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Iron Content and Cellular Proliferation in Thymus and Spleen of Hepatoma 22A Bearing Mice

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Abstract

It is well known, that tumor growth down-regulates T-cell immunity, but it also induces significant changes of iron metabolism. We hypothesized that iron deficiency may be one of the many factors linked to the development of immunodepression observed in tumor growth. Here for the first time we compared cellular proliferation in two lymphoid organs—thymus and spleen, with iron status of these organs in mice bearing transplantable tumor. Serum and liver iron levels were measured to evaluate general iron status. On day 21, thymus weight and cellularity started to dramatically decrease in hepatoma 22a bearing mice as compared to controls, while spleen weight and cellularity increased. Thymocyte proliferation was down-regulated in these animals, but no decrease of splenocyte proliferation was observed. At the same time, thymus non-heme iron content was higher and the spleen iron was lower in tumor mice compared to controls. It may be supposed, that spleen and thymus iron contents are sufficient to cover demands for cellular proliferation in these organs. The expression of surface transferrin receptor (CD71) on thymocytes did not diminish as well as thymus tissue catalase activity, which confirm the absence of iron deficiency in the thymus. Here we investigated parameters of iron metabolism in the thymus during the growth of transplantable tumor for the first time. Finelly, iron deficiency cannot be considered as a cause of immunological disorders, such as thymic involution and down-regulation of thymocytes proliferation, observed in mice bearing hepatoma 22a. Iron-independent mechanisms may play a role in these processes. This data elucidate one, related to iron, aspect of tumor-induced metabolic influence on the immune system.

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REFERENCES

  1. Breckelmans, P., van Soest, P., Leenen, P.J., and van Ewijk, W., Inhibition of proliferation and differentiation during early T cell development by anti-transferrin receptor antibody, Eur. J. Immunol., 1994, vol. 24, p. 2896.

    Article  Google Scholar 

  2. Carrio, R. and Lopez, D.M., Insights into thymic involution in tumor-bearing mice, Immunol. Res., 2013, vol. 57, p. 106.

    Article  CAS  Google Scholar 

  3. Chen, R. and Chen, G., Tumor-induced disorder of iron metabolism in major organs: a new insight from chemical speciation of iron, J. Int. Med. Res., 2018, vol. 46, p. 70.

    Article  CAS  Google Scholar 

  4. Eagon, P.K., Teepe, A.G., Elm, M.S., Tadic, S.D., Epley, M.J., Beiler, B.E., Shinozuka, H., and Rao, K.N., Hepatic hyperplasia and cancer in rats: alterations in copper metabolism, Carcinogenesis, 1999, vol. 20, p. 1091.

    Article  CAS  Google Scholar 

  5. Fu, Y., Paul, R.D., Wang, Y., and Lopez, D.M., Thymic involution and thymocyte phenotypic alterations induced by murine mammary adenocarcinomas, J. Immunol., 1989, vol. 143, p. 4300.

    CAS  PubMed  Google Scholar 

  6. Gagandeep Rao, A.R. and Kale, R.K., Oxidative stress in tumour-bearing fore-stomach and distant normal organs of Swiss albino mice, Ind. J. Biochem. Biophys., 2005, vol. 42, p. 216.

    Google Scholar 

  7. Hadwan, M.H. and Ali, S.K., New spectrophotometric assay for assessments of catalase activity in biological samples, Anal. Biochem., 2018, vol. 542, p. 29.

    Article  CAS  Google Scholar 

  8. Kampschmidt, R.F., Mechanism of liver catalase depression in tumor-bearing animals: a review, Cancer Res., 1965, vol. 25, p. 34.

    CAS  PubMed  Google Scholar 

  9. Kikuchi, Y., Hiramoto, R.N., and Ghanta, V., Mitogen response of peripheral blood and splenic lymphocytes and effect of 2-mercaptoethanol in tumor-bearing mice, Cancer Immunol. Immunother., 1982, vol. 12, p. 225.

    Article  Google Scholar 

  10. Kim, A., Rivera, S., Shprung, D., Limbrick, D., Gabayan, V., Nemeth, E., and Ganz, T., Mouse models of anemia of cancer, PLoS One, 2014, vol. 9, e93283.

