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The role of IGF/IGF-1R signaling in the regulation of cancer stem cells

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Abstract

Cancer stem cells (CSCs) are a group of tumor cells with high tumorigenic ability and self-renewal potential similar to those of normal stem cells. CSCs are the key “seeds” for tumor development, metastasis, and recurrence. A better insight into the key mechanisms underlying CSC survival improves the efficiency of cancer therapy via specific targeting of CSCs. Insulin-like growth factor (IGF)/IGF-1 receptor (IGF-1R) signaling plays an important role in the maintenance of cancer stemness. However, the effect of IGF/IGF-1R signaling on stemness and CSCs and the underlying mechanisms are still controversial. Based on the similarity between CSCs and normal stem cells, this review discusses emerging data on the functions of IGF/IGF-1R signaling in normal stem cells and CSCs and dissects the underlying mechanisms by which IGF/IGF-1R signaling is involved in CSCs. On the other hand, this review highlighted the role of IGF/IGF-1R signaling blockade in multiple CSCs as a potential strategy to improve CSC-based therapy.

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References

  1. Saygin C, Matei D, Majeti R, Reizes O, Lathia JD. Targeting cancer stemness in the clinic: from hype to hope. Cell Stem Cell. 2019;24(1):25–40.

    Article  CAS  PubMed  Google Scholar 

  2. Lytle NK, Barber AG, Reya T. Stem cell fate in cancer growth, progression and therapy resistance. Nat Rev Cancer. 2018;18(11):669–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Nassar D, Blanpain C. Cancer stem cells: basic concepts and therapeutic implications. Annu Rev Pathol. 2016;11:47–76.

    Article  CAS  PubMed  Google Scholar 

  4. Yang L, Shi P, Zhao G, Xu J, Peng W, Zhang J, Zhang G, Wang X, Dong Z, Chen F, et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther. 2020;5(1):8.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Batlle E, Clevers H. Cancer stem cells revisited. Nat Med. 2017;23(10):1124–34.

    Article  CAS  PubMed  Google Scholar 

  6. Hua H, Kong Q, Yin J, Zhang J, Jiang Y. Insulin-like growth factor receptor signaling in tumorigenesis and drug resistance: a challenge for cancer therapy. J Hematol Oncol. 2020;13(1):64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cao D, Lei Y, Ye Z, Zhao L, Wang H, Zhang J, He F, Huang L, Shi D, Liu Q, et al. Blockade of IGF/IGF-1R signaling axis with soluble IGF-1R mutants suppresses the cell proliferation and tumor growth of human osteosarcoma. Am J Cancer Res. 2020;10(10):3248–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Lero MW, Shaw LM. Diversity of insulin and IGF signaling in breast cancer: implications for therapy. Mol Cell Endocrinol. 2021;527:111213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lin SL, Lin CY, Lee W, Teng CF, Shyu WC, Jeng LB. Mini review: molecular interpretation of the IGF/IGF-1R axis in cancer treatment and stem cells-based therapy in regenerative medicine. Int J Mol Sci. 2022;23(19):11781.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Weroha SJ, Haluska P. The insulin-like growth factor system in cancer. Endocrinol Metab Clin North Am. 2012;41(2):335–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mancarella C, Morrione A, Scotlandi K. Novel regulators of the IGF system in cancer. Biomolecules. 2021;11(2):273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ziegler AN, Levison SW, Wood TL. Insulin and IGF receptor signalling in neural-stem-cell homeostasis. Nat Rev Endocrinol. 2015;11(3):161–70.

    Article  CAS  PubMed  Google Scholar 

  13. Takahashi SI. IGF research 2016–2018. Growth Horm IGF Res. 2019;48–49:65–9.

    Article  PubMed  Google Scholar 

  14. Kolb H, Kempf K, Rohling M, Martin S. Insulin: too much of a good thing is bad. BMC Med. 2020;18(1):224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Vigneri R, Sciacca L, Vigneri P. Rethinking the relationship between insulin and cancer. Trends Endocrinol Metab. 2020;31(8):551–60.

    Article  CAS  PubMed  Google Scholar 

  16. Clemmons DR. Modifying IGF1 activity: an approach to treat endocrine disorders, atherosclerosis and cancer. Nat Rev Drug Discov. 2007;6(10):821–33.

