Tumor Biology

, Volume 37, Issue 8, pp 10753–10761 | Cite as

Correlation of TGF-β1 and oxidative stress in the blood of patients with melanoma: a clue to understanding melanoma progression?

  • Sara Santos Bernardes
  • Fernando Pinheiro de Souza-Neto
  • Gabriella Pasqual Melo
  • Flávia Alessandra Guarnier
  • Poliana Camila Marinello
  • Rubens Cecchini
  • Alessandra L. Cecchini
Original Article

Abstract

TGF-β1 and oxidative stress are involved in cancer progression, but in melanoma, their role is still controversial. Our aim was to correlate plasma TGF-β1 levels and systemic oxidative stress biomarkers in patients with melanoma, with or without disease metastasis, to understand their participation in melanoma progression. Thirty patients were recruited for melanoma surveillance, together with 30 healthy volunteers. Patients were divided into two groups: Non-metastasis, comprising patients with tumor removal and no metastatic episode for 3 years; and Metastasis, comprising patients with a metastatic episode. The plasmatic cytokines TGF-β1, IL-1 β, and TNF-α were analyzed by ELISA. For oxidative stress, the following assays were performed: malondialdehyde (MDA), advanced oxidation protein products (AOPP) levels, total radical-trapping antioxidant parameter (TRAP) and thiol in plasma, and lipid peroxidation, SOD and catalase activity and GSH in erythrocytes. Patients with a metastatic episode had less circulating TGF-β1 and increased TRAP, thiol, AOPP and lipid peroxidation levels. MDA was increased in both melanoma groups, while catalase, GSH, and IL-1β was decreased in Non-metastasis patients. Significant negative correlations were observed between TGF-β1 levels and systemic MDA, and TGF-β1 levels and systemic AOPP, while a positive correlation was observed between TGF-β1 levels and erythrocyte GSH. Lower levels of TGF-β1 were related to increased oxidative stress in Metastasis patients, reinforcing new evidence that in melanoma TGF-β1 acts as a tumor suppressor, inhibiting tumor relapse. These findings provide new knowledge concerning this cancer pathophysiology, extending the possibilities of investigating new therapies based on this evidence.

Keywords

Melanoma Transforming growth factor beta Oxidative stress Neoplasm recurrence Malondialdehyde 

Notes

Acknowledgments

The authors are grateful to J.A. Vargas and P. S. R. D. Filho for their excellent technical assistance and E. C. B. Carmelo of the Department of Clinical Research of the Londrina Cancer Hospital for her important assistance in patient recruitment and interview. The authors would also like to thank physicians M. A. Buges and C. Z. Campos for allowing their patients to participate in the study. The authors also thank the Araucária Foundation for providing financial support.

Compliance with ethical standards

Conflicts of interest

None.

