Exploration of Medicine

Table 1. Evidence in support of a key role for the IGF1 system in cancer biology

Evidence
Epidemiological analyses identified serum IGF1 as a risk factor in various cancers
Cells deprived of the IGF1R do not undergo malignant transformation
Oncogenes adopt the IGF1 signaling pathway
Individuals with minimal IGF1 levels (Laron syndrome) are protected from cancer
Tumor cells express high IGF1R levels and exhibit a constitutively activated IGF1R pathway
IGF1R exhibits a very potent anti-apoptotic activity
The IGF1 system is an important player in angiogenesis

Return to article view

IGF1: insulin-like growth factor-1; IGF1R: IGF1 receptor

Declarations

Acknowledgments

The authors wish to thank the members of our team for their important comments and suggestions.

Author contributions

HW: Conceptualization, Investigation, Writing—original draft, Writing—review & editing. IB: Conceptualization, Investigation, Writing—original draft, Writing—review & editing. Both authors have read and agreed to the published version of the manuscript.

Conflicts of interest

Haim Werner who is the Guest Editor and Editorial Board Member of Exploration of Medicine had no involvement in the decision-making or the review process of this manuscript. Ilan Bruchim who is the Guest Editor of Exploration of Medicine had also no involvement in the decision-making or the review process of this manuscript.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work was supported by a generous award from the Israel Cancer Research Fund (ICRF, Montreal) [2026011] to IB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

Publisher’s note

Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

References

Collins FS, Morgan M, Patrinos A. The Human Genome Project: lessons from large-scale biology. Science. 2003;300:286–90. [DOI] [PubMed]

Green ED, Watson JD, Collins FS. Human Genome Project: Twenty-five years of big biology. Nature. 2015;526:29–31. [DOI] [PubMed] [PMC]

Saadeh C, Bright D, Rustem D. Precision Medicine in Oncology Pharmacy Practice. Acta Med Acad. 2019;48:90–104. [DOI] [PubMed]

Xu Y, Jiang X, Hu Z. Synergizing metabolomics and artificial intelligence for advancing precision oncology. Trends Mol Med. 2025;[Epub ahead of print]. [DOI] [PubMed]

LeRoith D, Yakar S. Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor 1. Nat Clin Pract Endocrinol Metab. 2007;3:302–10. [DOI] [PubMed]

Yakar S, Adamo ML. Insulin-like growth factor 1 physiology: lessons from mouse models. Endocrinol Metab Clin North Am. 2012;41:231–47. [DOI] [PubMed] [PMC]

Salmon WD Jr, Daughaday WH. A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro. J Lab Clin Med. 1957;49:825–36. [PubMed]

Abbott AM, Bueno R, Pedrini MT, Murray JM, Smith RJ. Insulin-like growth factor I receptor gene structure. J Biol Chem. 1992;267:10759–63. [PubMed]

Baserga R, Peruzzi F, Reiss K. The IGF-1 receptor in cancer biology. Int J Cancer. 2003;107:873–7. [DOI] [PubMed]

10.

Werner H. The IGF1 signaling pathway: from basic concepts to therapeutic opportunities. Int J Mol Sci. 2023;24:14882. [DOI] [PubMed] [PMC]

11.

De Meyts P, Whittaker J. Structural biology of insulin and IGF1 receptors: implications for drug design. Nat Rev Drug Discov. 2002;1:769–83. [DOI] [PubMed]

12.

Belfiore A, Malaguarnera R. Insulin receptor and cancer. Endocr Relat Cancer. 2011;18:R125–47. [DOI] [PubMed]

13.

Malaguarnera R, Belfiore A. The emerging role of insulin and insulin-like growth factor signaling in cancer stem cells. Front Endocrinol (Lausanne). 2014;5:10. [DOI] [PubMed] [PMC]

14.

De Meyts P. Insulin/receptor binding: the last piece of the puzzle? What recent progress on the structure of the insulin/receptor complex tells us (or not) about negative cooperativity and activation. Bioessays. 2015;37:389–97. [DOI] [PubMed]

15.

Turvey S, Muench SP, Issad T, Fishwick CWG, Kearney MT, Simmons KJ. Using site-directed mutagenesis to further the understanding of insulin receptor-insulin like growth factor-1 receptor heterodimer structure. Growth Horm IGF Res. 2024;77:101607. [DOI] [PubMed]

16.

Bach LA. Insulin-Like Growth Factor Binding Proteins--an Update. Pediatr Endocrinol Rev. 2015;13:521–30. [PubMed]

17.

