GALECTINS IN THE BLOOD SERUM OF PATIENTS WITH COLORECTAL CANCER: ASSOCIATION OF THEIR CONTENT WITH CLINICAL AND MORPHOLOGICAL CHARACTERISTICS OF TUMORS AND PROGNOSIS
Original research article
Published September 3, 2023
Keywords
galectin-1
colorectal cancer
galectin-7
galectin-9
colorectal cancer
galectin-7
galectin-9
How to Cite
Kushlinskii N. E., Kovaleva O. V., Kuzmin Y. B., Alferov A. A., Zybina N. N., Gratchev A. N., Mamedli Z. Z., Yanushevich O. O., Stilidi I. I. GALECTINS IN THE BLOOD SERUM OF PATIENTS WITH COLORECTAL CANCER: ASSOCIATION OF THEIR CONTENT WITH CLINICAL AND MORPHOLOGICAL CHARACTERISTICS OF TUMORS AND PROGNOSIS // Kremlin Medicine Journal. 2023. VOL. № 3. С. 50-55.
Abstract
Due to the variety of oncologic diseases, the functional role of galectins is rather controversial; however, for many types of neoplasms this marker plays a role of a tumor growth promoter. Purpose. To study the structure of galectins -1, -7, -9 in the blood serum of patients with colorectal cancer and to find any their association with clinical and morphological characteristics of tumors and prognosis. Materials and methods. The present trial included 140 patients with colorectal cancer (mean age 60.7 years) and 20 healthy donors (mean age 54.7 years). Clinical diagnosis in all patients was confirmed with morphological examination of tumors using International Histological Classification of Tumors of the Digestive System (WHO, 2019). Colon adenocarcinoma was confirmed in all of them. Galectins -1, -7, -9 concentrations in blood serum were tested with conventional techniques ( before the described method) using the reagent kits for direct enzyme immunoassay [ Human Galectin 1, -7, -9 Quantikine ELISA (R&D Systems)] observing the manufacturer's instructions. Measurements were made at automatic immunenzyme analyzer BEP 2000 Advance (Siemens Healthcare Diagnostics, Germany). The obtained data were processed with GraphPad Prizm 9.0 program. Nonparametric Mann–Whitney and Kruskal–Wallis techniques were used while comparing the obtained indicators and analyzing their relationships,. The overall survival rate was calculated with Kaplan – Meier method. Comparison of statistical significance of differences between indicators was made with the logarithmic rank test. To assess the potential impact of various risk factors at patient's survival, a multivariate analysis was additionally performed using nonparametric Cox proportional hazards model. Differences and correlations were considered statistically significant at p<0.05. Results. In CRC patients, median concentration of galectin-9 was significantly higher than in the control group: 11.05 (8.64–14.83) ng/mL vs. 9.61 (6.73–13.03) ng/mL, (p = 0.049). No significant differences were obtained for galectin-1 and galectin-7. The researchers analyzed diagnostic informativity of the studied blood serum galectins, taking into account sensitivity and specificity of each marker by constructing ROC curves and calculating the area under them (AUC). The analysis performed did not reveal any significant associations with clinical and morphological characteristics of the tumor in colorectal cancer patients. However, it should be noted that there is a tendency to the increased level of galectin–9 in the blood serum of patients with distant metastases and in case of tumor invading into all layers of the intestinal wall (T3–T4). A univariate analysis revealed a favorable prognostic significance of galectin-7 (p = 0.05). High levels of marker galectin–9 showed a trend toward favorable prognosis. The regression analysis of the studied galectin levels by Cox technique showed the absence of prognostic significance of the content of galectins -1, -7 and -9 in the blood serum of colorectal cancer patients. A direct correlation was found between levels of galectin-1 and galectin-9 (r = 0.216; p = 0.01); no such pattern was found for galectin-7. Conclusion. Further studies of galectins in colorectal cancer patients in combination with other biochemical markers are needed, so as to develop comprehensive diagnostic panels in clinical oncological practice.References
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4. Tureci O. et al. Molecular definition of a novel human galectin which is immunogenic in patients with Hodgkin's disease // J Biol Chem. – 1997. – V. 272. – № 10. – P. 6416–6422.
5. Wada J. et al. Identification and characterization of galectin-9, a novel beta-galactoside-binding mammalian lectin // J Biol Chem. – 1997. – V. 272. – № 9. – P. 6078–6086.
6. Chen X. et al. Intestinal epithelial cells express galectin-9 in patients with food allergy that plays a critical role in sustaining allergic status in mouse intestine // Allergy. – 2011. – V. 66. – № 8. – P. 1038–1046.
