Tumor Biology

, Volume 36, Issue 11, pp 8247–8257 | Cite as

Role of insulin-like growth factor-binding proteins in the pathophysiology and tumorigenesis of gastroesophageal cancers

  • Manoj K. Kashyap


The insulin family of proteins include insulin-like growth factor binding proteins (IGFBPs) that are classified into two groups based on their differential affinities to IGFs: IGF high-affinity binding proteins (IGFBP1-6) and IGF low-affinity IGFBP-related proteins (IGFBP-rP1-10). IGFBPs interact with many proteins, including their canonical ligands insulin-like growth factor 1 (IGF-I) and IGF-II. Together with insulin-like growth factor 1 (IGF1) receptor (IGF1R), IGF2R, and ligands (IGF1 and IGF2), IGFBPs participate in a complex signaling axis called IGF-IGFR-IGFBP. Numerous studies have demonstrated that the IGF-IGFR-IGFBP axis is relevant in gastrointestinal (GI) and other cancers. The presence of different IGFBPs have been reported in gastrointestinal cancers, including esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAD or EAC), and gastric adenocarcinoma (GAD or GAC). A literature-based survey clearly indicates that an urgent need exists for a focused review of the role of IGFBPs in gastrointestinal cancers. The aim of this review is to present the biochemical and molecular characteristics of IGFBPs with an emphasis specifically on the role of these proteins in the pathophysiology and tumorigenesis of gastroesophageal cancers.


ESCC Esophageal squamous cell carcinoma Esophageal adenocarcinoma Gastric adenocarcinoma IGFBP7 IGFBPs / IGFBP-rP 



Esophageal adenocarcinoma


Esophageal squamous cell carcinoma


Gastric adenocarcinoma


Gastrointestinal stromal tumor


Human protein reference database


Insulin-like growth factor


Insulin-like growth factor-binding proteins


IGF low-affinity IGFBP-related proteins


Isobaric tags for relative and absolute quantitation


Stable isotope labeling by amino acids in cell culture


Signal peptide



The author apologizes to all colleagues whose work could not be cited due to space limitations. The IHC data in Fig. 1 was used with prior permission from Kashyap et al. from the research article in IOS Press publication (2012–2013: Evaluation of protein expression pattern of stanniocalcin 2, insulin-like growth factor-binding protein 7, inhibin beta A, and four and a half LIM domains 1 in esophageal squamous cell carcinoma. Cancer Biomarkers 12(1):1–9.). MKK was supported by the Indian Council of Medical Research, New Delhi (IRIS ID: 2006-02010, ICMR).

