Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2024

Open Access 01-12-2024 | Bone Metastasis | Research

IGF-1R mediates crosstalk between nasopharyngeal carcinoma cells and osteoclasts and promotes tumor bone metastasis

Authors: Kaifan Yang, Yanjun Hu, Yuanyuan Feng, Kaiqun Li, Ziyan Zhu, Shuyi Liu, Yanling Lin, Bin Yu

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2024

Login to get access

Abstract

Background

Nasopharyngeal carcinoma (NPC) poses a significant health burden in specific regions of Asia, and some of NPC patients have bone metastases at the time of initial diagnosis. Bone metastasis can cause pathologic fractures and pain, reducing patients' quality of life, and is associated with worse survival. This study aims to unravel the complex role of insulin-like growth factor 1 receptor (IGF-1R) in NPC bone metastasis, offering insights into potential therapeutic targets.

Methods

We assessed IGF-1R expression in NPC cells and explored its correlation with bone metastasis. Experiments investigated the impact of osteoclast-secreted IGF-1 on the IGF-1R/AKT/S6 pathway in promoting NPC cell proliferation within the bone marrow. Additionally, the reciprocal influence of tumor-secreted Granulocyte–macrophage colony-stimulating factor (GM-CSF) on osteoclast differentiation and bone resorption was examined. The effects of IGF-1 neutralizing antibody, IGF-1R specific inhibitor (NVP-AEW541) and mTORC inhibitor (rapamycin) on nasopharyngeal carcinoma bone metastasis were also explored in animal experiments.

Results

Elevated IGF-1R expression in NPC cells correlated with an increased tendency for bone metastasis. IGF-1, secreted by osteoclasts, activated the IGF-1R/AKT/S6 pathway, promoting NPC cell proliferation in the bone marrow. Tumor-secreted GM-CSF further stimulated osteoclast differentiation, exacerbating bone resorption. The IGF-1 neutralizing antibody, NVP-AEW541 and rapamycin were respectively effective in slowing down the rate of bone metastasis and reducing bone destruction.