Baxter RC. IGF binding proteins in cancer: mechanistic and clinical insights. Nat Rev Cancer. 2014;14:329–41. [DOI] [PubMed]

18.

Lu K, Campisi J. Ras proteins are essential and selective for the action of insulin-like growth factor 1 late in the G1 phase of the cell cycle in BALB/c murine fibroblasts. Proc Natl Acad Sci U S A. 1992;89:3889–93. [DOI] [PubMed] [PMC]

19.

Dupont J, Pierre A, Froment P, Moreau C. The insulin-like growth factor axis in cell cycle progression. Horm Metab Res. 2003;35:740–50. [DOI] [PubMed]

20.

Werner H, Sarfstein R, LeRoith D, Bruchim I. Insulin-like growth factor 1 signaling axis meets p53 genome protection pathways. Front Oncol. 2016;6:159. [DOI] [PubMed] [PMC]

21.

Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science. 1998;279:563–6. [DOI] [PubMed]

22.

Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, et al. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet. 1998;351:1393–6. [DOI] [PubMed]

23.

Giovannucci E, Pollak MN, Platz EA, Willett WC, Stampfer MJ, Majeed N, et al. A prospective study of plasma insulin-like growth factor-1 and binding protein-3 and risk of colorectal neoplasia in women. Cancer Epidemiol Biomarkers Prev. 2000;9:345–9. [PubMed]

24.

Renehan AG, Zwahlen M, Minder C, O’Dwyer ST, Shalet SM, Egger M. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet. 2004;363:1346–53. [DOI] [PubMed]

25.

Domené S, Domené HM. Genetic mutations in the GH/IGF axis. Pediatr Endocrinol Rev. 2018;16:39–62. [DOI] [PubMed]

26.

Domené S, Scaglia PA, Gutiérrez ML, Domené HM. Applying bioinformatic platforms, in vitro, and in vivo functional assays in the characterization of genetic variants in the GH/IGF pathway affecting growth and development. Cells. 2021;10:2063. [DOI] [PubMed] [PMC]

27.

Ayyadevara S, Ganne A, Hendrix RD, Balasubramaniam M, Shmookler Reis RJ, Barger SW. Functional assessments through novel proteomics approaches: Application to insulin/IGF signaling in neurodegenerative diseases’. J Neurosci Methods. 2019;319:40–6. [DOI] [PubMed] [PMC]

28.

Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70. [DOI] [PubMed]

29.

Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022;12:31–46. [DOI] [PubMed]

30.

Singh AV, Bhardwaj P, Laux P, Pradeep P, Busse M, Luch A, et al. AI and ML-based risk assessment of chemicals: predicting carcinogenic risk from chemical-induced genomic instability. Front Toxicol. 2024;6:1461587. [DOI] [PubMed] [PMC]

31.

Baserga R. Oncogenes and the strategy of growth factors. Cell. 1994;79:927–30. [DOI] [PubMed]

32.

Bendall SC, Stewart MH, Menendez P, George D, Vijayaragavan K, Werbowetski-Ogilvie T, et al. IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro. Nature. 2007;448:1015–21. [DOI] [PubMed]

33.

Werner H, LeRoith D. Hallmarks of cancer: the insulin-like growth factors perspective. Front Oncol. 2022;12:1055589. [DOI] [PubMed] [PMC]

34.

Blecher A, Haran G, Brudner Y, Meisel-Sharon S, Sarfstein R, Hallak M, et al. The IGF pathway in gynecology-oncology: current knowledge and possible therapeutic implementations. J Gynecol Women’s Health. 2017;4.

35.

Baserga R, Rubin R. Cell cycle and growth control. Crit Rev Eukaryot Gene Expr. 1993;3:47–61. [PubMed]

36.

Florini JR, Ewton DZ, Roof SL. Insulin-like growth factor-I stimulates terminal myogenic differentiation by induction of myogenin gene expression. Mol Endocrinol. 1991;5:718–24. [DOI] [PubMed]

37.

LeRoith D, Werner H, Beitner-Johnson D, Roberts CT Jr. Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev. 1995;16:143–63. [DOI] [PubMed]

38.

Sarfstein R, Werner H. The Insulin/IGF1 receptors family. In: Wheeler DL, Yarden Y, editors. Receptor Tyrosine Kinases: Family and Subfamilies. New York: Springer Science; 2015. pp. 297–320. [DOI]

39.

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74. [DOI] [PubMed]

40.

Werner H. Tumor suppressors govern insulin-like growth factor signaling pathways: implications in metabolism and cancer. Oncogene. 2012;31:2703–14. [DOI] [PubMed]

41.