Conflicts of interest



  1. 1.
    Rajah R, Katz L, Nunn S, Solberg P, Beers T, Cohen P. Insulin-like growth factor binding protein (IGFBP) proteases: functional regulators of cell growth. Prog Growth Factor Res. 1995;6:273–84.CrossRefPubMedGoogle Scholar
  2. 2.
    Imsumran A, Adachi Y, Yamamoto H, Li R, Wang Y, Min Y, et al. Insulin-like growth factor-I receptor as a marker for prognosis and a therapeutic target in human esophageal squamous cell carcinoma. Carcinogenesis. 2007;28:947–56.CrossRefPubMedGoogle Scholar
  3. 3.
    Iravani S, Zhang HQ, Yuan ZQ, Cheng JQ, Karl RC, Jove R, et al. Modification of insulin-like growth factor 1 receptor, c-Src, and Bcl-XL protein expression during the progression of Barrett’s neoplasia. Hum Pathol. 2003;34:975–82.CrossRefPubMedGoogle Scholar
  4. 4.
    Chen SC, Chou CK, Wong FH, Chang CM, Hu CP. Overexpression of epidermal growth factor and insulin-like growth factor-I receptors and autocrine stimulation in human esophageal carcinoma cells. Cancer Res. 1991;51:1898–903.PubMedGoogle Scholar
  5. 5.
    Liu YC, Leu CM, Wong FH, Fong WS, Chen SC, Chang C, et al. Autocrine stimulation by insulin-like growth factor I is involved in the growth, tumorigenicity and chemoresistance of human esophageal carcinoma cells. J Biomed Sci. 2002;9:665–74.CrossRefPubMedGoogle Scholar
  6. 6.
    Piao W, Wang Y, Adachi Y, Yamamoto H, Li R, Imsumran A, et al. Insulin-like growth factor-I receptor blockade by a specific tyrosine kinase inhibitor for human gastrointestinal carcinomas. Mol Cancer Ther. 2008;7:1483–93.CrossRefPubMedGoogle Scholar
  7. 7.
    Doyle SL, Donohoe CL, Finn SP, Howard JM, Lithander FE, Reynolds JV, et al. IGF-1 and its receptor in esophageal cancer: association with adenocarcinoma and visceral obesity. Am J Gastroenterol. 107:196–204.Google Scholar
  8. 8.
    Huang XP, Zhou WH, Zhang YF. Genetic variations in the IGF-IGFR-IGFBP axis confer susceptibility to lung and esophageal cancer. Genet Mol Res. 13:2107–2119.Google Scholar
  9. 9.
    Ong J, Salomon J, te Morsche RH, Roelofs HM, Witteman BJ, Dura P, et al. Polymorphisms in the insulin-like growth factor axis are associated with gastrointestinal cancer. PLoS One. 9:e90916.Google Scholar
  10. 10.
    Smith E, Ruszkiewicz AR, Jamieson GG, Drew PA. IGFBP7 is associated with poor prognosis in oesophageal adenocarcinoma and is regulated by promoter DNA methylation. Br J Cancer. 110:775–782.Google Scholar
  11. 11.
    Zhu S, Xu F, Zhang J, Ruan W, Lai M. Insulin-like growth factor binding protein-related protein 1 and cancer. Clin Chim Acta. 2014;431C:23–32.CrossRefGoogle Scholar
  12. 12.
    Schwartz GK. Invasion and metastases in gastric cancer: in vitro and in vivo models with clinical correlations. Semin Oncol. 1996;23:316–24.PubMedGoogle Scholar
  13. 13.
    Anderson WF, Camargo MC, Fraumeni Jr JF, Correa P, Rosenberg PS, Rabkin CS. Age-specific trends in incidence of noncardia gastric cancer in US adults. JAMA. 2010;303:1723–8.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Camargo MC, Mera R, Correa P, Peek Jr RM, Fontham ET, Goodman KJ, et al. Interleukin-1beta and interleukin-1 receptor antagonist gene polymorphisms and gastric cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev. 2006;15:1674–87.CrossRefPubMedGoogle Scholar
  15. 15.
    Yi HK, Hwang PH, Yang DH, Kang CW, Lee DY. Expression of the insulin-like growth factors (IGFs) and the IGF-binding proteins (IGFBPs) in human gastric cancer cells. Eur J Cancer. 2001;37:2257–63.CrossRefPubMedGoogle Scholar
