Abstract
Despite epidemiological evidence that suggests diabetes mellitus is a risk factor for cancer, the link between diabetes mellitus and primary bone cancer is rarely discussed. Chondrosarcomas are primary malignant cartilage tumors with poor prognosis and high metastatic potential. It remains unclear whether hyperglycemia affects the stemness and malignancy of chondrosarcoma cells. Nε-(1-Carboxymethyl)-L-lysine (CML), an advanced glycation end product (AGE), is a major immunological epitope detected in the tissue proteins of diabetic patients. We hypothesized that CML could enhance cancer stemness in chondrosarcoma cells. CML enhanced tumor-sphere formation and the expression of cancer stem cell markers in human chondrosarcoma cell lines. Migration and invasion ability and the epithelial–mesenchymal transition (EMT) process were also induced by CML treatment. Moreover, CML increased the protein expression levels of the receptor for AGE (RAGE), phosphorylated NFκB-p65, and decreased the phosphorylation of AKT and GSK-3. We also found that hyperglycemia with high CML levels facilitated tumor metastasis, whereas tumor growth was not affected in the streptozotocin (STZ)-induced diabetic NOD/SCID tumor xenograft mouse models. Our results indicate that CML enhances chondrosarcoma stemness and metastasis, which may reveal the relationship between AGE and bone cancer metastasis.
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The data presented in this study are available from the corresponding author upon reasonable request.
References
Bao JM, He MY, Liu YW, Lu YJ, Hong YQ, Luo HH, Ren ZL, Zhao SC, Jiang Y (2015) AGE/RAGE/Akt pathway contributes to prostate cancer cell proliferation by promoting Rb phosphorylation and degradation. Am J Cancer Res 5(5):1741–1750
Barua R, Templeton AJ, Seruga B, Ocana A, Amir E, Ethier JL (2018) Hyperglycaemia and survival in solid tumours: a systematic review and meta-analysis. Clin Oncol (r Coll Radiol) 30(4):215–224. https://doi.org/10.1016/j.clon.2018.01.003
Brownlee M, Cerami A, Vlassara H (1988) Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med 318(20):1315–1321. https://doi.org/10.1056/NEJM198805193182007
Chen Q, Dong L, Wang L, Kang L, Xu B (2009) Advanced glycation end products impair function of late endothelial progenitor cells through effects on protein kinase Akt and cyclooxygenase-2. Biochem Biophys Res Commun 381(2):192–197. https://doi.org/10.1016/j.bbrc.2009.02.040
Cheng M, Chen DC, Lu CY (2008) The influence of different glucose concentrations on cellular activity of human osteosarcoma cell line MG63. Sichuan Da Xue Xue Bao Yi Xue Ban 39(2):239–242
Cheng LH, Hung KF, Huang TF, Hsieh HP, Wang SY, Huang CY, Lo JF (2016) Attenuation of cancer-initiating cells stemness properties by abrogating S100A4 calcium binding ability in head and neck cancers. Oncotarget 7(48):78946–78957. https://doi.org/10.18632/oncotarget.12935
Chow KH, Park HJ, George J, Yamamoto K, Gallup AD, Graber JH, Chen Y, Jiang W, Steindler DA, Neilson EG, Kim BYS, Yun K (2017) S100A4 Is a biomarker and regulator of glioma stem cells that is critical for mesenchymal transition in glioblastoma. Cancer Res 77(19):5360–5373. https://doi.org/10.1158/0008-5472.CAN-17-1294
Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378(6559):785–789. https://doi.org/10.1038/378785a0
Deng R, Wu H, Ran H, Kong X, Hu L, Wang X, Su Q (2017) Glucose-derived AGEs promote migration and invasion of colorectal cancer by up-regulating Sp1 expression. Biochim Biophys Acta Gen Subj 1861(5 Pt A):1065–1074. https://doi.org/10.1016/j.bbagen.2017.02.024
El-Far AH, Sroga G, Jaouni SKA, Mousa SA (2020) Role and mechanisms of RAGE-ligand complexes and RAGE-inhibitors in cancer progression. Int J Mol Sci. https://doi.org/10.3390/ijms21103613
Galan-Moya EM, Le Guelte A, Lima Fernandes E, Thirant C, Dwyer J, Bidere N, Couraud PO, Scott MG, Junier MP, Chneiweiss H, Gavard J (2011) Secreted factors from brain endothelial cells maintain glioblastoma stem-like cell expansion through the mTOR pathway. EMBO Rep 12(5):470–476. https://doi.org/10.1038/embor.2011.39
Gerling IC, Friedman H, Greiner DL, Shultz LD, Leiter EH (1994) Multiple low-dose streptozocin-induced diabetes in NOD-scid/scid mice in the absence of functional lymphocytes. Diabetes 43(3):433–440. https://doi.org/10.2337/diab.43.3.433
Guo J, Bian Y, Wang Y, Chen L, Yu A, Sun X (2016) S100A4 influences cancer stem cell-like properties of MGC803 gastric cancer cells by regulating GDF15 expression. Int J Oncol 49(2):559–568. https://doi.org/10.3892/ijo.2016.3556
Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, Avila C, Kambham N, Bierhaus A, Nawroth P, Neurath MF, Slattery T, Beach D, McClary J, Nagashima M, Morser J, Stern D, Schmidt AM (1999) RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 97(7):889–901. https://doi.org/10.1016/s0092-8674(00)80801-6
Hori O, Yan SD, Ogawa S, Kuwabara K, Matsumoto M, Stern D, Schmidt AM (1996) The receptor for advanced glycation end-products has a central role in mediating the effects of advanced glycation end-products on the development of vascular disease in diabetes mellitus. Nephrol Dial Transplant 11(Suppl 5):13–16. https://doi.org/10.1093/ndt/11.supp5.13
Hu P, Lai D, Lu P, Gao J, He H (2012) ERK and Akt signaling pathways are involved in advanced glycation end product-induced autophagy in rat vascular smooth muscle cells. Int J Mol Med 29(4):613–618. https://doi.org/10.3892/ijmm.2012.891
Huttunen HJ, Fages C, Rauvala H (1999) Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-kappaB require the cytoplasmic domain of the receptor but different downstream signaling pathways. J Biol Chem 274(28):19919–19924. https://doi.org/10.1074/jbc.274.28.19919
Huttunen HJ, Fages C, Kuja-Panula J, Ridley AJ, Rauvala H (2002) Receptor for advanced glycation end products-binding COOH-terminal motif of amphoterin inhibits invasive migration and metastasis. Cancer Res 62(16):4805–4811
Ikeda K, Higashi T, Sano H, Jinnouchi Y, Yoshida M, Araki T, Ueda S, Horiuchi S (1996) N (epsilon)-(carboxymethyl)lysine protein adduct is a major immunological epitope in proteins modified with advanced glycation end products of the Maillard reaction. Biochemistry 35(24):8075–8083. https://doi.org/10.1021/bi9530550
Janssen J (2021) Hyperinsulinemia and its pivotal role in aging, obesity, type 2 diabetes, cardiovascular disease and cancer. Int J Mol Sci. https://doi.org/10.3390/ijms22157797
Kadonosono T, Miyamoto K, Sakai S, Matsuo Y, Kitajima S, Wang Q, Endo M, Niibori M, Kuchimaru T, Soga T, Hirota K, Kizaka-Kondoh S (2022) AGE/RAGE axis regulates reversible transition to quiescent states of ALK-rearranged NSCLC and pancreatic cancer cells in monolayer cultures. Sci Rep 12(1):9886. https://doi.org/10.1038/s41598-022-14272-0
Keil L (2020) Bone tumors: primary bone cancers. FP Essent 493:22–26
Kim DS, Scherer PE (2021) Obesity, diabetes, and increased cancer progression. Diabetes Metab J 45(6):799–812. https://doi.org/10.4093/dmj.2021.0077
Kuniyasu H, Oue N, Wakikawa A, Shigeishi H, Matsutani N, Kuraoka K, Ito R, Yokozaki H, Yasui W (2002) Expression of receptors for advanced glycation end-products (RAGE) is closely associated with the invasive and metastatic activity of gastric cancer. J Pathol 196(2):163–170. https://doi.org/10.1002/path.1031
Kuniyasu H, Chihara Y, Kondo H (2003) Differential effects between amphoterin and advanced glycation end products on colon cancer cells. Int J Cancer 104(6):722–727. https://doi.org/10.1002/ijc.11016
Li M, Cao J, He Y, Zhou Z, He X, Zhang QQ, Wang LJ, Qi CL (2019) Generation and biological characteristics of a mouse model of breast cancer that copresents with diabetes mellitus. Anat Rec (Hoboken) 302(2):269–277. https://doi.org/10.1002/ar.23945
Li Y, Wang J, Song K, Liu S, Zhang H, Wang F, Ni C, Zhai W, Liang J, Qin Z, Zhang J (2020) S100A4 promotes hepatocellular carcinogenesis by intensifying fibrosis-associated cancer cell stemness. Oncoimmunology 9(1):1725355. https://doi.org/10.1080/2162402X.2020.1725355
Li ZY, Chen SY, Weng MH, Yen GC (2021) Ursolic acid restores sensitivity to gemcitabine through the RAGE/NF-kappaB/MDR1 axis in pancreatic cancer cells and in a mouse xenograft model. J Food Drug Anal 29(2):262–274. https://doi.org/10.38212/2224-6614.3346
Liang H (2020) Advanced glycation end products induce proliferation, invasion and epithelial-mesenchymal transition of human SW480 colon cancer cells through the PI3K/AKT signaling pathway. Oncol Lett 19(4):3215–3222. https://doi.org/10.3892/ol.2020.11413
Lu J, Ye X, Fan F, Xia L, Bhattacharya R, Bellister S, Tozzi F, Sceusi E, Zhou Y, Tachibana I, Maru DM, Hawke DH, Rak J, Mani SA, Zweidler-McKay P, Ellis LM (2013) Endothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of Jagged-1. Cancer Cell 23(2):171–185. https://doi.org/10.1016/j.ccr.2012.12.021
Moroz OV, Antson AA, Dodson EJ, Burrell HJ, Grist SJ, Lloyd RM, Maitland NJ, Dodson GG, Wilson KS, Lukanidin E, Bronstein IB (2002) The structure of S100A12 in a hexameric form and its proposed role in receptor signalling. Acta Crystallogr D Biol Crystallogr 58(Pt 3):407–413. https://doi.org/10.1107/s0907444901021278
Moy KA, Jiao L, Freedman ND, Weinstein SJ, Sinha R, Virtamo J, Albanes D, Stolzenberg-Solomon RZ (2013) Soluble receptor for advanced glycation end products and risk of liver cancer. Hepatology 57(6):2338–2345. https://doi.org/10.1002/hep.26264
Murata T, Nagai R, Ishibashi T, Inomuta H, Ikeda K, Horiuchi S (1997) The relationship between accumulation of advanced glycation end products and expression of vascular endothelial growth factor in human diabetic retinas. Diabetologia 40(7):764–769. https://doi.org/10.1007/s001250050747
Nam HK, Jeong SR, Pyo MC, Ha SK, Nam MH, Lee KW (2021) Methylglyoxal-derived advanced glycation end products (AGE4) promote cell proliferation and survival in renal cell carcinoma cells through the RAGE/Akt/ERK signaling pathways. Biol Pharm Bull 44(11):1697–1706. https://doi.org/10.1248/bpb.b21-00382
Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pan YC, Elliston K, Stern D, Shaw A (1992) Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J Biol Chem 267(21):14998–15004
Pan B, Ren H, He Y, Lv X, Ma Y, Li J, Huang L, Yu B, Kong J, Niu C, Zhang Y, Sun WB, Zheng L (2012) HDL of patients with type 2 diabetes mellitus elevates the capability of promoting breast cancer metastasis. Clin Cancer Res 18(5):1246–1256. https://doi.org/10.1158/1078-0432.CCR-11-0817
Qian F, Xiao J, Gai L, Zhu J (2019) HMGB1-RAGE signaling facilitates Ras-dependent Yap1 expression to drive colorectal cancer stemness and development. Mol Carcinog 58(4):500–510. https://doi.org/10.1002/mc.22944
Reddy S, Bichler J, Wells-Knecht KJ, Thorpe SR, Baynes JW (1995) N epsilon-(carboxymethyl)lysine is a dominant advanced glycation end product (AGE) antigen in tissue proteins. Biochemistry 34(34):10872–10878. https://doi.org/10.1021/bi00034a021
Rigiracciolo DC, Nohata N, Lappano R, Cirillo F, Talia M, Adame-Garcia SR, Arang N, Lubrano S, De Francesco EM, Belfiore A, Gutkind JS, Maggiolini M (2022) Focal adhesion kinase (FAK)-Hippo/YAP transduction signaling mediates the stimulatory effects exerted by S100A8/A9-RAGE system in triple-negative breast cancer (TNBC). J Exp Clin Cancer Res 41(1):193. https://doi.org/10.1186/s13046-022-02396-0
Satija A, Spiegelman D, Giovannucci E, Hu FB (2015) Type 2 diabetes and risk of cancer. BMJ 350:g7707. https://doi.org/10.1136/bmj.g7707
Schmidt AM, Hori O, Cao R, Yan SD, Brett J, Wautier JL, Ogawa S, Kuwabara K, Matsumoto M, Stern D (1996) RAGE: a novel cellular receptor for advanced glycation end products. Diabetes 45(Suppl 3):S77-80. https://doi.org/10.2337/diab.45.3.s77
Sutherland C, Leighton IA, Cohen P (1993) Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling. Biochem J 296(Pt 1):15–19. https://doi.org/10.1042/bj2960015
Taguchi A, Blood DC, del Toro G, Canet A, Lee DC, Qu W, Tanji N, Lu Y, Lalla E, Fu C, Hofmann MA, Kislinger T, Ingram M, Lu A, Tanaka H, Hori O, Ogawa S, Stern DM, Schmidt AM (2000) Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature 405(6784):354–360. https://doi.org/10.1038/35012626
Takeuchi A, Yamamoto Y, Tsuneyama K, Cheng C, Yonekura H, Watanabe T, Shimizu K, Tomita K, Yamamoto H, Tsuchiya H (2007) Endogenous secretory receptor for advanced glycation endproducts as a novel prognostic marker in chondrosarcoma. Cancer 109(12):2532–2540. https://doi.org/10.1002/cncr.22731
Takino J, Yamagishi S, Takeuchi M (2012) Glycer-AGEs-RAGE signaling enhances the angiogenic potential of hepatocellular carcinoma by upregulating VEGF expression. World J Gastroenterol 18(15):1781–1788. https://doi.org/10.3748/wjg.v18.i15.1781
Treutiger CJ, Mullins GE, Johansson AS, Rouhiainen A, Rauvala HM, Erlandsson-Harris H, Andersson U, Yang H, Tracey KJ, Andersson J, Palmblad JE (2003) High mobility group 1 B-box mediates activation of human endothelium. J Intern Med 254(4):375–385. https://doi.org/10.1046/j.1365-2796.2003.01204.x
Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R (2009) Diabetes and cancer. Endocr Relat Cancer 16(4):1103–1123. https://doi.org/10.1677/ERC-09-0087
Weinschenk RC, Wang WL, Lewis VO (2021) Chondrosarcoma. J Am Acad Orthop Surg 29(13):553–562. https://doi.org/10.5435/JAAOS-D-20-01188
Yang WS, Chen PC, Lin HJ, Su TC, Hsu HC, Chen MF, Lee YT, Chien KL (2017) Association between type 2 diabetes and cancer incidence in Taiwan: data from a prospective community-based cohort study. Acta Diabetol 54(5):455–461. https://doi.org/10.1007/s00592-017-0966-1
Yaser AM, Huang Y, Zhou RR, Hu GS, Xiao MF, Huang ZB, Duan CJ, Tian W, Tang DL, Fan XG (2012) The Role of receptor for advanced glycation end products (RAGE) in the proliferation of hepatocellular carcinoma. Int J Mol Sci 13(5):5982–5997. https://doi.org/10.3390/ijms13055982
Zhang Q, Jin Y, Zhao CF, Wang WJ, Liu GY (2016a) Receptor for advanced glycation end-products (RAGE) is overexpressed in human osteosarcoma and promotes the proliferation of osteosarcoma U-2OS cells in vitro. Genet Mol Res. https://doi.org/10.4238/gmr.15027817
Zhang QB, Jia QA, Wang H, Hu CX, Sun D, Jiang RD, Zhang ZL (2016b) High-mobility group protein box1 expression correlates with peritumoral macrophage infiltration and unfavorable prognosis in patients with hepatocellular carcinoma and cirrhosis. BMC Cancer 16(1):880. https://doi.org/10.1186/s12885-016-2883-z
Zill H, Gunther R, Erbersdobler HF, Folsch UR, Faist V (2001) RAGE expression and AGE-induced MAP kinase activation in Caco-2 cells. Biochem Biophys Res Commun 288(5):1108–1111. https://doi.org/10.1006/bbrc.2001.5901
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This research was funded in parts by the Ministry of Science and Technology, Taiwan (MOST 107-2314-B-002-063-MY3; MOST 110-2314-B-002-126-MY3).
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T-YC: data curation, formal analysis, validation, investigation, visualization, methodology, writing—original draft. C-HW: formal analysis, investigation, methodology. K-CL: resources, funding acquisition, validation, writing—review and editing. M-LS: resources, validation, visualization, methodology, writing—review and editing. R-SY: resources, funding acquisition, validation, methodology, writing—review and editing. S-HL: conceptualization, resources, funding acquisition, supervision, validation, writing—review and editing.
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Chang, TY., Lan, KC., Wu, CH. et al. Nε-(1-Carboxymethyl)-L-lysine, an advanced glycation end product, exerts malignancy on chondrosarcoma via the activation of cancer stemness. Arch Toxicol 97, 2231–2244 (2023). https://doi.org/10.1007/s00204-023-03539-8
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DOI: https://doi.org/10.1007/s00204-023-03539-8