References

  1. 1.
    Lebrun JJ. The dual role of TGF-beta in human cancer: from tumor suppression to cancer metastasis. ISRN Mol Biol. 2012. doi: 10.5402/2012/381428.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Humbert L, Lebrun JJ. TGF-beta inhibits human cutaneous melanoma cell migration and invasion through regulation of the plasminogen activator system. Cell Signal. 2013. doi: 10.1016/j.cellsig.2012.10.011.PubMedGoogle Scholar
  3. 3.
    Moustakas A. TGF-beta targets PAX3 to control melanocyte differentiation. Dev Cell. 2008. doi: 10.1016/j.devcel.2008.11.009.PubMedGoogle Scholar
  4. 4.
    Schriek G, Oppitz M, Busch C, Just L, Drews U. Human SK-Mel 28 melanoma cells resume neural crest cell migration after transplantation into the chick embryo. Melanoma Res. 2005;15:225–34.CrossRefPubMedGoogle Scholar
  5. 5.
    Perrot CY, Javelaud D, Mauviel A. Insights into the transforming growth factor-β signaling pathway in cutaneous melanoma. Ann Dermatol. 2013. doi: 10.5021/ad.2013.25.2.135.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Lo RS, Witte ON. Transforming growth factor-beta activation promotes genetic context-dependent invasion of immortalized melanocytes. Cancer Res. 2008;68:4248–57.CrossRefPubMedGoogle Scholar
  7. 7.
    Javelaud D, Alexaki VI, Mauviel A. Transforming growth factor-β in cutaneous melanoma. Pigment Cell Melanoma Res. 2008;21:123–32.CrossRefPubMedGoogle Scholar
  8. 8.
    Krasagakis K, Garbe C, Schrier PI, Orfanos CE. Paracrine and autocrine regulation of human melanocyte and melanoma cell growth by transforming growth factor beta in vitro. Anticancer Res. 1994;14:2565–71.PubMedGoogle Scholar
  9. 9.
    Krasagakis K, Thölke D, Farthmann B, Eberle J, Mansmann U, Orfanos CE. Elevated plasma levels of transforming growth factor (TGF)-beta 1 and TGF-beta 2 in patients with disseminated malignant melanoma. Br J Cancer. 1998;77:1492–4.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Ramont SP, Hornebeck W, Maquart FX, Monboisse JC. Transforming growth factor-β1 inhibits tumor growth in a mouse melanoma model by down-regulating the plasminogen activation system. Exp Cell Res. 2003;291:1–10.CrossRefPubMedGoogle Scholar
  11. 11.
    Malaponte G, Zacchia A, Bevelacqua Y, Marconi A, Perrotta R, Mazzarino MC, et al. Co-regulated expression of matrix metalloproteinase-2 and transforming growth factor-beta in melanoma development and progression. Oncol Rep. 2010;24:81–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Tas F, Karabulut S, Yasasever CT, Duranyildiz D. Serum transforming growth factor-beta 1 (TGF-β1) levels have diagnostic, predictive, and possible prognostic roles in patients with melanoma. Tumour Biol. 2014. doi: 10.1007/s13277-014-1984-z.Google Scholar
  13. 13.
    Meyer M, Pahl HL, Baeuerle PA. Regulation of the transcription factors NF-κB and AP-1 by redox changes. Chem Biol Interact. 1994;91:91–100.CrossRefPubMedGoogle Scholar
  14. 14.
    Meyskens Jr FL, McNulty SE, Buckmeier JA, Tohidian NB, Spillane TJ, Kahlon RS, et al. Aberrant redox regulation in human metastatic melanoma cells compared to normal melanocytes. Free Radic Biol Med. 2001;31:799–808.CrossRefPubMedGoogle Scholar
  15. 15.
    Sander CS, Hamm F, Elsner P, Thiele JJ. Oxidative stress in malignant melanoma and non-melanoma skin cancer. Br J Dermatol. 2003;148:913–22.CrossRefPubMedGoogle Scholar
  16. 16.
    Gadjeva V, Dimov A, Georgieva N. Influence of therapy on the antioxidant status in patients with melanoma. J Clin Pharm Ther. 2008. doi: 10.1111/j.1365-2710.2008.00909.x.PubMedGoogle Scholar
  17. 17.
    Picardo M, Grammatico P, Roccella F, Roccella M, Grandinetti M, Del Porto G, et al. Imbalance in the antioxidant pool in melanoma cells and normal melanocytes from patients with melanoma. J Investig Dermatol. 1996;107:322–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Barcellos-Hoff MH, Dix TA. Redox-mediated activation of latent transforming growth factor-beta 1. Mol Endocrinol. 1996;10:1077–83.PubMedGoogle Scholar