    Article  Google Scholar 

  11. Kiseleva, E.P. and Malygin, A.M., Splenocyte functional activity in mice growing the syngeneic transplantable hepatoma 22a, Tsitologiia, 1984, vol. 26, no. 12, p. 1409.

    CAS  PubMed  Google Scholar 

  12. Kiseleva, E.P., Suvorov, A.N., and Ogurtsov, R.P., The role of apoptosis in thymic involution during growth of a syngeneic transplantable murine tumor, Biol. Bull. (Moscow), 1998, vol. 25, no. 2, p. 129.

    Google Scholar 

  13. Klecha, A.J., Salgueiro, J., Wald, M., Boccio, J., Zubillaga, M., Leonardi, N.M., Gorelik, G., and Cremaschi, G.A., In vivo iron and zinc deficiency diminished T- and B-selective mitogen stimulation of murine lymphoid cells through protein kinase C-mediated mechanism, Biol. Trace Elem. Res., 2005, vol. 104, p. 173.

    Article  CAS  Google Scholar 

  14. Kuvibidila, S.R., Nauss, K.M., Baliga, S.B., and Suskind, R.M., Impairment of blastogenic response of splenic lymphocytes from iron-deficient mice. In vitro repletion by hemin, transferrin, and ferric chloride, Am. J. Clin. Nutr., 1983, vol. 37, p. 557.

    Article  CAS  Google Scholar 

  15. Kuvibidila, S.R., Dardenne, M., Savino, W., and Lepault, F., Influence of iron-deficiency anemia on selected thymus functions in mice: thymulin biological activity, T-cell subsets, and thymocyte proliferation, Am. J. Clin. Nutr., 1990, vol. 51, p. 228.

    Article  CAS  Google Scholar 

  16. Kuvibidila, S.R., Gardner, R., Velez, M., and Yu, L., Iron deficiency, but not underfeeding reduces the secretion of interferon-gamma by mitogen-activated murine spleen cells, Cytokine, 2012, vol. 52, p. 230.

    Article  Google Scholar 

  17. Lee, Y.-M., Chang, W.-C., and Ma, W.-L., Hypothesis: solid tumours behave as systemic metabolic dictators, J. Cell. Mol. Med., 2016, vol. 20, p. 1076.

    Article  Google Scholar 

  18. Macedo, M.F., de Sousa, M., Ned, R.M., Mascaren-has, C., Andrews, N.C., and Correia-Neves, M., Transferrin is required for early T-cell differentiation, Immunology, 2004, vol. 112, p. 543.

    Article  CAS  Google Scholar 

  19. Nakahara, W. and Fukuoka, F., The newer concept of cancer toxin, Adv. Cancer Res., 1958, vol. 5, p. 157.

    Article  CAS  Google Scholar 

  20. Omara, F.O. and Blakley, B.R., The effects of iron deficiency and iron overload on cell-mediated immunity in the mouse, Br. J. Nutr., 1994, vol. 72, p. 899.

    Article  CAS  Google Scholar 

  21. Pourcelot, E., Lénonn, M., Mobilia, N., Cahn, J.-Y., Arnaud, J., Fanchon, E., Moulis, J.-M., and Mossuz, P., Iron for proliferation of cell lines and hematopoietic progenitors: nailing down the intracellular functional iron concentration, Biochim. Biophys. Acta, 2015, vol. 1853, p. 1596.

    Article  CAS  Google Scholar 

  22. Radoja, S., Rao, T.D., Hillman, D., and Frey, A.B., Mice bearing late-stage tumors have normal functional systemic T cell responses in vitro and in vivo, J. Immunol., 2000, vol. 164, p. 2619.

    Article  CAS  Google Scholar 

  23. Rashid, R.M., Achille, N.J., Lee, J.M., Lathers, D.M., and Young, M.R., Decreased T-cell proliferation and skewed immune responses in LLC-bearing mice, J. Environ. Pathol. Toxicol. Oncol., 2005, vol. 24, p. 175.

    Article  CAS  Google Scholar 

  24. Rebouche, C.J., Wilcox, C.L., and Widness, J.A., Microanalysis of non-heme iron in animal tissues, J. Biochem. Biophys. Methods, 2004, vol. 58, p. 239.

