CORRELATION BETWEEN CYTOKINE CONTENT IN LYMPH OF THORACIC LYMPH DUCT AND MESENTERIC LYMPH NODE STRUCTURAL TRANSFORMATIONS IN EXPERIMENTAL MAMMARY TUMOR AND CHEMOTHERAPY

The aim of the study was to fulfill correlation analysis of morphometry of the mesenteric lymph nodes and the concentration of cytokines in the lymph of the thoracic duct in breast cancer induced by intramammary administration of N-methyl-N-nitrosourea, chemotherapy according to the CMF scheme (cyclophosphamide, methotrexate, 5-fluorouracil). The results of the study. At breast cancer revealed positive correlation: in the germinative centers and medullary cords of cytokine IL-5 with mitotically dividing cells, chemokines MIP-1α with average lymphocytes, in the germinative centers of immunoblasts with cytokine GRO/KC, in the paracortical zone chemokine MCP-1 with macrophages, reticular cells with IL-6 and M-CSF, in the medullary sinuses chemokine GRO/KC with small lymphocytes and mature plasma cells (number which decreases). All this may indicate the activity of the local immune response in the lymph nodes aimed on the antitumor protection. After chemotherapy of breast cancer, compared with breast cancer without treatment, revealed positive relationship, which may indicate increased immunomodulatory and antitumor actions of cytokines: correlation of interferon IFNγ with small lymphocytes (number which increased) and macrophages in the germinative centers and mitotically dividing cells in the medullary cords, correlation in the germinative centers of immunoblasts with MIP-1α and increased of number small lymphocytes in T-dependent zone lymph nodes, correlation in medullary cords of interleukin IL-17 with mature plasma cells (number which increased) , correlation of interleukin IL-18 with mature plasma cells in medullary sinuses. Conclusion. Study of the correlation of the concentration of cytokines in the lymph of the thoracic duct with structural changes in the mesenteric lymph nodes revealed dependencies aimed at increasing the immunomodulating and antitumor effects of cytokines.

1. Kabakov A.V., Lykov A.P., Morozov D.V., Kazakov O.V., Poveshchenko A.F., Rayter T.V., Strunkin D.N., Konenkov V.I. Phenotypical characteristics of chemically induced mammary tumor. Bull. Exp. Biol. Med. 2017; 163 (4): 490–492. doi: 10.1007/s10517-017-3835-6.

2. Ketlinskiy S.A., Simbirtsev A.S. Cytokines. Sankt-Peterburg: Foliant, 2008. [In Russian].

3. Poveshchenko A.F., Kazakov O.V., Orlov N.B., Poveshchenko O.V., Kim I.I., Bondarenko N.A., Solovyova I.G., Strunkin D.N., Kabakov A.V., Rayter T.V., Lykov A.P., Bogachev S.S., Pokushalov E.A., Konenkov V.I. Cytokines of lymph as markers of cancer progression and effectiveness of therapy in experimental breast tumors of rats WISTAR. Patologicheskaya fiziologiya i eksperimental’naya terapiya = Pathological Physiology and Experimental Therapy. 2016; 60 (3): 68–75. [In Russian].

4. Sosnina A.V., Velikaya N.V., Autenshlyus A.I. The role of cytokines in the pathogenesis of malignant neoplasms. Novosibirsk: Vektor-Best, 2013. 80 p. [In Russian].

5. Shipilov M.V., Ivanov V.V. Th17 response of an organism in acute respiratory viral infections of various origins. Tsitokiny i vospalenie = Cytokines and Inflammation. 2012; 11 (1): 109–113. [In Russian].

6. De Luca A., Gallo M., Aldinucci D., Ribatti D., Lamura L., D’Alessio A., de Filippi R., Pinto A., Normanno N. Role of the EGFR ligand/receptor system in the secretion of angiogenic factors in mesenchymal stem cells. J. Cell Physiol 2011; 226 (8): 2131–2138. doi: 10.1002/jcp.22548.

7. De Luca A., Lamura L., Gallo M., Maffia V., Normanno N. Mesenchymal stem cell-derived interleukin-6 and vascular endothelial growth factor promote breast cancer cell migration. J. Cell Biochem. 2012; 113 (11): 3363–3370. doi: 10.1002/jcb.24212.

8. Esendagli G., Yilmaz G., Canpinar H., Gunel-Ozcan А., Guc M., Guc D. Coexistence of different tissue tumourigenesis in an N-methyl-N-nitrosoureainduced mammary carcinoma model: a histopathological report in Sprague-Dawley rats. Lab. Animals. 2009; 43 (1): 60–64. doi: 10.1258/la.2008.007076.

9. Harrel M.I., Iritani B.M., Ruddell A. Tumorinduced sentinel lymph node lymphangiogenesis and increased lymph flow precede melanoma metastasis. Am. J. Pathol. 2007; 170 (2): 774–786. doi: 10.2353/ajpath.2007.060761.

10. Ikezawa Y., Nakazawa M., Tamura C., Takahashi K., Minami M., Ikezawa Z. Cyclophosphamide decreases the number, percentage and the function of CD25+ CD4+ regulatory T cells, which suppress induction of contact hypersensitivity. J. Dermatol. Sci. 2005; 39 (2): 105–112. doi: 10.1016/j.jdermsci.2005.02.002.

11. Meneses A., Verastegui E., Barrera J.L., de la Garza J., Hadden J.W. Lymph node histology in head and neck cancer: Impact of immunotherapy with IRX-2. Int. Immunol. 2003; 3 (8): 1083–1091. doi: 10.1016/S1567-5769(03)00017-1.

12. Merendino R.A., Gangemi S., Ruello A., Bene A., Losi E., Lonbardo G., Purello-Dambrosio G. Serum levels of interleukin-18 and sICAM-1 in patients affected by breast cancer: preliminary considerations. Int. J. Biol. Markers. 2001; 16 (2): 126–129.

13. Molloy A.P., Martin F.T., Dwyer R.M., Griffin T.P., Murphy M., Barry F.P., O’Brien T., Kerin M.J. Mesenchymal stem cell secretion of chemokines during differentiation into osteoblasts, and their potential role in mediating interactions with breast cancer cells. Int. J. Cancer. 2009; 124 (2): 326–332. doi: 10.1002/ijc.23939.

14. Sugama S., Conti B. Interleukin-18 and stress. Brain Res. Rev. 2008; 58 (1): 85–95. doi: 10.1016/j.brainresrev.

15. Dhesy-Thind S., Fletcher G.G., Blanchette P.S., Clemons M.J., Dillmon M.S., Frank E.S., Gandhi S., Gupta R., Mates M., Moy B., Vandenberg T., van Poznak C.H. Use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer: A Cancer Care Ontario and American Society of Clinical Oncology clinical practice guideline. J. Clin. Oncol. 2017; 35 (18): 2062–2081. doi: 10.1200/JCO.2016.70.7257.

16. Su Y.C., Rolph M.S., Cooley M.A., Sewell W.A. Cyclophosphamide augments inflammation by reducing immunosuppression in a mouse model of allergic airway disease. J. Allergy Clin. Immunol. 2006; 117 (3): 635–641. doi: 10.1016/j.jaci.2005.10.042.

17. Takatsu K. Interleukin 5 and B cell differentiation. Cytokine Growth Factor Rev. 1998; 9: 25–35.

18. Tsubura A., Lai Y.C., Miki H., Sasaki T., Uehara N., Yuri T., Yoshizawa K. Animal models of NMethyl-N-nitrosourea-induced mammary cancer and retinal degeneration with special emphasis on therapeutic trials. In Vivo. 2011; 25 (1): 11–22.