Reiss K, Ferber A, Travali S, Porcu P, Phillips PD, Baserga R. The protooncogene c-myb increases the expression of insulin-like growth factor 1 and insulin-like growth factor 1 receptor messenger RNAs by a transcriptional mechanism. Cancer Res. 1991;51:5997–6000. [PubMed]

42.

Peterson JE, Jelinek T, Kaleko M, Siddle K, Weber MJ. c phosphorylation and activation of the IGF-I receptor in src-transformed cells. J Biol Chem. 1994;269:27315–21. [PubMed]

43.

Werner H, Bruchim I. IGF-1 and BRCA1 signalling pathways in familial cancer. Lancet Oncol. 2012;13:e537–44. [DOI] [PubMed]

44.

Werner H, Karnieli E, Rauscher FJ, LeRoith D. Wild-type and mutant p53 differentially regulate transcription of the insulin-like growth factor I receptor gene. Proc Natl Acad Sci U S A. 1996;93:8318–23. [DOI] [PubMed] [PMC]

45.

Sarfstein R, Werner H. Tumor suppressor p53 regulates insulin receptor (INSR) gene expression via direct binding to the INSR promoter. Oncotarget. 2020;11:2424–37. [DOI] [PubMed] [PMC]

46.

Maor SB, Abramovitch S, Erdos MR, Brody LC, Werner H. BRCA1 suppresses insulin-like growth factor-I receptor promoter activity: potential interaction between BRCA1 and Sp1. Mol Genet Metab. 2000;69:130–6. [DOI] [PubMed]

47.

Shahrabani-Gargir L, Pandita TK, Werner H. Ataxia-telangiectasia mutated gene controls insulin-like growth factor I receptor gene expression in a deoxyribonucleic acid damage response pathway via mechanisms involving zinc-finger transcription factors Sp1 and WT1. Endocrinology. 2004;145:5679–87. [DOI] [PubMed]

48.

Maor S, Papa MZ, Yarden RI, Friedman E, Lerenthal Y, Lee SW, et al. Insulin-like growth factor-I controls BRCA1 gene expression through activation of transcription factor Sp1. Horm Metab Res. 2007;39:179–85. [DOI] [PubMed]

49.

Reizner N, Maor S, Sarfstein R, Abramovitch S, Welshons WV, Curran EM, et al. The WT1 Wilms’ tumor suppressor gene product interacts with estrogen receptor-alpha and regulates IGF-I receptor gene transcription in breast cancer cells. J Mol Endocrinol. 2005;35:135–44. [DOI] [PubMed]

50.

Yuen JS, Cockman ME, Sullivan M, Protheroe A, Turner GD, Roberts IS, et al. The VHL tumor suppressor inhibits expression of the IGF1R and its loss induces IGF1R upregulation in human clear cell renal carcinoma. Oncogene. 2007;26:6499–508. [DOI] [PubMed]

51.

Resnicoff M, Abraham D, Yutanawiboonchai W, Rotman HL, Kajstura J, Rubin R, et al. The insulin-like growth factor I receptor protects tumor cells from apoptosis in vivo. Cancer Res. 1995;55:2463–9. [PubMed]

52.

Andrews DW, Resnicoff M, Flanders AE, Kenyon L, Curtis M, Merli G, et al. Results of a pilot study involving the use of an antisense oligodeoxynucleotide directed against the insulin-like growth factor type I receptor in malignant astrocytomas. J Clin Oncol. 2001;19:2189–200. [DOI] [PubMed]

53.

Sell C, Baserga R, Rubin R. Insulin-like growth factor I (IGF-I) and the IGF-I receptor prevent etoposide-induced apoptosis. Cancer Res. 1995;55:303–6. [PubMed]

54.

O’Connor R, Kauffmann-Zeh A, Liu Y, Lehar S, Evan GI, Baserga R, et al. Identification of domains of the insulin-like growth factor I receptor that are required for protection from apoptosis. Mol Cell Biol. 1997;17:427–35. [DOI] [PubMed] [PMC]

55.

Sell C, Rubini M, Rubin R, Liu JP, Efstratiadis A, Baserga R. Simian virus 40 large tumor antigen is unable to transform mouse embryonic fibroblasts lacking type 1 insulin-like growth factor receptor. Proc Natl Acad Sci U S A. 1993;90:11217–21. [DOI] [PubMed] [PMC]

56.

Sell C, Dumenil G, Deveaud C, Miura M, Coppola D, DeAngelis T, et al. Effect of a null mutation of the insulin-like growth factor I receptor gene on growth and transformation of mouse embryo fibroblasts. Mol Cell Biol. 1994;14:3604–12. [DOI] [PubMed] [PMC]

57.