    Article  CAS  Google Scholar 

  25. Saldanha-Araujo, F. and Souza, A.M., Early effects on T lymphocyte response to iron deficiency in mice. Short communication, Biol. Trace Elem. Res., 2009, vol. 127, p. 95.

    Article  CAS  Google Scholar 

  26. Shanker, A., Singh, S.M., and Sodhi, A., Impairment of T‑cell functions with the progressive ascitic growth of a transplantable T-cell lymphoma of spontaneous origin, FEMS Immunol. Med. Microbiol., 2000, vol. 27, p. 247.

    Article  CAS  Google Scholar 

  27. Skrajnowska, D., Korczak, B.B., Tokarz, A., Kazimierczuk, A., Klepacz, M., Makowska, J., and Gadzinski, B., The effect of zinc and phytoestrogen supplementation on the changes in mineral content of the femur of rats with chemically induced mammary carcinogenesis, J. Trace Elem. Med. Biol., 2015, vol. 32, p. 79.

    Article  CAS  Google Scholar 

  28. Song, Y., Yu, R., Wang, C., Chi, F., Guo, Z., and Zhu, X., Disruption of the thymic microenvironment is associated with thymic involution of transitional cell cancer, Urol. Int., 2013, vol. 92, p. 104.

    Article  Google Scholar 

  29. Soyano, A., Candellel, D., and Layrisse, M., Effect of iron deficiency on the mitogen-induced proliferative response of rat lymphocytes, Int. Archs. Allergy Appl. Immun., 1982, vol. 69, p. 353.

    Article  CAS  Google Scholar 

  30. Vieyra-Reyes, P., Millán-Aldaco, D., Palomero-Rive-ro, M., Jiménez-Garcés, C., Hernández-González, M., and Caballero-Villarraso, J., An iron-deficient diet during development induces oxidative stress in relation to age and gender in Wistar rats, J. Physiol. Biochem., 2017, vol. 73, p. 99.

    Article  CAS  Google Scholar 

  31. Xia, A., Zhang, Y., Xu, J., Yin, T., and Lu, X.-J., T cell dysfunction in cancer immunity and immunotherapy, Front. Immunol., 2019, vol. 10. https://doi.org/10.3389/fimmu.2019.01719

  32. Youn, P., Kim, S., Ahn, J.H., Kim, Y., Park, J.D., and Ryu, D.Y., Regulation of iron metabolism-related genes in diethylnitrosamine-induced mouse liver tumors, Toxicol. Lett., 2009, vol. 184, p. 151.

    Article  CAS  Google Scholar 

  33. Zohora, F., Bidad, K., Pourpak, Z., and Moin, M., Biological and immunological aspects of iron deficiency anemia in cancer development: a narrative review, Nutr. Cancer, 2018, vol. 70, p. 546.

    Article  CAS  Google Scholar 

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Funding

This work was carried out within the framework of the planned research project of the Federal State Budgetary Scientific Institution “IEM” no. 0557-2019-0006.

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Authors and Affiliations

  1. Institute of Experimental Medicine, 197376, St. Petersburg, Russia

    E. A. Zelenskyi, K. V. Rutto, I. V. Kudryavtsev, A. V. Sokolov & E. P. Kisseleva

  2. North-Western State Medical University named after I.I. Mechnikov, 195067, St. Petersburg, Russia

    E. P. Kisseleva

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  1. E. A. Zelenskyi
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  2. K. V. Rutto
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  3. I. V. Kudryavtsev
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  4. A. V. Sokolov
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Correspondence to K. V. Rutto.

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Statement on the welfare of animals. The study followed all applicable international guidelines for the use of laboratory animals. The study was approved by the local ethical committee at the Federal State Budgetary Scientific Institution “IEM” (protocol no. 2/15 dated February 26, 2015).

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Zelenskyi, E.A., Rutto, K.V., Kudryavtsev, I.V. et al. Iron Content and Cellular Proliferation in Thymus and Spleen of Hepatoma 22A Bearing Mice. Cell Tiss. Biol. 15, 393–401 (2021). https://doi.org/10.1134/S1990519X21040118

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  • DOI: https://doi.org/10.1134/S1990519X21040118

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