Comparison of cytokine secretion and study of their effect on erythropoiesis in patients with malignant neoplasms with anemia of chronic disease, iron deficiency anemia, and their combination

Aim. To compare the secretion of interleukin-6 (IL-6), interleukin-10 (IL-10) and tumor necrosis factor-alpha (TNF-α) in cancer patients with anemia of chronic disease (ACD), iron deficiency anemia (IDA) and a combination of these two anemia types. To assess the effect of the studied cytokines on erythropoiesis in patients with malignant neoplasms separately for each type of anemia studied.

Materials and methods. 106 patients with stage II–IV of solid malignant neoplasms were examined: 84 with anemia (55 men, 29 women, 67.1 ± 9.9 years), 22 without anemia (17 men, 5 women, mean age 60.2 ± 14.9 years). In accordance with Van Santen and Worwood criteria, by determining the transferrin saturation coefficient, ferritin concentrations, C-reactive protein, patients were divided into 4 groups: group 1 – patients with ACD, 31 (20 / 11 patients), 2 group – ACD / IDA, 28 (18 / 10 patients), group 3 – IDA, 25 (17 / 8 patients), group 4 (control) – 22 patients without anemia. In all patients, the number of erythrocytes, the concentration of hemoglobin, ferritin, C-reactive protein, transferrin saturation coefficient, IL-6, TNF-α, IL-10 were determined. For quantitative indicators, the arithmetic mean and interquartile range (IQR) were calculated. Significance of differences between several unrelated groups was determined using the Kruskal–Wallis test. To assess the relationship between variables, the Spearman correlation coefficient (r) was calculated.

Results. In the ACD group, the maximum IL-6 concentration was 73.3 (IQR 6.2–51), TNF-α – 24.4 (IQR 15.3–60.7) and IL-10 – 8.7 (IQR 4.7–12.1) compared with the ACH3 / IDA group (IL-6 – 9.3 [IQR 4.4–13.2], TNF-α – 7.2 [IQR 4.5–9.6] and IL-10 – 6.7 [IQR 4.1–11.4]), and the IDA group (IL-6 – 3.4 [IQR 1.4–5.9], TNF-α – 4.6 [IQR 3.7–6] and IL-10 – 2.5 [IQR 0–5]) (p <0.05). In the ACD group, the highest correlation coefficients were found between IL-6 and erythrocytes (r = –0.74) and hemoglobin (r = –0.88), between TNF-α and erythrocytes (r = –0.66) and hemoglobin (r = –0.77), between IL-10 and erythrocytes (r = –0.36) and hemoglobin (r = –0.63). In the IDA group, the correlation coefficients between cytokines, erythrocytes, and hemoglobin are low or absent.

Conclusion. In cancer patients, ACD, IDA, as well as their combination can occur. Increased cytokine secretion in ACD group patients is important due to the proven strong negative effect of cytokines on erythropoiesis. Further study of ACD pathogenesis is needed in order to improve treatment.

1. Macciò A., Madeddu C., Gramignano G. et al. The role of inflammation, iron, and nutritional status in cancer-related anemia: results of a large, prospective, observational study. Haematologica 2015;100(1):124–32. DOI: 10.3324/haematol.2014.112813

2. Weiss G. Iron metabolism in the anemia of chronic disease. Biochim Biophy Acta 2009;1790(7):682–93. DOI: 10.1016/j.bbagen.2008.08.006

3. Sakhin V.T., Madzhanova E.R., Kryukov E.V. et al. Pathogenetic characteristics of anemia in patients with solid tumors. Klinicheskaya onkogematologiya = Clinical Oncohematology 2017;10(4):514–9. (In Russ.). DOI: 10.21320/2500-2139-2017-10-4-514-518

4. Stuklov N.I., Kozinets G.I., Tyurina N.G. Hematology tutorial. Moscow: Prakticheskaya meditsina, 2018. 336 p. (In Russ.).

5. Steinmetz T., Totzke U., Schweigert M. et al. A prospective observational study of anaemia management in cancer patients – results from the German Cancer Anaemia Registry. Eur J Cancer Care 2011;20(4):493–502. DOI: 10.1111/j.1365-2354.2010.01230.x

6. Anemia. Ed.: O.A. Rukavitsin. 2nd edn. Moscow: GEOTAR-Media, 2016. 256 p. (In Russ.).

7. Ganz T. Anemia of inflammation. N Engl J Med 2019;381(12):1148–57. DOI: 10.1056/NEJMra1804281

8. World Health Organisation. Nutritional Anemia: Report of WHO Scientific Group. Geneva, Switzerland: World health Organisation, 1968.

9. Van Santen S., Van Dongen-Lases E.C., de Vegt F. et al. Hepcidin and hemoglobin content parameters in the diagnosis of iron deficiency in rheumatoid arthritis patients with anemia. Arthritis Rheum 2011;63(12):3672–80. DOI: 10.1002/art.30623

10. Worwood M., May A. Iron deficiency anemia and iron overload. In: Dacie and Lewis Practical Haematology. Eds.: B.J. Bain, S.M. Lewis, I. Bates, M.A. Laffan). 11th edn. Philadelphia: Churchill Livingstone, 2011. Pp. 175–200. DOI: 10.1016/B978-0-7020-6696-2.00009-6

11. Sakhin V.T. Anemia of chronic disease: key mechanisms of pathogenesis in patients with malignancies and feasible classification approaches. Klinicheskaya onkogematologiya = Clinical Oncohematology 2019;12(3):344–9. (In Russ.). DOI: 10.21320/2500-2139-2019-12-3-344-349

12. McCranor B., Kim M., Cruz N. et al. Interleukin-6 directly impairs the erythroid development of human TF-1 erythroleukemic cells. Blood Cells Mol Dis 2014;52(2–3):126–33. DOI: 10.1016/j.bcmd.2013.09.004

13. Langdon J.M., Yates S.C., Femnou L.K. et al. Hepcidin-dependent and hepcidin-independent regulation of erythropoiesis in a mouse model of anemia of chronic inflammation. Am J Hematol 2014;89(5):470–9. DOI: 10.1002/ajh.23670

14. Katsoulidis E., Li Y., Yoon P. et al. Role of the p38 mitogenactivated protein kinase pathway in cytokine-mediated hematopoietic suppression in myelodysplastic syndromes. Cancer Res 2005;65(19):9029–37. DOI: 10.1158/0008-5472

15. Atkinson S.H., Rockett K.A., Morgan G. et al. Tumor necrosis factor SNP haplotypes are associated with iron deficiency anemia in West African children. Blood 2008;112(10):4276–83. DOI: 10.1182/blood-2008-06-162008

16. Nairz M., Theurl I., Swirski F.K., Weiss G. “Pumping iron” – how macrophages handle iron at the systemic, microenvironmental, and cellular levels. Pflugers Arch 2017;469(3–4):397–418. DOI: 10.1007/s00424-017-1944-8