    Article  CAS  PubMed  Google Scholar 

  17. Junnila RK, List EO, Berryman DE, Murrey JW, Kopchick JJ. The GH/IGF-1 axis in ageing and longevity. Nat Rev Endocrinol. 2013;9(6):366–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nordin M, Bergman D, Halje M, Engstrom W, Ward A. Epigenetic regulation of the Igf2/H19 gene cluster. Cell Prolif. 2014;47(3):189–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Selenou C, Brioude F, Giabicani E, Sobrier ML, Netchine I. IGF2: development, genetic and epigenetic abnormalities. Cells. 2022;11(12):1886.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. DeChiara TM, Robertson EJ, Efstratiadis A. Parental imprinting of the mouse insulin-like growth factor II gene. Cell. 1991;64(4):849–59.

    Article  CAS  PubMed  Google Scholar 

  21. Ma L, Zhao W, Huang S, Xu F, Wang Y, Deng D, Zhang T, Shu S, Chen X. IGF/IGF-1R signal pathway in pain: a promising therapeutic target. Int J Biol Sci. 2023;19(11):3472–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bach LA. IGF-binding proteins. J Mol Endocrinol. 2018;61(1):T11–28.

    Article  CAS  PubMed  Google Scholar 

  23. Forbes BE, Blyth AJ, Wit JM. Disorders of IGFs and IGF-1R signaling pathways. Mol Cell Endocrinol. 2020;518: 111035.

    Article  CAS  PubMed  Google Scholar 

  24. Miller BS, Rogol AD, Rosenfeld RG. The history of the insulin-like growth factor system. Horm Res Paediatr. 2022;95(6):619–30.

    Article  CAS  PubMed  Google Scholar 

  25. LeRoith D, Holly JMP, Forbes BE. Insulin-like growth factors: ligands, binding proteins, and receptors. Mol Metab. 2021;52:101245.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wamaitha SE, Grybel KJ, Alanis-Lobato G, Gerri C, Ogushi S, McCarthy A, Mahadevaiah SK, Healy L, Lea RA, Molina-Arcas M, et al. IGF1-mediated human embryonic stem cell self-renewal recapitulates the embryonic niche. Nat Commun. 2020;11(1):764.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Magner NL, Jung Y, Wu J, Nolta JA, Zern MA, Zhou P. Insulin and IGFs enhance hepatocyte differentiation from human embryonic stem cells via the PI3K/AKT pathway. Stem Cells. 2013;31(10):2095–103.

    Article  CAS  PubMed  Google Scholar 

  28. Young K, Eudy E, Bell R, Loberg MA, Stearns T, Sharma D, Velten L, Haas S, Filippi MD, Trowbridge JJ. Decline in IGF1 in the bone marrow microenvironment initiates hematopoietic stem cell aging. Cell Stem Cell. 2021;28(8):1473-1482 e1477.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cheng CW, Adams GB, Perin L, Wei M, Zhou X, Lam BS, Da Sacco S, Mirisola M, Quinn DI, Dorff TB, et al. Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell. 2014;14(6):810–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kuo YC, Au HK, Hsu JL, Wang HF, Lee CJ, Peng SW, Lai SC, Wu YC, Ho HN, Huang YH. IGF-1R Promotes symmetric self-renewal and migration of alkaline phosphatase(+) germ stem cells through HIF-2alpha-OCT4/CXCR4 loop under hypoxia. Stem Cell Rep. 2018;10(2):524–37.

    Article  CAS  Google Scholar 

  31. Zheng Y, Song Y, Han Q, Liu W, Xu J, Yu Z, Zhang R, Li N. Intestinal epithelial cell-specific IGF1 promotes the expansion of intestinal stem cells during epithelial regeneration and functions on the intestinal immune homeostasis. Am J Physiol Endocrinol Metab. 2018;315(4):E638–49.

    Article  CAS  PubMed  Google Scholar 

  32. Deng M, Guerrero-Juarez CF, Sheng X, Xu J, Wu X, Yao K, Li M, Yang X, Li G, **ao J, et al. Lepr(+) mesenchymal cells sense diet to modulate intestinal stem/progenitor cells via Leptin-Igf1 axis. Cell Res. 2022;32(7):670–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zheng Y, Luo L, Lambertz IU, Conti CJ, Fuchs-Young R. Early dietary exposures epigenetically program mammary cancer susceptibility through Igf1-mediated expansion of the mammary stem cell compartment. Cells. 2022;11(16):2258.

    Article  Google Scholar 

  34. Arsenijevic Y, Weiss S, Schneider B, Aebischer P. Insulin-like growth factor-I is necessary for neural stem cell proliferation and demonstrates distinct actions of epidermal growth factor and fibroblast growth factor-2. J Neurosci. 2001;21(18):7194–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kharat A, Chandravanshi B, Gadre S, Patil V, Bhonde R, Dubhashi A. IGF-1 and somatocrinin trigger islet differentiation in human amniotic membrane derived mesenchymal stem cells. Life Sci. 2019;216:287–94.