  16. 16.
    Lee DY, Yang DH, Kang CW, Kim SJ, Joo CU, Cho SC, et al. Serum insulin-like growth factors (IGFs) and IGF binding protein (IGFBP)-3 in patients with gastric cancer: IGFBP-3 protease activity induced by surgery. J Korean Med Sci. 1997;12:32–9.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Yamashita S, Tsujino Y, Moriguchi K, Tatematsu M, Ushijima T. Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2′-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006;97:64–71.CrossRefPubMedGoogle Scholar
  18. 18.
    Gu J, Li M, Dong P, Lu J, Tan Z, Wu X, et al. Role of polymorphisms of the IGF2 and IGFBP3 genes and risk of gastric carcinoma in China. Chin Med J. 2014;127:412–6.PubMedGoogle Scholar
  19. 19.
    Trent JC, Ramdas L, Dupart J, Hunt K, Macapinlac H, Taylor E, et al. Early effects of imatinib mesylate on the expression of insulin-like growth factor binding protein-3 and positron emission tomography in patients with gastrointestinal stromal tumor. Cancer. 2006;107:1898–908.CrossRefPubMedGoogle Scholar
  20. 20.
    Yang HP, Liu JF, Rao J, Zhang XM, Qian HL, Niu XQ, et al. (2014) Insulin-like growth factor binding protein-3 (IGFBP-3) genetic variant and the risk of esophageal squamous cell carcinoma in a Chinese population. Genet Mol Res. 13:4146–4153.Google Scholar
  21. 21.
    McElholm AR, McKnight AJ, Patterson CC, Johnston BT, Hardie LJ, Murray LJ. (2010) A population-based study of IGF axis polymorphisms and the esophageal inflammation, metaplasia, adenocarcinoma sequence. Gastroenterology. 139:204–21.Google Scholar
  22. 22.
    Chen W, Wang L, Ke Q, Jin G, Tan Y, Zhou Y, et al. The role of IGFBP3 functional polymorphisms in the risk of gastric cancer in a high-risk Chinese population. Eur J Cancer Prev. 2008;17:82–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Takeno A, Takemasa I, Doki Y, Yamasaki M, Miyata H, Takiguchi S, et al. Integrative approach for differentially overexpressed genes in gastric cancer by combining large-scale gene expression profiling and network analysis. Br J Cancer. 2008;99:1307–15.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Sato Y, Inokuchi M, Takagi Y, Otsuki S, Fujimori Y, Yanaka Y, et al. Relationship between expression of IGFBP7 and clinicopathological variables in gastric cancer. J Clin Pathol. 2015. doi: 10.1136/jclinpath-2015-202987.
  25. 25.
    Uhlen M, Oksvold P, Fagerberg L, Lundberg E, Jonasson K, Forsberg M, et al. Towards a knowledge-based human protein atlas. Nat Biotechnol. 2010;28:1248–50.CrossRefPubMedGoogle Scholar
  26. 26.
    Kashyap MK, Marimuthu A, Kishore CJ, Peri S, Keerthikumar S, Prasad TS, et al. Genomewide mRNA profiling of esophageal squamous cell carcinoma for identification of cancer biomarkers. Cancer Biol Ther. 2009;8:36–46.CrossRefPubMedGoogle Scholar
  27. 27.
    Kashyap MK, Pawar HA, Keerthikumar S, Sharma J, Goel R, Mahmood R, et al. Evaluation of protein expression pattern of stanniocalcin 2, insulin-like growth factor-binding protein 7, inhibin beta A and four and a half LIM domains 1 in esophageal squamous cell carcinoma. Cancer Biomark. 2013;12:1–9.CrossRefGoogle Scholar
  28. 28.
    Yanbin JWDYC, Yan Y. No association between two SNPs in the IGFBP1 gene and esophageal squamous cell carcinoma. J Baotou Med Coll. 2009;25:2001.Google Scholar
  29. 29.