Laron Z, Pertzelan A, Mannheimer S. Genetic pituitary dwarfism with high serum concentation of growth hormone--a new inborn error of metabolism? Isr J Med Sci. 1966;2:152–5. [PubMed]

58.

Laron Z. Laron syndrome (primary growth hormone resistance or insensitivity): the personal experience 1958-2003. J Clin Endocrinol Metab. 2004;89:1031–44. [DOI] [PubMed]

59.

Godowski PJ, Leung DW, Meacham LR, Galgani JP, Hellmiss R, Keret R, et al. Characterization of the human growth hormone receptor gene and demonstration of a partial gene deletion in two patients with Laron-type dwarfism. Proc Natl Acad Sci U S A. 1989;86:8083–7. [DOI] [PubMed] [PMC]

60.

Shevah O, Laron Z. Genetic analysis of the pedigrees and molecular defects of the GH-receptor gene in the Israeli cohort of patients with Laron syndrome. Pediatr Endocrinol Rev. 2006;3:489–97. [PubMed]

61.

Steuerman R, Shevah O, Laron Z. Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies. Eur J Endocrinol. 2011;164:485–9. [DOI] [PubMed]

62.

Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, Wei M, Madia F, Cheng CW, et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med. 2011;3:70ra13. [DOI] [PubMed] [PMC]

63.

Lapkina-Gendler L, Rotem I, Pasmanik-Chor M, Gurwitz D, Sarfstein R, Laron Z, et al. Identification of signaling pathways associated with cancer protection in Laron syndrome. Endocr Relat Cancer. 2016;23:399–410. [DOI] [PubMed]

64.

Laron Z, Kauli R, Lapkina L, Werner H. IGF-I deficiency, longevity and cancer protection of patients with Laron syndrome. Mutat Res Rev Mutat Res. 2017;772:123–33. [DOI] [PubMed]

65.

Werner H, Lapkina-Gendler L, Achlaug L, Nagaraj K, Somri L, Yaron-Saminsky D, et al. Genome-wide profiling of Laron syndrome patients identifies novel cancer protection pathways. Cells. 2019;8:596. [DOI] [PubMed] [PMC]

66.

Werner H, Sarfstein R, Nagaraj K, Laron Z. Laron syndrome research paves the way for new insights in oncological investigation. Cells. 2020;9:2446. [DOI] [PubMed] [PMC]

67.

Werner H. For debate: the pathophysiological significance of IGF-I receptor overexpression: new insights. Pediatr Endocrinol Rev. 2009;7:2–5. [PubMed]

68.

Bruchim I, Werner H. Targeting IGF-1 signaling pathways in gynecologic malignancies. Expert Opin Ther Targets. 2013;17:307–20. [DOI] [PubMed]

69.

Simpson A, Petnga W, Macaulay VM, Weyer-Czernilofsky U, Bogenrieder T. Insulin-like growth factor (IGF) pathway targeting in cancer: role of the IGF axis and opportunities for future combination studies. Target Oncol. 2017;12:571–97. [DOI] [PubMed] [PMC]

70.

Osher E, Macaulay VM. Therapeutic targeting of the IGF axis. Cells. 2019;8:895. [DOI] [PubMed] [PMC]

71.

Scotlandi K, Picci P. Targeting insulin-like growth factor 1 receptor in sarcomas. Curr Opin Oncol. 2008;20:419–27. [DOI] [PubMed]

72.

Chandrasekar V, Panicker AJ, Dey AK, Mohammad S, Chakraborty A, Samal SK, et al. Integrated approaches for immunotoxicity risk assessment: challenges and future directions. Discover Toxicol. 2024;1:9. [DOI]

73.

Schmid P, Sablin MP, Bergh J, Im SA, Lu YS, Martínez N, et al. A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer. Breast Cancer Res. 2021;23:8. [DOI] [PubMed] [PMC]

74.

Somri-Gannam L, Meisel-Sharon S, Hantisteanu S, Groisman G, Limonad O, Hallak M, et al. IGF1R axis inhibition restores dendritic cell antitumor response in ovarian cancer. Transl Oncol. 2020;13:100790. [DOI] [PubMed] [PMC]

75.

Somri-Gannam L, Meisel-Sharon S, Hantisteanu S, Bar-Noy T, Sigal E, Groisman G, et al. IGF1R inhibition and PD-1 blockade improve anti-tumor immune response in epithelial ovarian cancer. Front Oncol. 2024;14:1410447. [DOI] [PubMed] [PMC]

76.