    Article  CAS  PubMed  Google Scholar 

  36. An C, Cheng Y, Yuan Q, Li J. IGF-1 and BMP-2 induces differentiation of adipose-derived mesenchymal stem cells into chondrocytes-like cells. Ann Biomed Eng. 2010;38(4):1647–54.

    Article  PubMed  Google Scholar 

  37. Zhang X, Zhang L, Cheng X, Guo Y, Sun X, Chen G, Li H, Li P, Lu X, Tian M, et al. IGF-1 promotes Brn-4 expression and neuronal differentiation of neural stem cells via the PI3K/Akt pathway. PLoS ONE. 2014;9(12):e113801.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Zhao L, Feng Y, Chen X, Yuan J, Liu X, Chen Y, Zhao Y, Liu P, Li Y. Effects of IGF-1 on neural differentiation of human umbilical cord derived mesenchymal stem cells. Life Sci. 2016;151:93–101.

    Article  CAS  PubMed  Google Scholar 

  39. Huang B, Ning S, Zhang Q, Chen A, Jiang C, Cui Y, Hu J, Li H, Fan G, Qin L, et al. Bisphenol a represses dopaminergic neuron differentiation from human embryonic stem cells through downregulating the expression of insulin-like growth factor 1. Mol Neurobiol. 2017;54(5):3798–812.

    Article  CAS  PubMed  Google Scholar 

  40. Li J, Zhu K, Wang Y, Zheng J, Guo C, Lai H, Wang C. Combination of IGF-1 gene manipulation and 5-AZA treatment promotes differentiation of mesenchymal stem cells into cardiomyocyte-like cells. Mol Med Rep. 2015;11(2):815–20.

    Article  CAS  PubMed  Google Scholar 

  41. Muguruma Y, Reyes M, Nakamura Y, Sato T, Matsuzawa H, Miyatake H, Akatsuka A, Itoh J, Yahata T, Ando K, et al. In vivo and in vitro differentiation of myocytes from human bone marrow-derived multipotent progenitor cells. Exp Hematol. 2003;31(12):1323–30.

    Article  CAS  PubMed  Google Scholar 

  42. Bartunek J, Croissant JD, Wijns W, Gofflot S, de Lavareille A, Vanderheyden M, Kaluzhny Y, Mazouz N, Willemsen P, Penicka M, et al. Pretreatment of adult bone marrow mesenchymal stem cells with cardiomyogenic growth factors and repair of the chronically infarcted myocardium. Am J Physiol Heart Circ Physiol. 2007;292(2):H1095-1104.

    Article  CAS  PubMed  Google Scholar 

  43. Huang YL, Qiu RF, Mai WY, Kuang J, Cai XY, Dong YG, Hu YZ, Song YB, Cai AP, Jiang ZG. Effects of insulin-like growth factor-1 on the properties of mesenchymal stem cells in vitro. J Zhejiang Univ Sci B. 2012;13(1):20–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chen RL, Kassem NA, Sadeghi M, Preston JE. Insulin-like growth factor-II uptake into choroid plexus and brain of young and old sheep. J Gerontol A Biol Sci Med Sci. 2008;63(2):141–8.

    Article  PubMed  Google Scholar 

  45. DeChiara TM, Efstratiadis A, Robertson EJ. A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting. Nature. 1990;345(6270):78–80.

    Article  CAS  PubMed  Google Scholar 

  46. Bendall SC, Stewart MH, Menendez P, George D, Vijayaragavan K, Werbowetski-Ogilvie T, Ramos-Mejia V, Rouleau A, Yang J, Bosse M, et al. IGF and FGF cooperatively establish the regulatory stem cell niche of pluripotent human cells in vitro. Nature. 2007;448(7157):1015–21.

    Article  CAS  PubMed  Google Scholar 

  47. Montes R, Ligero G, Sanchez L, Catalina P, de la Cueva T, Nieto A, Melen GJ, Rubio R, Garcia-Castro J, Bueno C, et al. Feeder-free maintenance of hESCs in mesenchymal stem cell-conditioned media: distinct requirements for TGF-beta and IGF-II. Cell Res. 2009;19(6):698–709.

    Article  CAS  PubMed  Google Scholar 

  48. Ziegler AN, Schneider JS, Qin M, Tyler WA, Pintar JE, Fraidenraich D, Wood TL, Levison SW. IGF-II promotes stemness of neural restricted precursors. Stem Cells. 2012;30(6):1265–76.

