindholm M, Mattsson R, Thyberg J, Nilsson J: Insulin-like growth factor II plays a central role in atherosclerosis in a mouse model. J Biol Chem 2002;277:4505-4511.
© 2012 S. Karger AG, Basel
2012
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.