Conclusion

The intricate interplay among IGF-1R, IGF-1, and GM-CSF highlights potential therapeutic targets for precise control of NPC bone metastasis, providing valuable insights for developing targeted interventions.
Appendix
Available only for authorised users
Literature
1.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.PubMedCrossRef
2.
Baujat B, Audry H, Bourhis J, Chan AT, Onat H, Chua DT, et al. Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients. Int J Radiat Oncol Biol Phys. 2006;64:47–56.PubMedCrossRef
3.
4.
Tang LQ, Chen QY, Fan W, Liu H, Zhang L, Guo L, et al. Prospective study of tailoring whole-body dual-modality [18F]fluorodeoxyglucose positron emission tomography/computed tomography with plasma Epstein-Barr virus DNA for detecting distant metastasis in endemic nasopharyngeal carcinoma at initial staging. J Clin Oncol. 2013;31:2861–9.PubMedCrossRef
5.
Lin S, Tham IW, Pan J, Han L, Chen Q, Lu JJ. Combined high-dose radiation therapy and systemic chemotherapy improves survival in patients with newly diagnosed metastatic nasopharyngeal cancer. Am J Clin Oncol. 2012;35:474–9.PubMedCrossRef
6.
Chen MY, Jiang R, Guo L, Zou X, Liu Q, Sun R, et al. Locoregional radiotherapy in patients with distant metastases of nasopharyngeal carcinoma at diagnosis. Chin J Cancer. 2013;32:604–13.PubMedPubMedCentralCrossRef
7.
Wang CT, Cao KJ, Li Y, Xie GF. Huang PY [Prognosis analysis of nasopharyngeal carcinoma patients with distant metastasis]. Ai Zheng. 2007;26:212–5.PubMed
8.
Liao W, Tian M, Chen N. Characteristic and novel therapeutic strategies of nasopharyngeal carcinoma with synchronous metastasis. Cancer Manag Res. 2019;11:8431–42.PubMedPubMedCentralCrossRef
9.
Pan CC, Lu J, Chen P, Li X, Jin YD, Zhao M, et al. [Evaluation of the prognostic significance of refinement and stratification of distant metastasis status in 1016 cases of nasopharyngeal carcinoma]. Zhonghua Zhong Liu Za Zhi. 2013;35:595–9.PubMed
10.
Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell. 1993;75:59–72.PubMed
11.
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.PubMedCrossRef
12.
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.PubMedCrossRef
13.
Liu D, Rutter WJ, Wang LH. Modulating effects of the extracellular sequence of the human insulinlike growth factor I receptor on its transforming and tumorigenic potential. J Virol. 1993;67:9–18.PubMedPubMedCentralCrossRef
14.
Tahimic CG, Long RK, Kubota T, Sun MY, Elalieh H, Fong C, et al. Regulation of ligand and shear stress-induced Insulin-like Growth Factor 1 (IGF1) signaling by the integrin pathway. J Biol Chem. 2016;291:8140–9.PubMedPubMedCentralCrossRef
15.
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;8:10711.ADSPubMedPubMedCentralCrossRef
16.
Chen C, Gupta P, Parashar D, Nair GG, George J, Geethadevi A, et al. ERBB3-induced furin promotes the progression and metastasis of ovarian cancer via the IGF1R/STAT3 signaling axis. Oncogene. 2020;39:2921–33.PubMedPubMedCentralCrossRef
17.
Stalnecker CA, Coleman MF, Bryant KL. Susceptibility to autophagy inhibition is enhanced by dual IGF1R and MAPK/ERK inhibition in pancreatic cancer. Autophagy. 2022;18:1737–9.PubMedPubMedCentralCrossRef
18.
Szymonowicz K, Oeck S, Krysztofiak A, van der Linden J, Iliakis G, Jendrossek V. Restraining Akt1 Phosphorylation attenuates the repair of radiation-induced DNA double-strand breaks and reduces the survival of irradiated cancer cells. Int J Mol Sci. 2018;19:2233.PubMedPubMedCentralCrossRef
19.
Farabaugh SM, Boone DN, Lee AV. Role of IGF1R in breast cancer subtypes, stemness, and lineage differentiation. Front Endocrinol (Lausanne). 2015;6:59.PubMedCrossRef
20.
Law JH, Habibi G, Hu K, Masoudi H, Wang MY, Stratford AL, et al. Phosphorylated insulin-like growth factor-i/insulin receptor is present in all breast cancer subtypes and is related to poor survival. Cancer Res. 2008;68:10238–46.PubMedCrossRef
21.
Aleksic T, Verrill C, Bryant RJ, Han C, Worrall AR, Brureau L, et al. IGF-1R associates with adverse outcomes after radical radiotherapy for prostate cancer. Br J Cancer. 2017;117:1600–6.PubMedPubMedCentralCrossRef
22.
Wang Z, Liu G, Mao J, Xie M, Zhao M, Guo X, et al. IGF-1R Inhibition suppresses cell proliferation and increases radiosensitivity in nasopharyngeal carcinoma cells. Mediators Inflamm. 2019;2019:5497467.PubMedPubMedCentralCrossRef
23.
Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 2008;8:915–28.PubMedCrossRef
24.
Qiao C, Huang W, Chen J, Feng W, Zhang T, Wang Y, et al. IGF1-mediated HOXA13 overexpression promotes colorectal cancer metastasis through upregulating ACLY and IGF1R. Cell Death Dis. 2021;12:564.PubMedPubMedCentralCrossRef
25.
Xu L, Zhou R, Yuan L, Wang S, Li X, Ma H, et al. IGF1/IGF1R/STAT3 signaling-inducible IFITM2 promotes gastric cancer growth and metastasis. Cancer Lett. 2017;393:76–85.PubMedCrossRef
26.
27.
Crane JL, Zhao L, Frye JS, Xian L, Qiu T, Cao X. IGF-1 signaling is essential for differentiation of mesenchymal stem cells for peak bone mass. Bone Res. 2013;1:186–94.PubMedPubMedCentralCrossRef
28.
Bellacosa A, Kumar CC, Di Cristofano A, Testa JR. Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res. 2005;94:29–86.PubMedCrossRef
29.
Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev. 1999;13:2905–27.PubMedCrossRef
30.
31.
Alzahrani AS. PI3K/Akt/mTOR inhibitors in cancer: at the bench and bedside. Semin Cancer Biol. 2019;59:125–32.PubMedCrossRef
32.