    Article  CAS  PubMed  Google Scholar 

  49. Ziegler AN, Chidambaram S, Forbes BE, Wood TL, Levison SW. Insulin-like growth factor-II (IGF-II) and IGF-II analogs with enhanced insulin receptor-a binding affinity promote neural stem cell expansion. J Biol Chem. 2014;289(8):4626–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ziegler AN, Feng Q, Chidambaram S, Testai JM, Kumari E, Rothbard DE, Constancia M, Sandovici I, Cominski T, Pang K, et al. Insulin-like growth factor II: an essential adult stem cell niche constituent in brain and intestine. Stem Cell Rep. 2019;12(4):816–30.

    Article  CAS  Google Scholar 

  51. Li J, Li R, Jiang W, Sun J, Li J, Guo Y, Zhu K, Zhang C, Kong G, Li Z. Splenic serum from portal hypertensive patients enhances liver stem cell proliferation and self-renewal via the IGF-II/ERK signaling pathway. Dig Liver Dis. 2020;52(2):205–13.

    Article  CAS  PubMed  Google Scholar 

  52. Sui Y, Zhang W, Tang T, Gao L, Cao T, Zhu H, You Q, Yu B, Yang T. Insulin-like growth factor-II overexpression accelerates parthenogenetic stem cell differentiation into cardiomyocytes and improves cardiac function after acute myocardial infarction in mice. Stem Cell Res Ther. 2020;11(1):86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Lozano-Urena A, Lazaro-Carot L, Jimenez-Villalba E, Montalban-Loro R, Mateos-White I, Duart-Abadia P, Martinez-Gurrea I, Nakayama KI, Farinas I, Kirstein M, et al. IGF2 interacts with the imprinted gene Cdkn1c to promote terminal differentiation of neural stem cells. Development. 2023;150(1):200563.

    Article  Google Scholar 

  54. Venkatraman A, He XC, Thorvaldsen JL, Sugimura R, Perry JM, Tao F, Zhao M, Christenson MK, Sanchez R, Yu JY, et al. Maternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence. Nature. 2013;500(7462):345–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Barroca V, Lewandowski D, Jaracz-Ros A, Hardouin SN. Paternal insulin-like growth factor 2 (Igf2) regulates stem cell activity during adulthood. EBioMedicine. 2017;15:150–62.

    Article  PubMed  Google Scholar 

  56. Wang L, Schulz TC, Sherrer ES, Dauphin DS, Shin S, Nelson AM, Ware CB, Zhan M, Song CZ, Chen X, et al. Self-renewal of human embryonic stem cells requires insulin-like growth factor-1 receptor and ERBB2 receptor signaling. Blood. 2007;110(12):4111–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ungewitter E, Scrable H. Delta40p53 controls the switch from pluripotency to differentiation by regulating IGF signaling in ESCs. Genes Dev. 2010;24(21):2408–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Cheng CL, Yang SC, Lai CY, Wang CK, Chang CF, Lin CY, Chen WJ, Lin PY, Wu HC, Ma N, et al. CXCL14 maintains hESC self-renewal through binding to IGF-1R and activation of the IGF-1R pathway. Cells. 2020;9(7):1706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Baxter RC. IGF binding proteins in cancer: mechanistic and clinical insights. Nat Rev Cancer. 2014;14(5):329–41.

    Article  CAS  PubMed  Google Scholar 

  60. Huynh H, Zheng J, Umikawa M, Zhang C, Silvany R, Iizuka S, Holzenberger M, Zhang W, Zhang CC. IGF binding protein 2 supports the survival and cycling of hematopoietic stem cells. Blood. 2011;118(12):3236–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zhang CC, Kaba M, Iizuka S, Huynh H, Lodish HF. Angiopoietin-like 5 and IGFBP2 stimulate ex vivo expansion of human cord blood hematopoietic stem cells as assayed by NOD/SCID transplantation. Blood. 2008;111(7):3415–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wang Y, Liu Y, Fan Z, Liu D, Wang F, Zhou Y. IGFBP2 enhances adipogenic differentiation potentials of mesenchymal stem cells from Wharton’s jelly of the umbilical cord via JNK and Akt signaling pathways. PLoS ONE. 2017;12(8):e0184182.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Kalluri HS, Dempsey RJ. IGFBP-3 inhibits the proliferation of neural progenitor cells. Neurochem Res. 2011;36(3):406–11.

