The Role of IGF/IGF-1R Signaling in Hepatocellular Carcinomas: Stemness-Related Properties and Drug Resistance

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Abstract

Insulin-like Growth Factor (IGF)/IGF-1 Receptor (IGF-1R) signaling is known to regulate stem cell pluripotency and differentiation to trigger cell proliferation, organ development, and tissue regeneration during embryonic development. Unbalanced IGF/IGF-1R signaling can promote cancer cell proliferation and activate cancer reprogramming in tumor tissues, especially in the liver. Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death, with a high incidence and mortality rate in Asia. Most patients with advanced HCC develop tyrosine kinase inhibitor (TKI)-refractoriness after receiving TKI treatment. Dysregulation of IGF/IGF-1R signaling in HCC may activate expression of cancer stemness that leads to TKI refractoriness and tumor recurrence. In this review, we summarize the evidence for dysregulated IGF/IGF-1R signaling especially in hepatitis B virus (HBV)-associated HCC. The regulation of cancer stemness expression and drug resistance will be highlighted. Current clinical treatments and potential therapies targeting IGF/IGF-1R signaling for the treatment of HCC will be discussed.

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Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

Ahmedin Jemal, Lindsey A Torre, Rebecca Siegel … (2018)

This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.

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EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma

Valérie Vilgrain, Peter Galle, Alejandro Forner … (2018)

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Sorafenib in advanced hepatocellular carcinoma.

Josep Llovet, Sergio Ricci, Vincenzo Mazzaferro … (2008)

No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo. (ClinicalTrials.gov number, NCT00105443.) 2008 Massachusetts Medical Society

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Author and article information

Contributors

Claire M. Perks: Role: Academic Editor

Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 16 February 2021

Publication date Collection: February 2021

Volume: 22

Issue: 4

Electronic Location Identifier: 1931

Affiliations

[1 ]International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; ntmhuong@ 123456hpmu.edu.vn (M.-H.T.N.); fine.nanda@ 123456gmail.com (J.D.N.); brahmadhi@ 123456gmail.com (A.B.)

[2 ]Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan

[3 ]Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan; m609108001@ 123456tmu.edu.tw (H.-Y.J.); edditkuo@ 123456tmu.edu.tw (Y.-C.K.)

[4 ]Department and Graduate Institute of Pharmacology, National Taiwan University, Taipei 11031, Taiwan

[5 ]School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33382, Taiwan

[6 ]Division of Internal Medicine, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan

[7 ]Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan

[8 ]Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan

[9 ]Comprehensive Cancer Center, Taipei Medical University, Taipei 11031, Taiwan

[10 ]Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan

[11 ]PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan

Author notes

[* ]Correspondence: tyling@ 123456ntu.edu.tw (T.-Y.L.); cgmh3621@ 123456cgmh.org.tw (T.-S.C.); rita1204@ 123456tmu.edu.tw (Y.-H.H.); Tel.: +886-2-2312-3456 (ext. 8-8322) (T.-Y.L.); +886-5-3621-000 (ext. 2242) (T.-S.C.); +886-2-2736-1661 (ext. 3150) (Y.-H.H.)

[†]

These authors contributed equally to this work and are thus considered co-first authors.

Author information

Han-Yin Jeng https://orcid.org/0000-0002-1867-2177

Te-Sheng Chang https://orcid.org/0000-0002-1581-6948

Yen-Hua Huang https://orcid.org/0000-0001-6020-9998

Article

Publisher ID: ijms-22-01931

DOI: 10.3390/ijms22041931

PMC ID: 7919800

PubMed ID: 33669204

SO-VID: fcae092a-6406-49e4-a61e-16e1047270bc

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

The Role of IGF/IGF-1R Signaling in Hepatocellular Carcinomas: Stemness-Related Properties and Drug Resistance

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Neuronal Signaling

Most cited references 266

Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma

Sorafenib in advanced hepatocellular carcinoma.

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