IGF-IR Signaling in Epithelial to Mesenchymal Transition and Targeting IGF-IR Therapy: Overview and New Insights

Overview

Journal Mol Cancer

Publisher Biomed Central

Specialties Molecular Biology
Oncology

Date 2017 Feb 1

PMID 28137302

Citations 66

Authors

Heming Li

Izhar Singh Batth

Xiujuan Qu

Ling Xu

Na Song

Ruoyu Wang

Yunpeng Liu

Affiliations

Soon will be listed here.

Abstract

The insulin-like growth factor-I (IGF-I) signaling induces epithelial to mesenchymal transition (EMT) program and contributes to metastasis and drug resistance in several subtypes of tumors. In preclinical studies, targeting of the insulin-like growth factor-I receptor (IGF-IR) showed promising anti-tumor effects. Unfortunately, high expectations for anti-IGF-IR therapy encountered challenge and disappointment in numerous clinical trials. This review summarizes the regulation of EMT by IGF-I/IGF-IR signaling pathway and drug resistance mechanisms of targeting IGF-IR therapy. Most importantly, we address several factors in the regulation of IGF-I/IGF-IR-associated EMT progression that may be potential predictive biomarkers in targeted therapy.

Citing Articles

Elucidating the pharmacological foundations and mechanisms of the Sihai Shuyu formula in treating Graves' disease through integrated serum metabolomics and network pharmacology with molecular docking techniques.

Liu X, Li X, Huang W, Cui Y, Cheng F, Chen G Front Endocrinol (Lausanne). 2025; 16:1511808.

PMID: 39950029 PMC: 11821505. DOI: 10.3389/fendo.2025.1511808.

Therapeutic potential and impact of nanoengineered patient-derived mesenchymal stem cells in a murine resection and recurrence model of human glioblastoma.

Al-Kharboosh R, Bechtle A, Tzeng S, Zheng J, Mondal S, Wilson D Bioeng Transl Med. 2024; 9(6):e10675.

PMID: 39545093 PMC: 11558202. DOI: 10.1002/btm2.10675.

Decoding the Role of Insulin-like Growth Factor 1 and Its Isoforms in Breast Cancer.

Kotsifaki A, Maroulaki S, Karalexis E, Stathaki M, Armakolas A Int J Mol Sci. 2024; 25(17).

PMID: 39273251 PMC: 11394947. DOI: 10.3390/ijms25179302.

Putative epithelial-mesenchymal transitions during salamander limb regeneration: Current perspectives and future investigations.

Kim R, Whited J Ann N Y Acad Sci. 2024; 1540(1):89-103.

PMID: 39269330 PMC: 11471381. DOI: 10.1111/nyas.15210.

Anti-PEc: Development of a novel monoclonal antibody against prostate cancer.

Armakolas A, Alevizopoulos N, Stathaki M, Petraki C, Agrogiannis G, Samiotaki M Br J Cancer. 2024; 131(3):551-564.

PMID: 38902531 PMC: 11300853. DOI: 10.1038/s41416-024-02713-8.

References

Duan C, Ren H, Gao S . Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins: roles in skeletal muscle growth and differentiation. Gen Comp Endocrinol. 2010; 167(3):344-51. DOI: 10.1016/j.ygcen.2010.04.009. View

Denduluri S, Idowu O, Wang Z, Liao Z, Yan Z, Mohammed M . Insulin-like growth factor (IGF) signaling in tumorigenesis and the development of cancer drug resistance. Genes Dis. 2015; 2(1):13-25. PMC: 4431759. DOI: 10.1016/j.gendis.2014.10.004. View

Nahta R, Yuan L, Zhang B, Kobayashi R, Esteva F . Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res. 2005; 65(23):11118-28. DOI: 10.1158/0008-5472.CAN-04-3841. View

Peinado H, Olmeda D, Cano A . Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?. Nat Rev Cancer. 2007; 7(6):415-28. DOI: 10.1038/nrc2131. View

Laviola L, Natalicchio A, Giorgino F . The IGF-I signaling pathway. Curr Pharm Des. 2007; 13(7):663-9. DOI: 10.2174/138161207780249146. View