    Article  CAS  PubMed  Google Scholar 

  64. Chang KH, Chan-Ling T, McFarland EL, Afzal A, Pan H, Baxter LC, Shaw LC, Caballero S, Sengupta N, Li Calzi S, et al. IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development. Proc Natl Acad Sci U S A. 2007;104(25):10595–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kim JH, Yoon SM, Song SU, Park SG, Kim WS, Park IG, Lee J, Sung JH. Hypoxia suppresses spontaneous mineralization and osteogenic differentiation of mesenchymal stem cells via IGFBP3 up-regulation. Int J Mol Sci. 2016;17(9):1389.

    Article  PubMed  PubMed Central  Google Scholar 

  66. D’Addio F, La Rosa S, Maestroni A, Jung P, Orsenigo E, Ben Nasr M, Tezza S, Bassi R, Finzi G, Marando A, et al. Circulating IGF-I and IGFBP3 levels control human colonic stem cell function and are disrupted in diabetic enteropathy. Cell Stem Cell. 2015;17(4):486–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Vassilieva I, Kosheverova V, Vitte M, Kamentseva R, Shatrova A, Tsupkina N, Skvortsova E, Borodkina A, Tolkunova E, Nikolsky N, et al. Paracrine senescence of human endometrial mesenchymal stem cells: a role for the insulin-like growth factor binding protein 3. Aging (Albany NY). 2020;12(2):1987–2004.

    Article  CAS  PubMed  Google Scholar 

  68. Minato A, Ise H, Goto M, Akaike T. Cardiac differentiation of embryonic stem cells by substrate immobilization of insulin-like growth factor binding protein 4 with elastin-like polypeptides. Biomaterials. 2012;33(2):515–23.

    Article  CAS  PubMed  Google Scholar 

  69. Xue Y, Yan Y, Gong H, Fang B, Zhou Y, Ding Z, Yin P, Zhang G, Ye Y, Yang C, et al. Insulin-like growth factor binding protein 4 enhances cardiomyocytes induction in murine-induced pluripotent stem cells. J Cell Biochem. 2014;115(9):1495–504.

    Article  CAS  PubMed  Google Scholar 

  70. Severino V, Alessio N, Farina A, Sandomenico A, Cipollaro M, Peluso G, Galderisi U, Chambery A. Insulin-like growth factor binding proteins 4 and 7 released by senescent cells promote premature senescence in mesenchymal stem cells. Cell Death Dis. 2013;4(11):e911.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Han N, Zhang F, Li G, Zhang X, Lin X, Yang H, Wang L, Cao Y, Du J, Fan Z. Local application of IGFBP5 protein enhanced periodontal tissue regeneration via increasing the migration, cell proliferation and osteo/dentinogenic differentiation of mesenchymal stem cells in an inflammatory niche. Stem Cell Res Ther. 2017;8(1):210.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Wang Y, Jia Z, Diao S, Lin X, Lian X, Wang L, Dong R, Liu D, Fan Z. IGFBP5 enhances osteogenic differentiation potential of periodontal ligament stem cells and Wharton’s jelly umbilical cord stem cells, via the JNK and MEK/Erk signalling pathways. Cell Prolif. 2016;49(5):618–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Li L, Wang H, Yu D, Wang Y, Zhao Y, Yang H, Cao Y, Cao Y. Insulin-like growth factor binding protein 5 accelerate the senescence of periodontal ligament stem cells. Cell Tissue Bank. 2023;24(1):231–9.

    Article  CAS  PubMed  Google Scholar 

  74. Aboalola D, Han VKM. Insulin-like growth factor binding protein-6 promotes the differentiation of placental mesenchymal stem cells into skeletal muscle independent of insulin-like growth factor receptor-1 and insulin receptor. Stem Cells Int. 2019;2019:9245938.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Jeon HJ, Park J, Shin JH, Chang MS. Insulin-like growth factor binding protein-6 released from human mesenchymal stem cells confers neuronal protection through IGF-1R-mediated signaling. Int J Mol Med. 2017;40(6):1860–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Infante A, Rodriguez CI. Secretome analysis of in vitro aged human mesenchymal stem cells reveals IGFBP7 as a putative factor for promoting osteogenesis. Sci Rep. 2018;8(1):4632.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Zhang W, Chen E, Chen M, Ye C, Qi Y, Ding Q, Li H, Xue D, Gao X, Pan Z. IGFBP7 regulates the osteogenic differentiation of bone marrow-derived mesenchymal stem cells via Wnt/beta-catenin signaling pathway. FASEB J. 2018;32(4):2280–91.

