PRODUCTION OF PROINFLAMMATORY CYTOKINES AND ALPHA-2-MACROGLOBULIN BY PERIPHERAL BLOOD CELLS IN THE PATIENTS WITH COLORECTAL CANCER

Colorectal cancer (CRC) is the third most common cancer worldwide, being quite complicated, with respect to diagnostics and postoperative prognosis. Proinflammatory cytokines are shown to be involved into CRC pathogenesis. However, the changes in alpha-2-macroglobulin (α2-MG), a known regulator of cytokine production, still remain unclear. The aim of this work was to compare contents and production of a2-MG and several pro-inflammatory cytokines in blood serum and supernates from short-term blood cell cultures. The samples were taken from the patients with CRC at initial terms and after surgical removal of the tumor.

Studies of cytokines and a2-MG concentrations in serum and supernates of 24-h blood cell cultures from the patients with verified CRC (stages T2-3N0-1M0 and T4N0-1M0) have shown some sufficient differences from healthy volunteers (control group). Pre-surgery IL-6 and TNFα contents in blood of CRC patients was significantly increased agains healthy controls (respectively, 29.9±5.4 and 3.4±1.5 pg/mL) versus control group (1.0±0.3 and 0 pg/mL, respectively). Following surgical treatment, the cytokine levels were decreased by 40- 60% after the operation, however, without significant differences from initial values.

The supernates of blood cultures stimulated with polyclonal mitogens exhibited significant reduction of IFNγ levels prior to surgery (273±123 pg/ml versus 804±154 pg/mL), and elevated IL-6 levels (14412±2570 pg/mL versus 1970±457 pg/mL). The mean α2-MG concentrations before CRC surgery comprised 1.96±0.11 g/L for blood serum, 0.0304±0.0047 g/L, for non-stimulated blood cell cultures, and 0.0300±0.0052 g/L in mitogen-induced cultures. These parameters did not significantly differ from control values (2.21±0.17 g/L, 0.0328±0.0018 g/L, and 0.0314±0.0019 g/L, respectively). Similar results have been yielded with the samples obtained after surgical treatment of the CRC patients.

The obtained data indicate that surgical treatment of CRC does not lead to normalization of the serum levels and secretion of pro-inflammatory IL-6 and TNFα cytokines by the patients’ blood cells. Marginal changes in a2-MG levels in colorectal cancer seem to be not of such importance, as functional state of the molecules which may abnormally respond to changing cytokine contents. The revealed post-surgical suppression of mitogen-induced IFNγ secretion makes it necessary to suggest administration of IFNγ and IL-2 after surgical treatment of CRC.

1. Зорин Н.А., Зорина В.Н., Зорина Р.М. Роль белков семейства макроглобулинов в регуляции опухолевого роста (Обзор литературы) // Онтогенез, 2006. Т. 37, № 1. C. 12-19. [Zorin N.A., Zorina V.N., Zorina R.M. Role of proteins of the macroglobulin family in regulation of tumor growth. Ontogenez = Ontogenesis, 2006, Vol. 37, no. 1, pp. 12-19. (In Russ.)]

2. Кит О.И., Франциянц Е.М., Козлова Л.С., Терпугов А.Л. Серпины в гиперпластических тканях толстой кишки // Экспериментальная и клиническая гастроэнтерология, 2014. № 10. C. 18-21. [Kit O.I., Frantsiiants E.M., Kozlova L.S., Terpugov A.L. Serpins in hyperplastic colon tissue. Eksperimental`naya i klinicheskaya gastroenterologiya = Experimental and Сlinical Gastroenterology, 2014, no.10, pp.18-21. (In Russ.)]

3. Соснина А.В., Аутеншлюс А.И., Великая Н.В., Вараксин Н.А., Рукавишников М.Ю., Михайлова Е.С. Морозов Д.В., Фурсов С.А., Агарина Н.В. Цитокинпродуцирующая функция клеток периферической крови у больных колоректальным раком // Медицинская иммунология, 2011. Т. 13, № 2-3. C. 197-204. [Sosnina A.V., Aytenshlyus A.I., Velikaya N.V., Varaksin N.A., Rukhavishnikov M.Yu., Mikhailova E.S., Fursov S.A., Agarina N.V.

4. Cytokine-producing function of peripheral blood cells in colorectal cancer patients. Meditsinskaya immunologiya = Medical Immunology (Russia), 2011, Vol. 13, no. 2-3, pp. 197-204. (In Russ.)] http://dx.doi.org/10.15789/1563-0625-2011-2-3-197-204

5. Фрейдлин И.С. Паракринная и аутокринные механизмы цитокиновой иммунорегуляции // Иммунология, 2001. № 5. С. 4-7. [Freidlin I.S. Paracrine and autocrine mechanisms of cytokine immunoregulation. munologiya = Immunology, 2001, no. 5, pp. 4-7. (In Russ.)]

6. Amor S., Iglesias-de la Cruz M.C., Ferrero E., García-Villar O., Barrios V., Fernandez N., Monge L., GarcíaVillalón A.L., Granado M. Peritumoral adipose tissue as a source of inflammatory and angiogenic factors in colorectal cancer. Int. J. Colorectal Dis., 2016, Vol. 31, no. 2, pp. 365-375.

7. Khare P., Bose A., Singh P., Singh S., Javed S., Jain S.K., Singh O., Pal R. Gonadotropin and tumorigenesis: Direct and indirect effects on inflammatory andimmunosuppressive mediators and invasion. Mol. Carcinog., 2016 [Epub ahead of print].

8. Pietrzyk L., Torres A., Maciejewski R., Torres K. Obesity and Obese-related Chronic Low-grade Inflammation in Promotion of Colorectal Cancer Development. Asian Pac. J. Cancer Prev.. 2015, Vol. 16, no. 10, pp. 4161-4168.

9. Sparreboom C.L., Wu Z., Dereci A., Boersema G.S., Menon A.G., Ji J., Kleinrensink G.J., Lange J.F. Cytokines as Early Markers of Colorectal Anastomotic Leakage: A Systematic Review and Meta-Analysis. Gastroenterol. Res. Pract., 2016, 3786418.

10. Šunderić M., Đukanović B., Malenković V., Nedić O. Molecular forms of the insulin-like growth factorbinding rotein-2 in patients with colorectal cancer. Exp. Mol. Pathol., 2014, Vol. 96, no. 1, pp. 48-53.