Prognostic and Therapeutic Roles of the Insulin Growth Factor System in Glioblastoma

Overview

Journal Front Oncol

Specialty Oncology

Date 2021 Feb 19

PMID 33604294

Citations 23

Authors

Elena Tirro

Michele Massimino

Chiara Romano

Federica Martorana

Maria Stella Pennisi

Stefania Stella

Giuliana Pavone

Sandra Di Gregorio

Adriana Puma

Cristina Tomarchio

Silvia Rita Vitale

Livia Manzella

Paolo Vigneri

Affiliations

Soon will be listed here.

Abstract

Glioblastoma multiforme (GBM) is the most common primary brain malignancy and is often resistant to conventional treatments due to its extensive cellular heterogeneity. Thus, the overall survival of GBM patients remains extremely poor. Insulin-like growth factor (IGF) signaling entails a complex system that is a key regulator of cell transformation, growth and cell-cycle progression. Hence, its deregulation is frequently involved in the development of several cancers, including brain malignancies. In GBM, differential expression of several IGF system components and alterations of this signaling axis are linked to significantly worse prognosis and reduced responsiveness to temozolomide, the most commonly used pharmacological agent for the treatment of the disease. In the present review we summarize the biological role of the IGF system in the pathogenesis of GBM and comprehensively discuss its clinical significance and contribution to the development of resistance to standard chemotherapy and experimental treatments.

Citing Articles

The role of lncRNAs in the interplay of signaling pathways and epigenetic mechanisms in glioma.

Bora Yildiz C, Du J, Mohan K, Zimmer-Bensch G, Abdolahi S Epigenomics. 2025; 17(2):125-140.

PMID: 39829063 PMC: 11792803. DOI: 10.1080/17501911.2024.2442297.

Transcranial Magnetic Stimulation Enhances the Therapeutic Effect of IGF-Trap in Intracerebral Glioma Models.

Perrino S, Vazana U, Prager O, Schori L, Ben-Arie G, Minarik A Pharmaceuticals (Basel). 2025; 17(12.

PMID: 39770449 PMC: 11677529. DOI: 10.3390/ph17121607.

Impact of Radiation on Invasion and Migration of Glioma In Vitro and In Vivo.

Santiago Franco M, Raulefs S, Schilling D, Combs S, Schmid T Cancers (Basel). 2024; 16(23).

PMID: 39682088 PMC: 11640451. DOI: 10.3390/cancers16233900.

Practical immunomodulatory landscape of glioblastoma multiforme (GBM) therapy.

Norollahi S, Yousefi B, Nejatifar F, Yousefzadeh-Chabok S, Rashidy-Pour A, Samadani A J Egypt Natl Canc Inst. 2024; 36(1):33.

PMID: 39465481 DOI: 10.1186/s43046-024-00240-4.

T cell-mediated tumor killing based signature to predict the prognosis and immunotherapy for glioblastoma.

Liu H, Shi K, Wei Z, Zhang Y, Li J Heliyon. 2024; 10(10):e31207.

PMID: 38813229 PMC: 11133811. DOI: 10.1016/j.heliyon.2024.e31207.

References

Gong Y, Ma Y, Sinyuk M, Loganathan S, Thompson R, Sarkaria J . Insulin-mediated signaling promotes proliferation and survival of glioblastoma through Akt activation. Neuro Oncol. 2015; 18(1):48-57. PMC: 4677408. DOI: 10.1093/neuonc/nov096. View

Hakuno F, Takahashi S . IGF1 receptor signaling pathways. J Mol Endocrinol. 2018; 61(1):T69-T86. DOI: 10.1530/JME-17-0311. View

Bao S, Wu Q, McLendon R, Hao Y, Shi Q, Hjelmeland A . Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006; 444(7120):756-60. DOI: 10.1038/nature05236. View

Sachdev D, Yee D . The IGF system and breast cancer. Endocr Relat Cancer. 2001; 8(3):197-209. DOI: 10.1677/erc.0.0080197. View

Thota B, Arimappamagan A, Kandavel T, Shastry A, Pandey P, Chandramouli B . STAT-1 expression is regulated by IGFBP-3 in malignant glioma cells and is a strong predictor of poor survival in patients with glioblastoma. J Neurosurg. 2014; 121(2):374-83. DOI: 10.3171/2014.4.JNS131198. View