    Article  CAS  PubMed  Google Scholar 

  78. Li N, Han J, Tang J, Ying Y. IGFBP-7 inhibits the differentiation of oligodendrocyte precursor cells via regulation of Wnt/beta-Catenin signaling. J Cell Biochem. 2018;119(6):4742–50.

    Article  CAS  PubMed  Google Scholar 

  79. Li X, Feng L, Zhang C, Wang J, Wang S, Hu L. Insulin-like growth factor binding proteins 7 prevents dental pulp-derived mesenchymal stem cell senescence via metabolic downregulation of p21. Sci China Life Sci. 2022;65(11):2218–32.

    Article  CAS  PubMed  Google Scholar 

  80. Osuka S, Zhu D, Zhang Z, Li C, Stackhouse CT, Sampetrean O, Olson JJ, Gillespie GY, Saya H, Willey CD, et al. N-cadherin upregulation mediates adaptive radioresistance in glioblastoma. J Clin Invest. 2021;131(6):136098.

    Article  PubMed  Google Scholar 

  81. Ramakrishnan V, Xu B, Akers J, Nguyen T, Ma J, Dhawan S, Ning J, Mao Y, Hua W, Kokkoli E, et al. Radiation-induced extracellular vesicle (EV) release of miR-603 promotes IGF1-mediated stem cell state in glioblastomas. EBioMedicine. 2020;55:102736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Bu Y, Jia QA, Ren ZG, Zhang JB, Jiang XM, Liang L, Xue TC, Zhang QB, Wang YH, Zhang L, et al. Maintenance of stemness in oxaliplatin-resistant hepatocellular carcinoma is associated with increased autocrine of IGF1. PLoS ONE. 2014;9(3):e89686.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Cao Z, Scandura JM, Inghirami GG, Shido K, Ding BS, Rafii S. Molecular checkpoint decisions made by subverted vascular niche transform indolent tumor cells into chemoresistant cancer stem cells. Cancer Cell. 2017;31(1):110–26.

    Article  CAS  PubMed  Google Scholar 

  84. Murakami A, Takahashi F, Nurwidya F, Kobayashi I, Minakata K, Hashimoto M, Nara T, Kato M, Tajima K, Shimada N, et al. Hypoxia increases gefitinib-resistant lung cancer stem cells through the activation of insulin-like growth factor 1 receptor. PLoS ONE. 2014;9(1):e86459.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Liu P, Zhang R, Yu W, Ye Y, Cheng Y, Han L, Dong L, Chen Y, Wei X, Yu J. FGF1 and IGF1-conditioned 3D culture system promoted the amplification and cancer stemness of lung cancer cells. Biomaterials. 2017;149:63–76.

    Article  CAS  PubMed  Google Scholar 

  86. Giambra V, Gusscott S, Gracias D, Song R, Lam SH, Panelli P, Tyshchenko K, Jenkins CE, Hoofd C, Lorzadeh A et al. (2018) Epigenetic Restoration of Fetal-like IGF1 Signaling Inhibits Leukemia Stem Cell Activity. Cell Stem Cell 23(5): 714–726717.

  87. Kaneda A, Wang CJ, Cheong R, Timp W, Onyango P, Wen B, Iacobuzio-Donahue CA, Ohlsson R, Andraos R, Pearson MA, et al. Enhanced sensitivity to IGF-II signaling links loss of imprinting of IGF2 to increased cell proliferation and tumor risk. Proc Natl Acad Sci U S A. 2007;104(52):20926–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Gao T, Liu X, He B, Pan Y, Wang S. IGF2 loss of imprinting enhances colorectal cancer stem cells pluripotency by promoting tumor autophagy. Aging (Albany NY). 2020;12(21):21236–52.

    Article  CAS  PubMed  Google Scholar 

  89. Xu WW, Li B, Zhao JF, Yang JG, Li JQ, Tsao SW, He QY, Cheung ALM. IGF2 induces CD133 expression in esophageal cancer cells to promote cancer stemness. Cancer Lett. 2018;425:88–100.

    Article  CAS  PubMed  Google Scholar 

  90. Tominaga K, Shimamura T, Kimura N, Murayama T, Matsubara D, Kanauchi H, Niida A, Shimizu S, Nishioka K, Tsuji EI, et al. Addiction to the IGF2-ID1-IGF2 circuit for maintenance of the breast cancer stem-like cells. Oncogene. 2017;36(9):1276–86.

