The role of the sialic acid in monitoring the evolution of malignant melanoma. From murine models to human research

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Purpose: To identify sialic acid as a tumor marker to be used in experimental models. Obtained data will be extrapolated to humans, so that this marker can be used in clinical practice. Materials and methods: We used B16 melanoma cells. The lot was composed of 30 male C57Bl6 mice, which received subcutaneous injections of 5x105 B16 melanoma cells into the right flank. Tumor volume was measured with a vernier caliper. Sialic acid was determined from the serum obtained by cardiac puncture. The second step of our research was performed on a number of 25 patients with cutaneous melanoma. Determination of sialic acid was performed using the Kattermann colorimetric method. The correlation between sialic acid and disease progression was exemplified in two clinical cases. Sialic acid determination was performed dynamically from diagnosis, following disease progression. Results: In murine models tumors increased after a lag period of up to 10 days. Tumor growth was recorded by measuring the tumor’s diameters and calculating its volume. We observed a progressive increase of sialic acid in parallel with tumor volume. In human subjects, sialic acid levels increase in metastatic disease and are common in localized disease. In the two clinical cases there was a very strong correlation between sialic acid and disease progression. Conclusions: B16 melanoma cells are highly metastatic. Sialic acid level was increased in metastatic tumor animals compared to normal animals. Higher levels of sialic acid have been shown to correlate with the metastatic potential of tumor cells. For humans, determination of total serum sialic acid would be more useful for diagnosis of advanced melanoma stage rather than for early detection and screening.

1. Hayat MJ, Howlader N, Reichman ME, Edwards BK. Cancer statistics, trends, and multiple primary cancer analyses from the Surveillance, Epidemiology, and End Results (SEER) Program. Oncologist. 2007 Jan;12(1):20-37.

2. DeVita V, Lawrence T, Rosenberg S. Principles & Practice of oncology, 9th edition. 2011;119:1660-76.

3. Ross MI, Stern SJ. Mucosal Melanomas. St. Louis Quality Medical Publishing Inc. 1998;3:195-208.

4. Chang P, Knapper WH. Metastatic Melanoma of Unknown Primary. Cancer. 2006;49(6):1106-11.

5. Murali R, Shaw HM, Lai K, et al. Prognostic Factors in Cutaneous Desmoplastic Melanoma: A Study of 252 Patients. Cancer. 2010;116(17):4130.

6. Schrohl AS, Anderson MH, Sweep F, Schmitt M, Harbeck N, Foekens J, et al. Tumor Markers: From Laboratory to Clinical Utility. Mol Cell Proteomics. 2003 Jun;2:378-87.

7. Wu JT. Diagnosis and Management of Cancer Using Serological Tumor Markers. Henry′s Clinical Diagnosis and Management by Laboratory Methods. 2007; 21: 47-52.

8. Gershou YL, Stanley H, Jules H, John MJ. ASCO 2006 Update of Recomandations for the Use of Tumor Markers in Colon Cancer. Jurnal of Clinical Oncology. 2006 Jun;6:23-26.

9. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM. Reporting Recommendations for Tumor Marker Prognostic Studies. Journal of Clinical Oncology. 2005;23(36): 9067-72.

10. Clinical Practice Guidelines for the Use of Tumor Markers in Breast and Colorectal Cancer. Adopted on May 17, 1996, by the American Society of Clinical Oncology. Journal of Clinical Oncology. 1996;14:2843-77.

11. International Germ Cell Consensus Classification: A Prognostic Factor-based Staging System for Metastatic Germ Cell Cancers. International Germ Cell Cancer Collaborative Group. Journal of Clinical Oncology. 1997;15:594-603.

12. Eriksson B, Oberg K, Stridsberg M. Tumor Markers in Neuroendocrine Tumors. Digestion International Journal of Gastroenterology. 2000;62:33-38.

13. Sturgeon C. Practice Guidelines for Tumor Marker Use in Clinic. Clin Chem. 2002;48:1151-59.

14. Locker GY, Hamilton S, Harris J. ASCO 2006 Update of Recommendations for the Use of Tumor Markers in Gastrointestinal Cancer. Journal of Clinical Oncology. 2006;24:5313-27.

15. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer. V.3.2011. Accessed at on March 14, 2011.

16. Gajeroski TF, Grimm EA, Nickoloff BJ. New Potential Therapeutic Targets in Melanoma. ASCO Annual Meeting. 2008;123-125.

17. Narayanan S. Sialic Acid as a Tumor Marker. Ann Clin Lab Sci. 1994 Jul-Aug;24(4):376-84.

18. Dube HD, Bertozzi RC. Glycans in Cancer and Inflamation -potential for therapeutics and diagnostics. Nature Reviews Drug Discovery. 2005 June;4:477-448.

19. Feijoo C, Paez de la Cadena M, Rodriguez-Berrocal FJ, Martinez-Zorzano VS. Sialic Acid Levels in Serum and Tissue from Colorectal Cancer Patients. Cancer Lett. 1997;112:155-160.

20. Redondo-Garcia P, Nakamura CV, Souza W, Morgado- Diaz JA. Differential Expression of Sialic Acid and N-acetyl-galactosamine Residues on the Cell Surface of Intestinal Epithelial Cells According to Normal or Metastatic Potential. J Histochem Cytochem. 2004 May;52:629-40.

21. Holzmann B, Brocker E, Lehmann MJ, Ruiter DJ, Sorg C, Riethmuller G. Tumor Progression in Human Malignant Melanoma: Five Stages Defined by Their Antigenic Phenotypes. International Journal of Cancer. 1987 April;39:466-71.

