CYTOKINE-PRODUCING RESERVE OF IMMUNOCOMPETENT CELLS FROM BLOOD AND INVASIVE DUCTAL BREAST CANCER TISSUES: ITS CORRELATION WITH HISTOPATHOLOGICAL AND IMMUNOHISTOCHEMICAL PARAMETERS OF MALIGNANT NEOPLASIA

The aim of the study was to investigate a relationship between cytokine-producing reserve of invasive ductal cancer cells and its microenvironment, and cytokine-producing reserve of immunocompetent blood cells (IBC), as well as with histopathological and immunohistochemical characteristics of breast cancer. Using ELISA method we investigated the spontaneous and stimulated with polyclonal activators (PA) cytokine-producing reserve of IBC and biopsy specimens from invasive ductal cancer (adenocarcinoma) in 34 women. Appropriate values were expressed by the Influence Index of polyclonal activators (IIPA) upon cytokine production (IL-2, IL-6, IL-8, IL-10, IL-17, IL-18, IL-1β, IL-1ra, TNFα, IFNγ, G-CSF, GM-CSF, VEGF-A, MCP-1). In tumor biopsies, we studied expression of VEGF-A, estrogen receptor, progesteron receptor and pro-proliferation marker Ki-67 by means of immunohistochemical method. Activation values of blood IBC in most cases, except of IL-18, IL-1β and MCP-1, were higher than appropriate effects upon cytokine production by tumor tisuues. Meanwhile, the IIPA activation index upon IL-18 (a proinflammatory and prooncogene cytokine) production by tumor cells and its microenvironment proved to be elevated, as compared to appropriate IIPA by the blood IBC. Statistical studies showed a direct correlation between IIPA and cytokine production in tumor supernates, IIPA of VEGF-A expression in tumor tissue, with pathohistological parameters and expression of estrogen and progesterone receptors and Ki-67 proliferation marker. A high positive correlation was obtained between IIPA TNFα production by the tumor tissue, and degree of tumor vascularization.

We have revealed a negative correlation between IIPA for IL-6, MCP-1 and Ki-67 marker of cell proliferation. A direct correlation was found between IIPA values for IL-1ra/IL-1β production ratios in blood cells, and IIPA for VEGF-A expression in adenocarcinoma tissues, thus indicating to probable connections between IL-1ra production by IBC and VEGF-A expression. We have discerned several intersecting, diverging, and even circle-closed correlative chains of correlation, e.g.: VEGF-A (immunohistochemical marker of IIPA expression) – IL-10 and IL-8 (IIPA for supernate products); MCP-1, IL-6, and IL-10 (IIPA for supernate products)– VEGF-A (immunohistochemical indicator of expression for IIPA). The results of this study suggest a relationship between cytokine-producing reserves of the tumor identified by appropriate PA correlations with the processes occurring in malignant tumors, as assessed by histopathological and immunohistochemical parameters. The data are indicative for some complex mechanisms mediated by cytokines which provide invasive growth of malignant tumor.

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