Chandrasekar V, Mohammad S, Aboumarzouk O, Singh AV, Dakua SP. Quantitative prediction of toxicological points of departure using two-stage machine learning models: A new approach methodology (NAM) for chemical risk assessment. J Hazard Mater. 2025;487:137071. [DOI] [PubMed]

77.

Abramovitch S, Glaser T, Ouchi T, Werner H. BRCA1-Sp1 interactions in transcriptional regulation of the IGF-IR gene. FEBS Lett. 2003;541:149–54. [DOI] [PubMed]

78.

Cohen-Sinai T, Cohen Z, Werner H, Berger R. Identification of BRCA1 as a potential biomarker for insulin-like growth factor-1 receptor targeted therapy in breast cancer. Front Endocrinol (Lausanne). 2017;8:148. [DOI] [PubMed] [PMC]

79.

Sinai-Livne T, Pasmanik-Chor M, Cohen Z, Tsarfaty I, Werner H, Berger R. Proteomic analysis of combined IGF1 receptor targeted therapy and chemotherapy identifies signatures associated with survival in breast cancer patients. Oncotarget. 2020;11:1515–30. [DOI] [PubMed] [PMC]

80.

Xu J, Song Y, Zhou B, Yuan S, Gao S. Prognostic and diagnostic value of circulating IGFBP2 in pancreatic cancer. Open Med (Wars). 2024;19:20230893. [DOI] [PubMed] [PMC]

81.

Prayudi PKA, Budiana ING, Mahayasa PD, Surya IGNHW, Wiradnyana AAGP, Suwiyoga K. Diagnostic accuracy of serum insulin-like growth factor-binding protein 2 for ovarian cancer. Int J Gynecol Cancer. 2020;30:1762–7. [DOI] [PubMed]

82.

Godina C, Rosendahl AH, Gonçalves de Oliveira K, Khazaei S, Björner S, Jirström K, et al. Genetic determinants and clinical significance of circulating and tumor-specific levels of insulin-like growth factor binding protein 7 (IGFBP7) in a Swedish breast cancer cohort. Carcinogenesis. 2025;46:bgaf020. [DOI] [PubMed] [PMC]

83.

Godina C, Pollak MN, Jernström H. Targeting IGF-IR improves neoadjuvant chemotherapy efficacy in breast cancers with low IGFBP7 expression. NPJ Precis Oncol. 2024;8:212. [DOI] [PubMed] [PMC]

84.

Evdokimova V, Tognon CE, Benatar T, Yang W, Krutikov K, Pollak M, et al. IGFBP7 binds to the IGF-1 receptor and blocks its activation by insulin-like growth factors. Sci Signal. 2012;5:ra92. [DOI] [PubMed]

85.

Best MG, Wesseling P, Wurdinger T. Tumor-educated platelets as a noninvasive biomarker source for cancer detection and progression monitoring. Cancer Res. 2018;78:3407–12. [DOI] [PubMed]

86.

McCaffery I, Tudor Y, Deng H, Tang R, Suzuki S, Badola S, et al. Putative predictive biomarkers of survival in patients with metastatic pancreatic adenocarcinoma treated with gemcitabine and ganitumab, an IGF1R inhibitor. Clin Cancer Res. 2013;19:4282–9. [DOI] [PubMed]

87.

Yee D, Isaacs C, Wolf DM, Yau C, Haluska P, Giridhar KV, et al. Ganitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer. NPJ Breast Cancer. 2021;7:131. [DOI] [PubMed] [PMC]

88.

Ordóñez-Rubiano EG, Rincón-Arias N, Shelton WJ, Salazar AF, Sierra MA, Bertani R, et al. Current applications of single-cell RNA sequencing in glioblastoma: a scoping review. Brain Sci. 2025;15:309. [DOI] [PubMed] [PMC]

89.

Hu J, Sa X, Yang Y, Han Y, Wu J, Sun M, et al. Multi-transcriptomics reveals niche-specific expression programs and endothelial cells in glioblastoma. J Transl Med. 2025;23:444. [DOI] [PubMed] [PMC]

90.

Shu S, Wu HJ, Ge JY, Zeid R, Harris IS, Jovanović B, et al. Synthetic lethal and resistance interactions with BET bromodomain inhibitors in triple-negative breast cancer. Mol Cell. 2020;78:1096–113.e8. [DOI] [PubMed] [PMC]

91.

Ge JY, Shu S, Kwon M, Jovanović B, Murphy K, Gulvady A, et al. Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer. Nat Commun. 2020;11:2350. [DOI] [PubMed] [PMC]