22. Silver HK, Rangel DM, Morton DL. Serum Sialic Acid Elevations in Malignant Melanoma Patients. Cancer. 1978;41(4):1497-99.

23. Taylor G. Sialidases: Structures, Biological Significance and Therapeutic Potential. Curr Opin Struct Biol. 1996;6:830-37.

24. Watkins E, Anderson I, Nebril LR, Waters IF, Connery CK. Neuraminidase-mediated Augmentation of in Vitro Immune Response of Patients with Solid Tumors. Int. J. Cancer. 2007;14:799-805.

25. Ros-Bullon MR, Sanchez-Pedreno P, Martinez-Liarte JH. Serum Sialic Acid in Malignant Melanoma Patients: an ROC Curve Analysis. Anticancer Res. 1999 Jul- Aug;19(4C):3619-22.

26. Miyata M, Kambe M, Tajima O, Moriya S, Kondo Y, Narimatsu H, et al. Membrane sialidase NEU3 is Highly Expressed in Human Melanoma Cells Promoting Cell Growth with Minimal Changes in the Composition of Gangliosides. Cancer Science. 2011 Dec;102:2139-49.

27. Miyagi T, Wada T, Yamaguchi K. Roles of Plasma Membrane-associated Sialidase NEU3 in Human Cancers. Biochim Biophys Acta. 2008;(7):532-78.

28. Suzuki Y, Ito T, Suzuki T. Sialic Acid Species as a Determinant of the Host Range of Influenza A Viruses. J Virol. 2000;74:11825-831.

29. Lehmann F, Tiralongo E, Tiralongo J. Sialic Acid - Specific Lectins: Occurrence, Specificity and Function. Cell Mol Life Sci. 2006;63:1331-54.

30. Katterman R, Kriege R. Chem. Biochem. 1981;19(1):31-4.

31. Kinoshita Y, Sato S, Takeuchi T. Cellular Sialic Acid Level and Phenotypic Expression in B16 Melanoma Cells: Comparison of Spontaneous Variations and Bromodeoxyuridine- and Theophylline-Induced Changes. Cell Structure and Function. 1989;14:35-43.

32. Korangath Preethi C, Kodappully Siveen S, Kuttan R, Kuttan G. Inhibition of Metastasis of B16-F10 Melanoma Cells in C57BL/6 Mice by an Extract of Calendula Officinalis L Flowers. Asian Pacific Journal of Cancer Prevention. 2010;11:1773-79.

33. Schauer R. Sialic Acids as Regulators of Molecular and Cellular Interactions. Curr Opin Struct Biol. 2009;19:507-514.

34. Lloyd KO, Furukawa K. Biosynthesis and Functions of Gangliosides: Recent Advances. Glycoconj J. 1998;15:627-36.

35. Wada T, Hata K, Yamaguchi K. A Crucial Role of Plasma Membrane-associated Sialidase in the Survival of Human Cancer Cells. Oncogene. 2007;26:2483-90.

36. Monti E, Bassi MT, Papini N. Identification and Expression of NEU 3, a Novel Human Sialidase- associated to the plasma membrane. Biochem J. 2000;349:343-51.

37. Kannagi R. Carbohydrate Antigen Sialyl Lewis Pathophysiological Significance and Induction Mechanism in Cancer Progression. Chang Gung Med J. 2007;30:189-209.

38. Patra SK. Dissecting lipid raft facilitated cell signaling pathways in cancer. Biochim. Biophys. Acta. 2008 Apr;1785(2):182-206.

39. Schauer R. Achievements and Challenges of Sialic Acid Research. Glycoconj J. 2000;17:485-99.

40. Bardor M, Nguyen DH, Diaz S, Varki A. Mechanism of Uptake and Incorporation of the non-human Sialic Acid N-glycolylneuraminic acid into human cells. J Biol Chem. 2005;280:4228-37.

41. Hedlund M, Tangvoranuntakul P, Takematsu H, Long JM, Housley GD, Kozutsumi Y, et al. N-glycolylneuraminic Acid Deficiency in Mice: Implications for hu- man biology and evolution. Moll Cell Biol. 2007;27:4340-46.

42. Varki A. Glycan-based Interactions Involoving Vertebrate Sialic Acid Recognizing Proteins. Nature. 2007; 446:1023-9.

43. Gabri R, Otero L, Gomez D, Alonso D. Exogenous Incorporation of Neugc-rich Mucin Augments n-glycolyl Sialic Acid Content and Promotes Malignant Phenotype in Mouse Tumor Cell Lines. Journal of Experimental and Clinical Cancer Research. 2009;28:146-158.

44. Ohyama C. Glycosylation in Bladder Cancer. Int. J. Clin. Oncol. 2008;13:308-13.

45. Yin J, Hashimoto A, Izawa M, Miyazaki K, Chen GY, Tkematsu H, et al. Hipoxic Cultures Induces Expression of Sialin, a Sialic Acid Transporter and Cancer Associated gangliosides containing non-human sialic acid on Human Cancer Cells. Cancer Res. 2006;66:2937-45.

46. Engers R, Gabbert HE. Mechanism of Tumor Metastasis: Cell Biological Aspects and Clinical Implications. J. Cancer Res Clin Oncol. 2000;126:682-92.

Revista Romana de Medicina de Laborator

Romanian Journal of Laboratory Medicine

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