  19. 19.
    Bauer G. Elimination of transformed cells by normal cells: a novel concept for the control of carcinogenesis. Histol Histopathol. 1996;11:237–55.PubMedGoogle Scholar
  20. 20.
    Häufel T, Dormann S, Hanusch J, Schwieger A, Bauer G. Three distinct roles for TGF-beta during intercellular induction of apoptosis: a review. Anticancer Res. 1999;19:105–11.PubMedGoogle Scholar
  21. 21.
    De Bleser PJ, Xu G, Rombouts K, Rogiers V, Geerts A. Glutathione levels discriminate between oxidative stress and transforming growth factor-beta signaling in activated rat hepatic stellate cells. J Biol Chem. 1999;274:33881–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through VI. Arch Dermatol. 1988;124:869–71.CrossRefPubMedGoogle Scholar
  23. 23.
    (INCA), I. N. D. C. Estimativas da incidência e mortalidade por câncer no Brasil. Rio de Janeiro: Ministério da Saúde; 2014.Google Scholar
  24. 24.
    Lawanga SK, Lemeshow S. Sample size determination in health studies. World Health Organization – Geneva, 1991. ISBN 92 4 154405.Google Scholar
  25. 25.
    Victorino VJ, Panis C, Campos FC, Cayres RC, Colado-Simão AN, Oliveira SR, et al. Decreased oxidant profile and increased antioxidant capacity in naturally postmenopausal women. Age (Dordr). 2013;35:1411–21. doi: 10.1007/s11357-012-9431-9.CrossRefGoogle Scholar
  26. 26.
    Descamps-Latscha B, Witko-Sarsat V, Nguyen-Khoa T, Nguyen AT, Gausson V, Mothu N, et al. Early prediction of IgA nephropathy progression: proteinuria and AOPP are strong prognostic markers. Kidney Int. 2004;66:1606–12.CrossRefPubMedGoogle Scholar
  27. 27.
    Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ. Protein measurement with the folin phenol reagent. J Biol Chem. 1951;193:265–72.PubMedGoogle Scholar
  28. 28.
    Miller G. Protein determination of large numbers of samples. Anal Chem. 1959;31:964.CrossRefGoogle Scholar
  29. 29.
    Repetto M, Reides C, Gomez Carretero ML, Costa M, Griemberg G, Llesuy S. Oxidative stress in blood of HIV infected patients. Clin Chim Acta. 1996;255:107–17.CrossRefPubMedGoogle Scholar
  30. 30.
    Hu ML. Measurement of protein thiol groups and GSH in plasma. In: Sies H, Abelson J, Simon M, editors. Methods in enzymoly 233. San Diego: Academic; 2004. p. 380–5.Google Scholar
  31. 31.
    Panis C, Herrera AC, Victorino VJ, Campos FC, Freitas LF, De Rossi T, et al. Oxidative stress and hematological profiles of advanced breast cancer patients subjected to paclitaxel or doxorubicin chemotherapy. Breast Cancer Res Treat. 2012;133:89–97.CrossRefPubMedGoogle Scholar
  32. 32.
    Marklund S, Marklund G. Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem. 1974;47:469–74.CrossRefPubMedGoogle Scholar
  33. 33.
    Aebi H. Catalase in vitro. In: Sies H, Kaplan N, Colowick N, editors. Methods in enzymoly 105. San Diego: Academic; 1984. p. 121–1266.Google Scholar
  34. 34.
    Tietze F. Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues. Anal Biochem. 1969;27:502–22.CrossRefPubMedGoogle Scholar
  35. 35.
    Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman J, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809–19.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Rizos H, Menzies AM, Pupo GM, Carlino MS, Fung C, Hyman J, et al. BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin Cancer Res. 2014;20:1965–77.CrossRefPubMedGoogle Scholar
  37. 37.
    Kim CJ, Reintgen DS, Balch CM. The new melanoma staging system. Cancer Control. 2002;9:9–15.PubMedGoogle Scholar
  38. 38.