Sandhu M, Dunger D, Giovannucci E . Insulin, insulin-like growth factor-I (IGF-I), IGF binding proteins, their biologic interactions, and colorectal cancer. J Natl Cancer Inst. 2002; 94(13):972-80. DOI: 10.1093/jnci/94.13.972. View

Kurzrock R, Patnaik A, Aisner J, Warren T, Leong S, Benjamin R . A phase I study of weekly R1507, a human monoclonal antibody insulin-like growth factor-I receptor antagonist, in patients with advanced solid tumors. Clin Cancer Res. 2010; 16(8):2458-65. DOI: 10.1158/1078-0432.CCR-09-3220. View

Shan J, Shen J, Liu L, Xia F, Xu C, Duan G . 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. DOI: 10.1002/hep.25745. View

Timmerman L, Grego-Bessa J, Raya A, Bertran E, Perez-Pomares J, Diez J . Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev. 2004; 18(1):99-115. PMC: 314285. DOI: 10.1101/gad.276304. View

10.

Desbois-Mouthon C, Cadoret A, Bertrand F, Cherqui G, Perret C, Capeau J . Insulin and IGF-1 stimulate the beta-catenin pathway through two signalling cascades involving GSK-3beta inhibition and Ras activation. Oncogene. 2001; 20(2):252-9. DOI: 10.1038/sj.onc.1204064. View

11.

Doepfner K, Spertini O, Arcaro A . Autocrine insulin-like growth factor-I signaling promotes growth and survival of human acute myeloid leukemia cells via the phosphoinositide 3-kinase/Akt pathway. Leukemia. 2007; 21(9):1921-30. DOI: 10.1038/sj.leu.2404813. View

12.

Fang X, Cai Y, Liu J, Wang Z, Wu Q, Zhang Z . Twist2 contributes to breast cancer progression by promoting an epithelial-mesenchymal transition and cancer stem-like cell self-renewal. Oncogene. 2011; 30(47):4707-20. DOI: 10.1038/onc.2011.181. View

13.

de Lint K, Poell J, Soueidan H, Jastrzebski K, Vidal Rodriguez J, Lieftink C . Sensitizing Triple-Negative Breast Cancer to PI3K Inhibition by Cotargeting IGF1R. Mol Cancer Ther. 2016; 15(7):1545-56. DOI: 10.1158/1535-7163.MCT-15-0865. View

14.

Singh A, Settleman J . EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 2010; 29(34):4741-51. PMC: 3176718. DOI: 10.1038/onc.2010.215. View

15.

Grego-Bessa J, Diez J, Timmerman L, de la Pompa J . Notch and epithelial-mesenchyme transition in development and tumor progression: another turn of the screw. Cell Cycle. 2004; 3(6):718-21. View

16.

Fang D, Wang H, Fang N, Altman Y, Elly C, Liu Y . Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells. J Biol Chem. 2000; 276(7):4872-8. DOI: 10.1074/jbc.M008901200. View

17.

Fuchs C, Azevedo S, Okusaka T, Van Laethem J, Lipton L, Riess H . A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Ann Oncol. 2015; 26(5):921-927. PMC: 4804122. DOI: 10.1093/annonc/mdv027. View

18.

Gombos A, Metzger-Filho O, Dal Lago L, Awada-Hussein A . Clinical development of insulin-like growth factor receptor--1 (IGF-1R) inhibitors: at the crossroad?. Invest New Drugs. 2012; 30(6):2433-42. PMC: 3484277. DOI: 10.1007/s10637-012-9811-0. View

19.

Ding Q, Xia W, Liu J, Yang J, Lee D, Xia J . Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. Mol Cell. 2005; 19(2):159-70. DOI: 10.1016/j.molcel.2005.06.009. View

20.

Frasca F, Pandini G, Scalia P, Sciacca L, MINEO R, Costantino A . Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol Cell Biol. 1999; 19(5):3278-88. PMC: 84122. DOI: 10.1128/MCB.19.5.3278. View