Kim G, Ko Y . Small molecule tyrosine kinase inhibitors in glioblastoma. Arch Pharm Res. 2020; 43(4):385-394. DOI: 10.1007/s12272-020-01232-3. View

Trojan J, Cloix J, Ardourel M, Chatel M, Anthony D . Insulin-like growth factor type I biology and targeting in malignant gliomas. Neuroscience. 2007; 145(3):795-811. DOI: 10.1016/j.neuroscience.2007.01.021. View

Chen K, Chen P, Ho K, Shih C, Chou C, Cheng C . IGF-1-enhanced miR-513a-5p signaling desensitizes glioma cells to temozolomide by targeting the NEDD4L-inhibited Wnt/β-catenin pathway. PLoS One. 2019; 14(12):e0225913. PMC: 6894868. DOI: 10.1371/journal.pone.0225913. View

Qazi M, Vora P, Venugopal C, Sidhu S, Moffat J, Swanton C . Intratumoral heterogeneity: pathways to treatment resistance and relapse in human glioblastoma. Ann Oncol. 2017; 28(7):1448-1456. DOI: 10.1093/annonc/mdx169. View

10.

Vella V, Nicolosi M, Cantafio P, Massimino M, Lappano R, Vigneri P . DDR1 regulates thyroid cancer cell differentiation via IGF-2/IR-A autocrine signaling loop. Endocr Relat Cancer. 2018; 26(1):197-214. DOI: 10.1530/ERC-18-0310. View

11.

Chakravarti A, Loeffler J, Dyson N . Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer Res. 2002; 62(1):200-7. View

12.

Zhang Y, Chen X, Lian H, Liu J, Zhou B, Han S . MicroRNA-503 acts as a tumor suppressor in glioblastoma for multiple antitumor effects by targeting IGF-1R. Oncol Rep. 2014; 31(3):1445-52. PMC: 4440219. DOI: 10.3892/or.2013.2951. View

13.

Praveen Kumar V, Sehgal P, Thota B, Patil S, Santosh V, Kondaiah P . Insulin like growth factor binding protein 4 promotes GBM progression and regulates key factors involved in EMT and invasion. J Neurooncol. 2014; 116(3):455-64. DOI: 10.1007/s11060-013-1324-y. View

14.

Quail D, Bowman R, Akkari L, Quick M, Schuhmacher A, Huse J . The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. Science. 2016; 352(6288):aad3018. PMC: 5450629. DOI: 10.1126/science.aad3018. View

15.

Chen P, Cheng C, Shih C, Ho K, Lin C, Lee C . The Inhibition of microRNA-128 on IGF-1-Activating mTOR Signaling Involves in Temozolomide-Induced Glioma Cell Apoptotic Death. PLoS One. 2016; 11(11):e0167096. PMC: 5125683. DOI: 10.1371/journal.pone.0167096. View

16.

Simpson A, Petnga W, Macaulay V, 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(5):571-597. PMC: 5610669. DOI: 10.1007/s11523-017-0514-5. View

17.

Tan A, Ashley D, Lopez G, Malinzak M, Friedman H, Khasraw M . Management of glioblastoma: State of the art and future directions. CA Cancer J Clin. 2020; 70(4):299-312. DOI: 10.3322/caac.21613. View

18.

Bowers L, Rossi E, OFlanagan C, DeGraffenried L, Hursting S . The Role of the Insulin/IGF System in Cancer: Lessons Learned from Clinical Trials and the Energy Balance-Cancer Link. Front Endocrinol (Lausanne). 2015; 6:77. PMC: 4432799. DOI: 10.3389/fendo.2015.00077. View

19.

Weller M, Wick W, Aldape K, Brada M, Berger M, Pfister S . Glioma. Nat Rev Dis Primers. 2016; 1:15017. DOI: 10.1038/nrdp.2015.17. View

20.

Zhang M, Liu J, Li M, Zhang S, Lu Y, Liang Y . Insulin-like growth factor 1/insulin-like growth factor 1 receptor signaling protects against cell apoptosis through the PI3K/AKT pathway in glioblastoma cells. Exp Ther Med. 2018; 16(2):1477-1482. PMC: 6090237. DOI: 10.3892/etm.2018.6336. View