    Schmid P, Itin P, Rufli T. In situ analysis of transforming growth factor-beta s (TGF-beta 1, TGF-beta 2, TGF-beta 3), and TGF-beta type II receptor expression in malignant melanoma. Carcinogenesis. 1995;16:1499–503.CrossRefPubMedGoogle Scholar
  39. 39.
    Van Belle P, Rodeck U, Nuamah I, Halpern AC, Elder DE. Melanoma-associated expression of transforming growth factor-beta isoforms. Am J Pathol. 1996;148:1887–94.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Hassona Y, Cirillo N, Lim KP, Herman A, Mellone M, Thomas GJ, et al. Progression of genotype-specific oral cancer leads to senescence of cancer-associated fibroblasts and is mediated by oxidative stress and TGF-β. Carcinogenesis. 2013;34(6):1286–95.CrossRefPubMedGoogle Scholar
  41. 41.
    Bounaama A, Djerdjouri B, Laroche-Clary A, Le Morvan V, Robert J. Short curcumin treatment modulates oxidative stress, arginase activity, aberrant crypt foci, and TGF-β1 and HES-1 transcripts in 1,2-dimethylhydrazine-colon carcinogenesis in mice. Toxicology. 2012;302(2–3):308–17.CrossRefPubMedGoogle Scholar
  42. 42.
    Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J, et al. The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell. 1999;96:319–28.CrossRefPubMedGoogle Scholar
  43. 43.
    Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature. 1992;359:693–9.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Panis C, Herrera AC, Victorino VJ, Aranome AM, Cecchini R. Screening of circulating TGF-β levels and its clinicopathological significance in human breast cancer. Anticancer Res. 2013;33:737–42.PubMedGoogle Scholar
  45. 45.
    Cui Y, Robertson J, Maharaj S, Waldhauser L, Niu J, Wang J, et al. Oxidative stress contributes to the induction and persistence of TGF-β1 induced pulmonary fibrosis. Int J Biochem Cell Biol. 2011;43:1122–33.CrossRefPubMedGoogle Scholar
  46. 46.
    Halliwel B, Gutteridge JMC. Free radicals in biology and medicine. 4th ed. Oxford: Oxford University Press; 2007.Google Scholar
  47. 47.
    Korkmaz GG, Altınoglu E, Civelek S, Sozer V, Erdenen F, Tabak O, et al. The association of oxidative stress markers with conventional risk factors in the metabolic syndrome. Metabolism. 2013;62:828–35.CrossRefPubMedGoogle Scholar
  48. 48.
    Letterio JJ, Roberts AB. Regulation of immune responses by TGF-beta. Annu Rev Immunol. 1998;16:137–61.CrossRefPubMedGoogle Scholar
  49. 49.
    Suzuki Y, Ohno S, Okuyama R, Aruga A, Yamamoto M, Miura S, et al. Determination of chronic inflammatory states in cancer patients using assay of reactive oxygen species production by neutrophils. Anticancer Res. 2012;32:565–70.PubMedGoogle Scholar
  50. 50.
    Azorin I, Bella MC, Iborra FJ, Fornas E, Renau-Piqueras J. Effect of tert-butyl hydroperoxide addition on spontaneous chemiluminescence in brain. Free Radic Biol Med. 1995;19:795–803.CrossRefPubMedGoogle Scholar
  51. 51.
    Halliwell B. Oxidative stress and cancer: have we moved forward? Biochem J. 2007;401:1–11.CrossRefPubMedGoogle Scholar
  52. 52.
    Bernardes SS, Souza-Neto FP, Ramalho LN, Derossi DR, Guarnier FA, Silva CF, et al. Systemic oxidative profile after tumor removal and the tumor microenvironment in melanoma patients. Cancer Lett. 2015. doi: 10.1016/j.canlet.2015.03.007.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Sara Santos Bernardes
    • 1
  • Fernando Pinheiro de Souza-Neto
    • 1
  • Gabriella Pasqual Melo
    • 1
  • Flávia Alessandra Guarnier
    • 2
  • Poliana Camila Marinello
    • 1
  • Rubens Cecchini
    • 3
  • Alessandra L. Cecchini
    • 1
  1. 1.Laboratory of Molecular PathologyLondrina State University (UEL)LondrinaBrazil
  2. 2.Laboratory of the Pathophysiology of Muscle AdaptationsLondrina State University (UEL)LondrinaBrazil
  3. 3.Laboratory of Pathophysiology and Free RadicalsLondrina State University (UEL)LondrinaBrazil

Personalised recommendations