    Hu YC, Lam KY, Law S, Wong J, Srivastava G. Profiling of differentially expressed cancer-related genes in esophageal squamous cell carcinoma (ESCC) using human cancer cDNA arrays: overexpression of oncogene MET correlates with tumor differentiation in ESCC. Clin Cancer Res. 2001;7:3519–25.PubMedGoogle Scholar
  30. 30.
    Subbannayya Y, Mir SA, Renuse S, Manda SS, Pinto SM, Puttamallesh VN, et al. Identification of differentially expressed serum proteins in gastric adenocarcinoma. J Proteomics. 2015. doi:  10.1016/j.jprot.2015.04.021.
  31. 31.
    Takaoka M, Harada H, Andl CD, Oyama K, Naomoto Y, Dempsey KL, et al. Epidermal growth factor receptor regulates aberrant expression of insulin-like growth factor-binding protein 3. Cancer Res. 2004;64:7711–23.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Lee JJ, Natsuizaka M, Ohashi S, Wong GS, Takaoka M, Michaylira CZ, et al. Hypoxia activates the cyclooxygenase-2-prostaglandin E synthase axis. Carcinogenesis. 2010;31:427–34.CrossRefPubMedGoogle Scholar
  33. 33.
    Su H, Hu N, Yang HH, Wang C, Takikita M, Wang QH, et al. Global gene expression profiling and validation in esophageal squamous cell carcinoma and its association with clinical phenotypes. Clin Cancer Res. 2011;17:2955–66.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Zhao L, He LR, Zhang R, Cai MY, Liao YJ, Qian D, et al. Low expression of IGFBP-3 predicts poor prognosis in patients with esophageal squamous cell carcinoma. Med Oncol. 2012;29:2669–76.CrossRefPubMedGoogle Scholar
  35. 35.
    Di Martino E, Wild CP, Rotimi O, Darnton JS, Olliver RJ, Hardie LJ. IGFBP-3 and IGFBP-10 (CYR61) up-regulation during the development of Barrett’s oesophagus and associated oesophageal adenocarcinoma: potential biomarkers of disease risk. Biomarkers. 2006;11:547–61.CrossRefPubMedGoogle Scholar
  36. 36.
    Siahpush SH, Vaughan TL, Lampe JN, Freeman R, Lewis S, Odze RD, et al. Longitudinal study of insulin-like growth factor, insulin-like growth factor binding protein-3, and their polymorphisms: risk of neoplastic progression in Barrett’s esophagus. Cancer Epidemiol Biomarkers Prev. 2007;16:2387–95.CrossRefPubMedGoogle Scholar
  37. 37.
    Sohda M, Kato H, Miyazaki T, Nakajima M, Fukuchi M, Manda R, et al. The role of insulin-like growth factor 1 and insulin-like growth factor binding protein 3 in human esophageal cancer. Anticancer Res. 2004;24:3029–34.PubMedGoogle Scholar
  38. 38.
    Yilmaz O, Eroglu A, Dag E, Karaoglanoglu N, Yilmaz A. Serum levels of IGF-I and IGFBP-III and their relation with carcinoembryonic antigen and carbohydrate antigen 19–9 in cases of esophageal cancer. Int J Clin Pract. 2006;60:1604–8.CrossRefPubMedGoogle Scholar
  39. 39.
    Gray A, Aronson WJ, Barnard RJ, Mehta H, Wan J, Said J, et al. Global Igfbp1 deletion does not affect prostate cancer development in a c-Myc transgenic mouse model. J Endocrinol. 2011;211:297–304.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Kashyap MK, Harsha HC, Renuse S, Pawar H, Sahasrabuddhe NA, Kim MS, et al. SILAC-based quantitative proteomic approach to identify potential biomarkers from the esophageal squamous cell carcinoma secretome. Cancer Biol Ther. 2010;10:796–810.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Gerrie AS, Toze CL, Ramadan KM, Li CH, Sutherland J, Yee A, et al. Oral fludarabine and rituximab as initial therapy for chronic lymphocytic leukemia or small lymphocytic lymphoma: population-based experience matches clinical trials. Leuk Lymphoma. 2012;53:77–82.CrossRefPubMedGoogle Scholar