7. Imaizumi T. et al. Interferon-gamma stimulates the expression of galectin-9 in cultured human endothelial cells // J Leukoc Biol. – 2002. – V. 72. – № 3. – P. 486–491.
8. Morishita A. et al. Galectin-9 in gastroenterological cancer // Int J Mol Sci. – 2023. – V. 24. – № 7. – P. 6174.
9. Hirashima M. et al. Galectin-9 in physiological and pathological conditions // Glycoconj J. – 2002. – V. 19. – № 7–9. – P. 593–600.
10. Chabot S. et al. Regulation of galectin-9 expression and release in Jurkat T cell line cells // Glycobiology. – 2002. – V. 12. – № 2. – P. 111–118.
11. Oomizu S. et al. Cell surface galectin-9 expressing Th cells regulate Th17 and Foxp3+ Treg development by galectin-9 secretion // PLoS One. – 2012. – V. 7. – № 11. – P. e48574.
12. Moar P. et al. Galectin-9 as a biomarker of disease severity // Cell Immunol. – 2021. – V. 361. – P. 104287.
13. Zhu C. et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity // Nat Immunol. – 2005. – V. 6. – № 12. – P. 1245–1252.
14. Daley D. et al. Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance // Nat Med. – 2017. – V. 23. – № 5. – P. 556–5567.
15. Wu C. et al. Galectin-9-CD44 interaction enhances stability and function of adaptive regulatory T cells // Immunity. – 2014. – V. 41. – № 2. – P. 270–282.
16. Madireddi S. et al. Regulatory T cell-mediated suppression of inflammation induced by DR3 signaling is dependent on galectin-9 // J Immunol. – 2017. – V. 199. – № 8. – P. 2721–2728.
17. Yasinska I.M. et al. Ligand-receptor interactions of galectin-9 and VISTA suppress human T lymphocyte cytotoxic activity // Front Immunol. – 2020. – V. 11. – P. 580557.
18. Camby I. et al. Galectin-1: a small protein with major functions // Glycobiology. – 2006. – V. 16. – № 11. – P. 137R–157R.
19. Paz A. et al. Galectin-1 binds oncogenic H-Ras to mediate Ras membrane anchorage and cell transformation // Oncogene. – 2001. – V. 20. – № 51. – P. 7486–7493.
20. Cagnoni A.J. et al. Galectin-1 fosters an immunosuppressive microenvironment in colorectal cancer by reprogramming CD8(+) regulatory T cells // Proc Natl Acad Sci U S A. – 2021. – V. 118. – № 21. – P. e2102950118.
21. Madsen P. et al. Cloning, expression, and chromosome mapping of human galectin-7 // J Biol Chem. – 1995. – V. 270. – № 11. – P. 5823–5829.
22. Saussez S. et al. Galectin-7 // Cell Mol Life Sci. – 2006. – V. 63. – № 6. – P. 686–697.
23. Watanabe M. et al. Clinical significance of circulating galectins as colorectal cancer markers // Oncol Rep. – 2011. – V. 25. – № 5. – P. 1217–1226.
24. Barrow H. et al. Serum galectin-2, -4, and -8 are greatly increased in colon and breast cancer patients and promote cancer cell adhesion to blood vascular endothelium // Clin Cancer Res. – 2011. – V. 17. – № 22. – P. 7035–7046.
25. Sideras K. et al. Circulating levels of PD-L1 and galectin-9 are associated with patient survival in surgically treated hepatocellular carcinoma independent of their intra-tumoral expression levels // Sci Reports. – 2019. – V. 9. – № 1. – P. 10677.
26. Wang Y. et al. Reduced expression of galectin-9 contributes to a poor outcome in colon cancer by inhibiting NK cell chemotaxis partially through the Rho/ROCK1 signaling pathway // PLoS One. – 2016. – Vol. 11. – № 3. – Р. e0152599.
27. Yang Q. et al. miR-455-5p functions as a potential oncogene by targeting galectin-9 in colon cancer // Oncol Lett. – 2017. – V. 13. – № 3. – P. 1958–1964.
28. Kang C.W. et al. Apoptosis of tumor infiltrating effector TIM-3+CD8+ T-cells in colon cancer // Sci Rep. – 2015. – V. 5. – P. 15659.
29. Sakhnevych S.S. et al. Mitochondrial defunctionalization supresses Tim-3-Galectin-9 secretory pathway in human colorectal cancer cells and thus can possibly affect tumor immune escape // Front Pharmacol. – 2019. – V. 10. – № 342.
30. Lim L.C. et al. Identification of differentially expressed proteins in the serum of colorectal cancer patients using 2D-DIGE proteomics analysis // Pathol Oncol Res. – 2016. – V. 22. – № 1. – P. 169–177.