    Article  CAS  PubMed  Google Scholar 

  91. Vaquero J, Lobe C, Tahraoui S, Claperon A, Mergey M, Merabtene F, Wendum D, Coulouarn C, Housset C, Desbois-Mouthon C, et al. The IGF2/IR/IGF1R pathway in tumor cells and myofibroblasts mediates resistance to EGFR inhibition in cholangiocarcinoma. Clin Cancer Res. 2018;24(17):4282–96.

    Article  CAS  PubMed  Google Scholar 

  92. Murayama T, Nakaoku T, Enari M, Nishimura T, Tominaga K, Nakata A, Tojo A, Sugano S, Kohno T, Gotoh N. Oncogenic fusion gene CD74-NRG1 confers cancer stem cell-like properties in lung cancer through a IGF2 autocrine/paracrine circuit. Cancer Res. 2016;76(4):974–83.

    Article  CAS  PubMed  Google Scholar 

  93. Xu DD, Wang Y, Zhou PJ, Qin SR, Zhang R, Zhang Y, Xue X, Wang J, Wang X, Chen HC, et al. The IGF2/IGF1R/Nanog signaling pathway regulates the proliferation of acute myeloid leukemia stem cells. Front Pharmacol. 2018;9:687.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Shan J, Shen J, Liu L, **a F, Xu C, Duan G, Xu Y, Ma Q, Yang Z, Zhang Q, et al. Nanog regulates self-renewal of cancer stem cells through the insulin-like growth factor pathway in human hepatocellular carcinoma. Hepatology. 2012;56(3):1004–14.

    Article  CAS  PubMed  Google Scholar 

  95. Chen WJ, Ho CC, Chang YL, Chen HY, Lin CA, Ling TY, Yu SL, Yuan SS, Chen YJ, Lin CY, et al. Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling. Nat Commun. 2014;5:3472.

    Article  PubMed  Google Scholar 

  96. Lv J, Liu C, Chen FK, Feng ZP, Jia L, Liu PJ, Yang ZX, Hou F, Deng ZY. M2-like tumour-associated macrophage-secreted IGF promotes thyroid cancer stemness and metastasis by activating the PI3K/AKT/mTOR pathway. Mol Med Rep. 2021;24(2):604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Li L, Li JC, Yang H, Zhang X, Liu LL, Li Y, Zeng TT, Zhu YH, Li XD, Li Y, et al. Expansion of cancer stem cell pool initiates lung cancer recurrence before angiogenesis. Proc Natl Acad Sci U S A. 2018;115(38):E8948–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Hsieh A, Ellsworth R, Hsieh D. Hedgehog/GLI1 regulates IGF dependent malignant behaviors in glioma stem cells. J Cell Physiol. 2011;226(4):1118–27.

    Article  CAS  PubMed  Google Scholar 

  99. Ferreira Mendes JM, de Faro VL, Torres Andion Vidal M, Paredes BD, Coelho P, Allahdadi KJ, Coletta RD, Souza BSF, Rocha CAG: Effects of IGF-1 on proliferation, angiogenesis, tumor stem cell populations and activation of AKT and hedgehog pathways in oral squamous cell carcinoma. Int J Mol Sci. 2020;21(18):6487.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Xu C, **e D, Yu SC, Yang XJ, He LR, Yang J, ** YF, Wang B, Yang L, Xu SL, et al. beta-Catenin/POU5F1/SOX2 transcription factor complex mediates IGF-I receptor signaling and predicts poor prognosis in lung adenocarcinoma. Cancer Res. 2013;73(10):3181–9.

    Article  CAS  PubMed  Google Scholar 

  101. Chan YT, Lin RJ, Wang YH, Hung TH, Huang Y, Yu J, Yu JC, Yu AL. The interplay between IGF-1R signaling and Hippo-YAP in breast cancer stem cells. Cell Commun Signal. 2023;21(1):81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Lee JH, Choi SI, Kim RK, Cho EW, Kim IG. Tescalcin/c-Src/IGF1Rbeta-mediated STAT3 activation enhances cancer stemness and radioresistant properties through ALDH1. Sci Rep. 2018;8(1):10711.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Bodzin AS, Wei Z, Hurtt R, Gu T, Doria C. Gefitinib resistance in HCC mahlavu cells: upregulation of CD133 expression, activation of IGF-1R signaling pathway, and enhancement of IGF-1R nuclear translocation. J Cell Physiol. 2012;227(7):2947–52.