  42. 42.
    Harris PJ, Takebe N, Ivy SP. Molecular conversations and the development of the hair follicle and basal cell carcinoma. Cancer Prev Res (Phila). 2010;3:1217–21.CrossRefGoogle Scholar
  43. 43.
    Villani RM, Adolphe C, Palmer J, Waters MJ, Wainwright BJ. Patched1 inhibits epidermal progenitor cell expansion and basal cell carcinoma formation by limiting Igfbp2 activity. Cancer Prev Res (Phila). 2010;3:1222–34.CrossRefGoogle Scholar
  44. 44.
    Busund LT, Richardsen E, Busund R, Ukkonen T, Bjornsen T, Busch C, et al. Significant expression of IGFBP2 in breast cancer compared with benign lesions. J Clin Pathol. 2005;58:361–6.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Soh CL, McNeil K, Owczarek CM, Hardy MP, Fabri LJ, Pearse M, et al. Exogenous administration of protease-resistant, non-matrix-binding IGFBP-2 inhibits tumour growth in a murine model of breast cancer. Br J Cancer. 2014;110:2855–64.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Probst-Hensch NM, Steiner JH, Schraml P, Varga Z, Zürrer-Härdi U, Storz M, et al. IGFBP2 and IGFBP3 protein expressions in human breast cancer: association with hormonal factors and obesity. Clin Cancer Res. 2010;16:1025–32.CrossRefPubMedGoogle Scholar
  47. 47.
    Neuhouser ML, Platz EA, Till C, Tangen CM, Goodman PJ, Kristal A, et al. Insulin-like growth factors and insulin-like growth factor-binding proteins and prostate cancer risk: results from the prostate cancer prevention trial. Cancer Prev Res (Phila). 2013;6:91–9.CrossRefGoogle Scholar
  48. 48.
    Figueroa JA, De Raad S, Tadlock L, Speights VO, Rinehart JJ. Differential expression of insulin-like growth factor binding proteins in high versus low Gleason score prostate cancer. J Urol. 1998;159:1379–83.CrossRefPubMedGoogle Scholar
  49. 49.
    Mehta HH, Gao Q, Galet C, Paharkova V, Wan J, Said J, et al. IGFBP-3 is a metastasis suppression gene in prostate cancer. Cancer Res. 2011;71:5154–63.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Zachara NE, Molina H, Wong KY, Pandey A, Hart GW. The dynamic stress-induced “O-GlcNAc-ome” highlights functions for O-GlcNAc in regulating DNA damage/repair and other cellular pathways. Amino Acids. 2011;40:793–808.CrossRefPubMedGoogle Scholar
  51. 51.
    Greenall SA, Bentley JD, Pearce LA, Scoble JA, Sparrow LG, Bartone NA, et al. Biochemical characterization of individual human glycosylated pro-insulin-like growth factor (IGF)-II and big-IGF-II isoforms associated with cancer. J Biol Chem. 2013;288:59–68.CrossRefPubMedGoogle Scholar
  52. 52.
    Butt AJ, Firth SM, King MA, Baxter RC. Insulin-like growth factor-binding protein-3 modulates expression of Bax and Bcl-2 and potentiates p53-independent radiation-induced apoptosis in human breast cancer cells. J Biol Chem. 2000;275:39174–81.CrossRefPubMedGoogle Scholar
  53. 53.
    Silha JV, Sheppard PC, Mishra S, Gui Y, Schwartz J, Dodd JG, et al. Insulin-like growth factor (IGF) binding protein-3 attenuates prostate tumor growth by IGF-dependent and IGF-independent mechanisms. Endocrinology. 2006;147:2112–21.CrossRefPubMedGoogle Scholar
  54. 54.
    Oh SH, Kim WY, Lee OH, Kang JH, Woo JK, Kim JH, et al. Insulin-like growth factor binding protein-3 suppresses vascular endothelial growth factor expression and tumor angiogenesis in head and neck squamous cell carcinoma. Cancer Sci. 2012;103:1259–66.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Liu B, Lee KW, Li H, Ma L, Lin GL, Chandraratna RA, et al. Combination therapy of insulin-like growth factor binding protein-3 and retinoid X receptor ligands synergize on prostate cancer cell apoptosis in vitro and in vivo. Clin Cancer Res. 2005;11:4851–6.CrossRefPubMedGoogle Scholar