Lin Y, Zhou X, Yang K, Chen Y, Wang L, Luo W, et al. Protein tyrosine phosphatase receptor type D gene promotes radiosensitivity via STAT3 dephosphorylation in nasopharyngeal carcinoma. Oncogene. 2021;40:3101–17.PubMedPubMedCentralCrossRef
33.
34.
He Y, Luo W, Liu Y, Wang Y, Ma C, Wu Q, et al. IL-20RB mediates tumoral response to osteoclastic niches and promotes bone metastasis of lung cancer. J Clin Invest. 2022;132:157917.CrossRef
35.
36.
Liang YL, Zhang Y, Tan XR, Qiao H, Liu SR, Tang LL, et al. A lncRNA signature associated with tumor immune heterogeneity predicts distant metastasis in locoregionally advanced nasopharyngeal carcinoma. Nat Commun. 2022;13:2996.ADSPubMedPubMedCentralCrossRef
37.
Riedemann J, Macaulay VM. IGF1R signalling and its inhibition. Endocr Relat Cancer. 2006;13(Suppl 1):S33-43.PubMedCrossRef
38.
Kobashi S, Terashima T, Katagi M, Nakae Y, Okano J, Suzuki Y, et al. Transplantation of M2-deviated microglia promotes recovery of motor function after spinal cord injury in mice. Mol Ther. 2020;28:254–65.PubMedCrossRef
39.
Kohno K, Shirasaka R, Yoshihara K, Mikuriya S, Tanaka K, Takanami K, et al. A spinal microglia population involved in remitting and relapsing neuropathic pain. Science. 2022;376:86–90.ADSPubMedCrossRef
40.
41.
Zumsteg A, Caviezel C, Pisarsky L, Strittmatter K, Garcia-Echeverria C, Hofmann F, et al. Repression of malignant tumor progression upon pharmacologic IGF1R blockade in a mouse model of insulinoma. Mol Cancer Res. 2012;10:800–9.PubMedCrossRef
42.
Scotlandi K, Manara MC, Nicoletti G, Lollini PL, Lukas S, Benini S, et al. Antitumor activity of the insulin-like growth factor-I receptor kinase inhibitor NVP-AEW541 in musculoskeletal tumors. Cancer Res. 2005;65:3868–76.PubMedCrossRef
43.
Clezardin P, Coleman R, Puppo M, Ottewell P, Bonnelye E, Paycha F, et al. Bone metastasis: mechanisms, therapies, and biomarkers. Physiol Rev. 2021;101:797–855.PubMedCrossRef
44.
Ramaswamy S, Ross KN, Lander ES, Golub TR. A molecular signature of metastasis in primary solid tumors. Nat Genet. 2003;33:49–54.PubMedCrossRef
45.
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;13:64.PubMedPubMedCentralCrossRef
46.
Varkaris A, Gaur S, Parikh NU, Song JH, Dayyani F, Jin JK, et al. Ligand-independent activation of MET through IGF-1/IGF-1R signaling. Int J Cancer. 2013;133:1536–46.PubMedPubMedCentralCrossRef
47.
Jaquish DV, Yu PT, Shields DJ, French RP, Maruyama KP, Niessen S, et al. IGF1-R signals through the RON receptor to mediate pancreatic cancer cell migration. Carcinogenesis. 2011;32:1151–6.PubMedPubMedCentralCrossRef
48.
Kim HJ, Litzenburger BC, Cui X, Delgado DA, Grabiner BC, Lin X, et al. Constitutively active type I insulin-like growth factor receptor causes transformation and xenograft growth of immortalized mammary epithelial cells and is accompanied by an epithelial-to-mesenchymal transition mediated by NF-kappaB and snail. Mol Cell Biol. 2007;27:3165–75.PubMedPubMedCentralCrossRef
49.
Taliaferro-Smith L, Oberlick E, Liu T, McGlothen T, Alcaide T, Tobin R, et al. FAK activation is required for IGF1R-mediated regulation of EMT, migration, and invasion in mesenchymal triple negative breast cancer cells. Oncotarget. 2015;6:4757–72.PubMedPubMedCentralCrossRef
50.
Sachdev D, Zhang X, Matise I, Gaillard-Kelly M, Yee D. The type I insulin-like growth factor receptor regulates cancer metastasis independently of primary tumor growth by promoting invasion and survival. Oncogene. 2010;29:251–62.PubMedCrossRef
51.
Ravid D, Maor S, Werner H, Liscovitch M. Caveolin-1 inhibits cell detachment-induced p53 activation and anoikis by upregulation of insulin-like growth factor-I receptors and signaling. Oncogene. 2005;24:1338–47.PubMedCrossRef
52.
53.
Kiely PA, Sant A, O’Connor R. RACK1 is an insulin-like growth factor 1 (IGF-1) receptor-interacting protein that can regulate IGF-1-mediated Akt activation and protection from cell death. J Biol Chem. 2002;277:22581–9.PubMedCrossRef
54.
Chen YH, Wang CW, Wei MF, Tzeng YS, Lan KH, Cheng AL, et al. Maintenance BEZ235 treatment prolongs the therapeutic effect of the combination of BEZ235 and radiotherapy for colorectal cancer. Cancers (Basel). 2019;11:1204.PubMedCrossRef
55.
Metadata
Title
IGF-1R mediates crosstalk between nasopharyngeal carcinoma cells and osteoclasts and promotes tumor bone metastasis
Authors
Kaifan Yang
Yanjun Hu
Yuanyuan Feng
Kaiqun Li
Ziyan Zhu
Shuyi Liu
Yanling Lin
Bin Yu
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2024
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-024-02970-8

Other articles of this Issue 1/2024

Journal of Experimental & Clinical Cancer Research 1/2024 Go to the issue

Review

T-cell infiltration and its regulatory mechanisms in cancers: insights at single-cell resolution

Research

LINC00606 promotes glioblastoma progression through sponge miR-486-3p and interaction with ATP11B

Research

EGR1 suppresses HCC growth and aerobic glycolysis by transcriptionally downregulating PFKL

Research

HDAC1/2 control mesothelium/ovarian cancer adhesive interactions impacting on Talin-1-α5β1-integrin-mediated actin cytoskeleton and extracellular matrix protein remodeling

Research

The synergism of SMC1A cohesin gene silencing and bevacizumab against colorectal cancer

Correction

Correction: VEGF-A/VEGFR-1 signalling and chemotherapy-induced neuropathic pain: therapeutic potential of a novel anti-VEGFR-1 monoclonal antibody
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits