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Molecular Medicine

, Volume 17, Issue 9–10, pp 980–989 | Cite as

Prognostic Potential and Tumor Growth-Inhibiting Effect of Plasma Advanced Glycation End Products in Non-Small Cell Lung Carcinoma

  • Babett Bartling
  • Hans-Stefan Hofmann
  • Antonia Sohst
  • Yvonne Hatzky
  • Veronika Somoza
  • Rolf-Edgar Silber
  • Andreas Simm
Research Article

Abstract

The plasma fluorescence related to the standard fluorescence of advanced glycation end products (AGEs) is a simple measurable blood parameter for distinct diseases but its importance in human cancer, including non-small cell lung carcinoma (NSCLC), is unknown. Plasma samples of 70 NSCLC patients who underwent resection surgery of the tumor were analyzed for the distinct AGE-related fluorescence at 370 nm excitation/440 nm emission. In a retrospective study, we tested the prognostic relevance of this AGE-related plasma fluorescence. The effect of circulating AGEs on the NSCLC growth was studied experimentally in vitro and in vivo. NSCLC patients with high (> median) AGE-related plasma fluorescence were characterized by a later reoccurrence of the tumor after curative surgery and a higher survival rate compared with patients with low plasma fluorescence (25% versus 47% 5-y survival, P = 0.011). Treating NSCLC cell spheroids with patients’ plasma showed an inverse correlation between the growth of spheroids in vitro and the individual AGE-related fluorescence of each plasma sample. To confirm the impact of circulating AGEs on the NSCLC progression, we studied the NSCLC growth in mice whose circulating AGE level was elevated by AGE-rich diet. In vivo tumorigenicity assays demonstrated that mice with higher levels of circulating AGEs developed smaller tumors than mice with normal AGE levels. The AGE-related plasma fluorescence has prognostic relevance for NSCLC patients in whom the tumor growth-inhibiting effect of circulating AGEs might play a critical role.

Notes

Acknowledgments

The authors thank Renate Donath, Stephanie Tuche and Sabine Koitzsch for technical assistance and Peter Schmidt (Medical Faculty, Halle [Saale]) for clinical assistance. We also thank Gesine Hansen (Hannover Medical School, Germany), Stefan Burdach (Technical University Munich, Germany) and Vesselin Christov (Medical Faculty, Halle [Saale]) for cooperation with the microarray analysis. This study was supported by Deutsche Krebshilfe (107078), Deutsche Forschungsgemeinschaft (Si-1317/1-1) and Wilhelm Roux grants (FKZ 7/04, FKZ14/14).

References

  1. 1.
    Wittekind C, Meyer H-J, Bootz F. (2003) TNM classification of malignant tumours. Union Internationale Contre le Cancer. In: Cancer UICl (ed.). Springer, Berlin Heidelberg New York, p. 223.Google Scholar
  2. 2.
    Goldstraw P, et al. (2007) The IASLC lung cancer staging project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J. Thorac. Oncol. 2:706–14.CrossRefPubMedGoogle Scholar
  3. 3.
    Wrobel K, Wrobel K, Garay-Sevilla ME, Nava LE, Malacara JM. (1997) Novel analytical approach to monitoring advanced glycosylation end products in human serum with on-line spectrophotometric and spectrofluorometric detection in a flow system. Clin. Chem. 43:1563–9.PubMedGoogle Scholar
  4. 4.
    Muench G, et al. (1997) Determination of advanced glycation end products in serum by fluorescence spectroscopy and competitive ELISA. Eur. J. Clin. Chem. Clin. Biochem. 35:669–77.Google Scholar
  5. 5.
    Yanagisawa K, et al. (1998) Specific fluorescence assay for advanced glycation end products in blood and urine of diabetic patients. Metabolism. 47:1348–53.CrossRefPubMedGoogle Scholar
  6. 6.
    Sebekova K, et al. (2001) Plasma levels of advanced glycation end products in children with renal disease. Pediatr. Nephrol. 16:1105–12.CrossRefPubMedGoogle Scholar
  7. 7.
    Uribarri J, et al. (2007) Circulating glycotoxins and dietary advanced glycation endproducts: two links to inflammatory response, oxidative stress, and aging. J. Gerontol. A Biol. Sci. Med. Sci. 62:427–33.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Chuyen NV. (2006) Toxicity of the AGEs generated from the Maillard reaction: on the relationship of food-AGEs and biological-AGEs. Mol. Nutr. Food. Res. 50:1140–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Schmitt A, Schmitt J, Munch G, Gasic-Milencovic J. (2005) Characterization of advanced glycation end products for biochemical studies: side chain modifications and fluorescence characteristics. Anal. Biochem. 338:201–15.CrossRefPubMedGoogle Scholar
  10. 10.
    Scivittaro V, Ganz MB, Weiss MF. (2000) AGEs induce oxidative stress and activate protein kinase C-beta(II) in neonatal mesangial cells. Am. J. Physiol. Renal Physiol. 278:F676–83.CrossRefPubMedGoogle Scholar
  11. 11.
    Grimsrud PA, Xie H, Griffin TJ, Bernlohr DA. (2008) Oxidative stress and covalent modification of protein with bioactive aldehydes. J. Biol. Chem. 283:21837–41.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Cerami C, et al. (1997) Tobacco smoke is a source of toxic reactive glycation products. Proc. Natl. Acad. Sci. U. S. A. 94:13915–20.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Miyata T, van Ypersele de Strihou C, Kurokawa K, Baynes J. (1999) Alterations in non-enzymatic biochemistry in uremia: origin and significance of “carbonyl stress” in long-term uremic complications. Kidney Int. 55:389–99.CrossRefPubMedGoogle Scholar
  14. 14.
    Goldberg T, et al. (2004) Advanced glycoxidation end products in commonly consumed foods. J. Am. Diet. Assoc. 104:1287–91.CrossRefPubMedGoogle Scholar
  15. 15.
    Tessier FJ, Birlouez-Aragon I. (2010) Health effects of dietary Maillard reaction products: the results of ICARE and other studies. Amino Acids. 2010, Oct 15 [Epub ahead of print]Google Scholar
  16. 16.
    Bunn HF, Higgins PJ. (1981) Reaction of monosaccharides with proteins: possible evolutionary significance. Science. 213:222–4.CrossRefPubMedGoogle Scholar
  17. 17.
    Vlassara H. (2005) Advanced glycation in health and disease: role of the modern environment. Ann. N. Y. Acad. Sci. 1043:452–60.CrossRefPubMedGoogle Scholar
  18. 18.
    Esposito F, et al. (2003) Moderate coffee consumption increases plasma glutathione but not homocysteine in healthy subjects. Aliment. Pharmacol. Ther. 17:595–601.CrossRefPubMedGoogle Scholar
  19. 19.
    Somoza V. (2005) Five years of research on health risks and benefits of Maillard reaction products: an update. Mol. Nutr. Food Res. 49:663–72.CrossRefPubMedGoogle Scholar
  20. 20.
    Ruhs S, et al. (2011) Preconditioning with Maillard reaction products improves antioxidant defence leading to increased stress tolerance in cardiac cells. Exp. Gerontol. 45:752–62.CrossRefGoogle Scholar
  21. 21.
    Bartling B, Desole M, Rohrbach S, Silber R-E, Simm A. (2009) Age-associated changes of extracellular matrix collagen impair lung cancer cell migration. FASEB J. 23:1510–20.CrossRefPubMedGoogle Scholar
  22. 22.
    Ershler WB, Socinski MA, Greene CJ. (1983) Bronchogenic cancer, metastases, and aging. J. Am. Geriatr. Soc. 31:673–6.CrossRefPubMedGoogle Scholar
  23. 23.
    Nerlich AG, Hagedorn HG, Boheim M, Schleicher ED. (1998) Patients with diabetes-induced microangiopathy show a reduced frequency of carcinomas. In Vivo. 12:667–70.PubMedGoogle Scholar
  24. 24.
    De Giorgio R, Giovanni B, Cecconi A, Corinaldesi R, Mancini A. (2000) Diabetes is associated with longer survival rates in patients with malignant tumors. Arch. Intern. Med. 160:2217.CrossRefPubMedGoogle Scholar
  25. 25.
    Bartling B, Simm A, Sohst A, Silber R, Hofmann H. (2011) Effect of diabetes mellitus on the outcome of patients with resected non-small cell lung carcinoma. Gerontology. 2011, Mar 11 [Epub ahead of print.]Google Scholar
  26. 26.
    Ulrich P, Cerami A. (2001) Protein glycation, diabetes, and aging. Recent Prog. Horm. Res. 56:1–21.CrossRefPubMedGoogle Scholar
  27. 27.
    Lindenmeier M, Faist V, Hofmann T. (2002) Structural and functional characterization of pronyl-lysine, a novel protein modification in bread crust melanoidins showing in vitro antioxidative and phase I/II enzyme modulating activity. J. Agric. Food Chem. 50:6997–7006.CrossRefPubMedGoogle Scholar
  28. 28.
    Simm A, et al. (1997) Advanced glycation end-products stimulate the MAP-kinase pathway in tubulus cell line LLC-PK1. FEBS Lett. 410:481–4.CrossRefPubMedGoogle Scholar
  29. 29.
    Hofmann H-S, et al. (2004) Classification of human lung neoplasm by two target genes. Am. J. Respir. Crit. Care Med. 170:516–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Bartling B, Rehbein G, Simm A, Silber RE, Hofmann HS. (2010) Porcupine expression is associated with the expression of S100P and other cancer-related molecules in non-small cell lung carcinoma. Int. J. Oncol. 36:1015–21.CrossRefPubMedGoogle Scholar
  31. 31.
    Bartling B, Hofmann H, Weigle B, Silber R, Simm A. (2005) Down-regulation of the receptor for advanced glycation end-products (RAGE) supports non-small cell lung carcinoma. Carcinogenesis. 26:293–301.CrossRefPubMedGoogle Scholar
  32. 32.
    Sebekova K, Faist V, Hofmann T, Schinzel R, Heidland A. (2003) Effects of a diet rich in advanced glycation end products in the rat remnant kidney model. Am. J. Kidney Dis. 41:S48–51.CrossRefPubMedGoogle Scholar
  33. 33.
    Somoza V, et al. (2005) Influence of feeding malt, bread crust, and a pronylated protein on the activity of chemopreventive enzymes and antioxidative defense parameters in vivo. J. Agric. Food Chem. 53:8176–82.CrossRefPubMedGoogle Scholar
  34. 34.
    Bartling B, Rehbein G, Somoza V, Silber RE, Simm A. (2005) Maillard reaction product-rich food impair cell proliferation and induce cell death in vitro. Signal Transduction. 6:303–13.CrossRefGoogle Scholar
  35. 35.
    Gerdemann A, et al. (2002) Plasma levels of advanced glycation end products during haemodialysis, haemodiafiltration and haemofiltration: potential importance of dialysate quality. Nephrol. Dial. Transplant. 17:1045–9.CrossRefPubMedGoogle Scholar
  36. 36.
    Henle T. (2007) Dietary advanced glycation end products: a risk to human health? A call for an interdisciplinary debate. Mol. Nutr. Food. Res. 51:1075–8.CrossRefPubMedGoogle Scholar
  37. 37.
    Birlouez-Aragon I, et al. (2010) A diet based on high-heat-treated foods promotes risk factors for diabetes mellitus and cardiovascular diseases. Am. J. Clin. Nutr. 91:1220–6.CrossRefPubMedGoogle Scholar
  38. 38.
    Tesarova P, et al. (2007) Carbonyl and oxidative stress in patients with breast cancer — is there a relation to the stage of the disease? Neoplasma. 54:219–24.PubMedGoogle Scholar
  39. 39.
    Egyud LG, Szent-Gyorgyi A. (1968) Cancerostatic action of methylglyoxal. Science. 160:1140.CrossRefPubMedGoogle Scholar
  40. 40.
    Ghosh M, et al. (2006) In vivo assessment of toxicity and pharmacokinetics of methylglyoxal. Augmentation of the curative effect of methylglyoxal on cancer-bearing mice by ascorbic acid and creatine. Toxicol. Appl. Pharmacol. 212:45–58.CrossRefPubMedGoogle Scholar
  41. 41.
    Ray M, Ghosh S, Kar M, Datta SC, Ray S. (2006) Implication of the bioelectronic principle in cancer therapy: treatment of cancer patients by methylglyoxal-based formulation. Cancer Therapy. 4:205–22.Google Scholar
  42. 42.
    Du J, et al. (2000) Methylglyoxal induces apoptosis in Jurkat leukemia T cells by activating c-Jun N-terminal kinase. J. Cell. Biochem. 77:333–44.CrossRefPubMedGoogle Scholar
  43. 43.
    Ray S, Dutta S, Halder J, Ray M. (1994) Inhibition of electron flow through complex I of the mitochondrial respiratory chain of Ehrlich ascites carcinoma cells by methylglyoxal. Biochem. J. 303 (Pt 1): 69–72.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Krajcovicova-Kudlackova M, Sebekova K, Schinzel R, Klvanova J. (2002) Advanced glycation end products and nutrition. Physiol. Res. 51:313–6.PubMedGoogle Scholar
  45. 45.
    Wu X, Monnier VM. (2003) Enzymatic deglycation of proteins. Arch. Biochem. Biophys. 419:16–24.CrossRefPubMedGoogle Scholar
  46. 46.
    Horiuchi S, Sakamoto Y, Sakai M. (2003) Scavenger receptors for oxidized and glycated proteins. Amino Acids. 25:283–92.CrossRefPubMedGoogle Scholar
  47. 47.
    Grune T, Davies KJ. (2003) The proteasomal system and HNE-modified proteins. Mol. Aspects Med. 24:195–204.CrossRefPubMedGoogle Scholar
  48. 48.
    Henle T, Miyata T. (2003) Advanced glycation end products in uremia. Adv. Ren. Replace. Ther. 10:321–31.CrossRefPubMedGoogle Scholar
  49. 49.
    Finot P, Magnenat E. (1981) Metabolic transit of early and advanced Maillard products. Prog. Fd. Nutr. Sci. 5:193–207.Google Scholar
  50. 50.
    Foerster A, Henle T. (2003) Glycation in food and metabolic transit of dietary AGEs (advanced glycation end-products): studies on the urinary excretion of pyrraline. Biochem. Soc. Trans. 31:1383–5.CrossRefPubMedGoogle Scholar
  51. 51.
    Thornalley PJ. (1998) Cell activation by glycated proteins. AGE receptors, receptor recognition factors and functional classification of AGEs. Cell. Mol. Biol. (Noisy-le-grand). 44:1013–23.Google Scholar
  52. 52.
    Cai W, He JC, Zhu L, Lu C, Vlassara H. (2006) Advanced glycation end product (AGE) receptor 1 suppresses cell oxidant stress and activation signaling via EGF receptor. Proc. Natl. Acad. Sci. U. S. A. 103:13801–6.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Domingo G, et al. (2010) EGF receptor in lung cancer: a successful story of targeted therapy. Expert Rev. Anticancer Ther. 10:1577–87.CrossRefPubMedGoogle Scholar
  54. 54.
    Bartling B, Desole M, Silber RE, Simm A. (2007) Dicarbonyl-mediated protein modifications affect matrix metalloproteinase (MMP) activity. Z. Gerontol. Geriatr. 40:357–61.CrossRefPubMedGoogle Scholar
  55. 55.
    Nass N, et al. (2010) Glycation of PDGF results in decreased biological activity. Int. J. Biochem. Cell. Biol. 42:749–754.CrossRefPubMedGoogle Scholar
  56. 56.
    Panneer Selvam J, Aranganathan S, Nalini N. (2008) Aberrant crypt foci and AgNORs as putative biomarkers to evaluate the chemopreventive efficacy of pronyl-lysine in rat colon carcinogenesis. Invest. New Drugs. 26:531–10.CrossRefPubMedGoogle Scholar
  57. 57.
    Marko D, et al. (2003) Maillard reaction products modulating the growth of human tumor cells in vitro. Chem. Res. Toxicol. 16:48–55.CrossRefPubMedGoogle Scholar

Copyright information

© The Feinstein Institute for Medical Research 2011
www.feinsteininstitute.org

Authors and Affiliations

  • Babett Bartling
    • 1
  • Hans-Stefan Hofmann
    • 1
    • 2
  • Antonia Sohst
    • 1
  • Yvonne Hatzky
    • 1
  • Veronika Somoza
    • 3
  • Rolf-Edgar Silber
    • 1
  • Andreas Simm
    • 1
  1. 1.Department of Cardio and Thoracic Surgery, University Hospital Halle (Saale)Martin Luther University Halle-WittenbergHalle (Saale)Germany
  2. 2.Department of Thoracic SurgeryHospital Barmherzige Brüder RegensburgRegensburgGermany
  3. 3.Research Platform for Molecular Food ScienceUniversity of ViennaViennaAustria

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