  56. 56.
    Kalinina T, Gungor C, Thieltges S, Moller-Krull M, Penas EM, Wicklein D, et al. Establishment and characterization of a new human pancreatic adenocarcinoma cell line with high metastatic potential to the lung. BMC Cancer. 2010;10:295.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Ingermann AR, Yang YF, Han J, Mikami A, Garza AE, Mohanraj L, et al. Identification of a novel cell death receptor mediating IGFBP-3-induced anti-tumor effects in breast and prostate cancer. J Biol Chem. 2010;285:30233–46.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Peng L, Malloy PJ, Feldman D. Identification of a functional vitamin D response element in the human insulin-like growth factor binding protein-3 promoter. Mol Endocrinol. 2004;18:1109–19.CrossRefPubMedGoogle Scholar
  59. 59.
    Boyle BJ, Zhao XY, Cohen P, Feldman D. Insulin-like growth factor binding protein-3 mediates 1 alpha,25-dihydroxyvitamin d(3) growth inhibition in the LNCaP prostate cancer cell line through p21/WAF1. J Urol. 2001;165:1319–24.CrossRefPubMedGoogle Scholar
  60. 60.
    McCarthy BA, Boyle E, Wang XP, Guzowski D, Paul S, Catera R, et al. Surface expression of Bcl-2 in chronic lymphocytic leukemia and other B-cell leukemias and lymphomas without a breakpoint t(14;18). Mol Med. 2008;14:618–27.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Peng L, Malloy PJ, Wang J, Feldman D. Growth inhibitory concentrations of androgens up-regulate insulin-like growth factor binding protein-3 expression via an androgen response element in LNCaP human prostate cancer cells. Endocrinology. 2006;147:4599–607.CrossRefPubMedGoogle Scholar
  62. 62.
    Hung PS, Kao SY, Shih YH, Chiou SH, Liu CJ, Chang KW, et al. Insulin-like growth factor binding protein-5 (IGFBP-5) suppresses the tumourigenesis of head and neck squamous cell carcinoma. J Pathol. 2008;214:368–76.CrossRefPubMedGoogle Scholar
  63. 63.
    Rho SB, Dong SM, Kang S, Seo SS, Yoo CW, Lee DO, et al. Insulin-like growth factor-binding protein-5 (IGFBP-5) acts as a tumor suppressor by inhibiting angiogenesis. Carcinogenesis. 2008;29:2106–11.CrossRefPubMedGoogle Scholar
  64. 64.
    Su Y, Wagner ER, Luo Q, Huang J, Chen L, He BC, et al. Insulin-like growth factor binding protein 5 suppresses tumor growth and metastasis of human osteosarcoma. Oncogene. 2011;30:3907–17.CrossRefPubMedGoogle Scholar
  65. 65.
    Russo VC, Schutt BS, Andaloro E, Ymer SI, Hoeflich A, Ranke MB, et al. Insulin-like growth factor binding protein-2 binding to extracellular matrix plays a critical role in neuroblastoma cell proliferation, migration, and invasion. Endocrinology. 2005;146:4445–55.CrossRefPubMedGoogle Scholar
  66. 66.
    Huynh H, Yang XF, Pollak M. A role for insulin-like growth factor binding protein 5 in the antiproliferative action of the antiestrogen ICI 182780. Cell Growth Differ. 1996;7:1501–6.PubMedGoogle Scholar
  67. 67.
    Tennant MK, Thrasher JB, Twomey PA, Birnbaum RS, Plymate SR. Insulin-like growth factor-binding proteins (IGFBP)-4, -5, and -6 in the benign and malignant human prostate: IGFBP-5 messenger ribonucleic acid localization differs from IGFBP-5 protein localization. J Clin Endocrinol Metab. 1996;81:3783–92.PubMedGoogle Scholar