    Article  CAS  PubMed  Google Scholar 

  104. Verhagen H, van Gils N, Martianez T, van Rhenen A, Rutten A, Denkers F, de Leeuw DC, Smit MA, Tsui ML, de Vos Klootwijk LLE, et al. IGFBP7 induces differentiation and loss of survival of human acute myeloid leukemia stem cells without affecting normal hematopoiesis. Cell Rep. 2018;25(11):3021-3035 e3025.

    Article  CAS  PubMed  Google Scholar 

  105. van Gils N, Verhagen H, Rutten A, Menezes RX, Tsui ML, Vermue E, Dekens E, Brocco F, Denkers F, Kessler FL, et al. IGFBP7 activates retinoid acid-induced responses in acute myeloid leukemia stem and progenitor cells. Blood Adv. 2020;4(24):6368–83.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Chen X, Zheng J, Zou Y, Song C, Hu X, Zhang CC. IGF binding protein 2 is a cell-autonomous factor supporting survival and migration of acute leukemia cells. J Hematol Oncol. 2013;6(1):72.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Hsieh D, Hsieh A, Stea B, Ellsworth R. IGFBP2 promotes glioma tumor stem cell expansion and survival. Biochem Biophys Res Commun. 2010;397(2):367–72.

    Article  CAS  PubMed  Google Scholar 

  108. Masuo K, Chen R, Yogo A, Sugiyama A, Fukuda A, Masui T, Uemoto S, Seno H, Takaishi S. SNAIL2 contributes to tumorigenicity and chemotherapy resistance in pancreatic cancer by regulating IGFBP2. Cancer Sci. 2021;112(12):4987–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Lin W, Niu R, Park SM, Zou Y, Kim SS, **a X, **ng S, Yang Q, Sun X, Yuan Z, et al. IGFBP5 is an ROR1 ligand promoting glioblastoma invasion via ROR1/HER2-CREB signaling axis. Nat Commun. 2023;14(1):1578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Takada Y, Takada YK, Fujita M. Crosstalk between insulin-like growth factor (IGF) receptor and integrins through direct integrin binding to IGF1. Cytokine Growth Factor Rev. 2017;34:67–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Meier C, Hardtstock P, Joost S, Alla V, Putzer BM. p73 and IGF1R regulate emergence of aggressive cancer stem-like features via miR-885-5p control. Cancer Res. 2016;76(2):197–205.

    Article  CAS  PubMed  Google Scholar 

  112. Leong HS, Chong FT, Sew PH, Lau DP, Wong BH, Teh BT, Tan DS, Iyer NG. Targeting cancer stem cell plasticity through modulation of epidermal growth factor and insulin-like growth factor receptor signaling in head and neck squamous cell cancer. Stem Cells Transl Med. 2014;3(9):1055–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Dixit D, Prager BC, Gimple RC, Poh HX, Wang Y, Wu Q, Qiu Z, Kidwell RL, Kim LJY, **e Q, et al. The RNA m6A reader YTHDF2 maintains oncogene expression and is a targetable dependency in glioblastoma stem cells. Cancer Discov. 2021;11(2):480–99.

    Article  CAS  PubMed  Google Scholar 

  114. Guo Y, Mehrabi Nasab E, Hassanpour F, Athari SS. Linsitinib and aspirin as the IGF1-R antagonists, inhibit regorafenib-resistant chemotherapy in colon cancer. Saudi J Biol Sci. 2022;29(2):872–7.

    Article  CAS  PubMed  Google Scholar 

  115. Hart LS, Dolloff NG, Dicker DT, Koumenis C, Christensen JG, Grimberg A, El-Deiry WS. Human colon cancer stem cells are enriched by insulin-like growth factor-1 and are sensitive to figitumumab. Cell Cycle. 2011;10(14):2331–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Chang WW, Lin RJ, Yu J, Chang WY, Fu CH, Lai A, Yu JC, Yu AL. The expression and significance of insulin-like growth factor-1 receptor and its pathway on breast cancer stem/progenitors. Breast Cancer Res. 2013;15(3):R39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (Grant Number: 82103662).

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  1. Liver Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, China

    Fengchao Liu, Susu Ye, Liu Zhao & Qinghui Niu

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Conceptualization, L.F.C.; writing—original draft, L.F.C.; writing—review and editing, L.F.C; Y.S.S. and Z.L.; supervision, Y.S.S.; N.Q.H and Z.L., financial Acquisition, L.F.C. All authors have read and agreed to the published version of the manuscript.

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Liu, F., Ye, S., Zhao, L. et al. The role of IGF/IGF-1R signaling in the regulation of cancer stem cells. Clin Transl Oncol (2024). https://doi.org/10.1007/s12094-024-03561-x

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