  68. 68.
    Kimura G, Kasuya J, Giannini S, Honda Y, Mohan S, Kawachi M, et al. Insulin-like growth factor (IGF) system components in human prostatic cancer cell-lines: LNCaP, DU145, and PC-3 cells. Int J Urol. 1996;3:39–46.CrossRefPubMedGoogle Scholar
  69. 69.
    Miyake H, Nelson C, Rennie PS, Gleave ME. Overexpression of insulin-like growth factor binding protein-5 helps accelerate progression to androgen-independence in the human prostate LNCaP tumor model through activation of phosphatidylinositol 3′-kinase pathway. Endocrinology. 2000;141:2257–65.PubMedGoogle Scholar
  70. 70.
    Miyake H, Pollak M, Gleave ME. Castration-induced up-regulation of insulin-like growth factor binding protein-5 potentiates insulin-like growth factor-I activity and accelerates progression to androgen independence in prostate cancer models. Cancer Res. 2000;60:3058–64.PubMedGoogle Scholar
  71. 71.
    Simon S, Grabellus F, Ferrera L, Galietta L, Schwindenhammer B, Mühlenberg T, et al. DOG1 regulates growth and IGFBP5 in gastrointestinal stromal tumors. Cancer Res. 2013;73:3661–70.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Bach LA. IGFBP-6 five years on; not so ‘forgotten’? Growth Hormon IGF Res. 2005;15:185–92.CrossRefGoogle Scholar
  73. 73.
    Grellier P, De Galle B, Babajko S. Expression of insulin-like growth factor-binding protein 6 complementary DNA alters neuroblastoma cell growth. Cancer Res. 1998;58:1670–6.PubMedGoogle Scholar
  74. 74.
    Braulke T, Dittmer F, Gotz W, von Figura K. Alteration in pancreatic immunoreactivity of insulin-like growth factor (IGF)-binding protein (IGFBP)-6 and in intracellular degradation of IGFBP-3 in fibroblasts of IGF-II receptor/IGF-II-deficient mice. Horm Metab Res. 1999;31:235–41.CrossRefPubMedGoogle Scholar
  75. 75.
    Hwa V, Oh Y, Rosenfeld RG. The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocr Rev. 1999;20:761–87.PubMedGoogle Scholar
  76. 76.
    Coverley JA, Baxter RC. Phosphorylation of insulin-like growth factor binding proteins. Mol Cell Endocrinol. 1997;128:1–5.CrossRefPubMedGoogle Scholar
  77. 77.
    Kang HC, Kim IJ, Park JH, Shin Y, Ku JL, Jung MS, et al. Identification of genes with differential expression in acquired drug-resistant gastric cancer cells using high-density oligonucleotide microarrays. Clin Cancer Res. 2004;10:272–84.CrossRefPubMedGoogle Scholar
  78. 78.
    Jee CD, Kim MA, Jung EJ, Kim J, Kim WH. Identification of genes epigenetically silenced by CpG methylation in human gastric carcinoma. Eur J Cancer. 2009;45:1282–93.CrossRefPubMedGoogle Scholar
  79. 79.
    Wu C, Kraft P, Zhai K, Chang J, Wang Z, Li Y, et al. (2012) Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions. Nat Genet. 44:1090–1097.Google Scholar
  80. 80.
    Zhao L, He LR, Xi M, Cai MY, Shen JX, Li QQ, et al. Nimotuzumab promotes radiosensitivity of EGFR-overexpression esophageal squamous cell carcinoma cells by upregulating IGFBP-3. J Transl Med. 2012;10:249.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Yuka Isozaki IH, Yasunori A, Aki A, Naoki A, Nobuyoshi T, Tetsuro M, et al. Role of IGFBP4 and IGF-I expression in esophageal squamous cell carcinoma. Esophagus. 2013;10:79–95.CrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Moores Cancer CenterUniversity of California San DiegoLa JollaUSA
  2. 2.Department of BiotechnologyShoolini University of Biotechnology and Management SciencesSolanIndia

Personalised recommendations