الفهرس 
TitleOnly 14 pages are availabe for public view
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Abstract
cancer worldwide, representing 11.7% of all cancer cases and 6.9% of total cancer deaths among females. In Egypt, it is estimated that approximately 22038 (32.4%) new cases of breast cancer were diagnosed in Egyptian women, with a mortality rate of approximately 10.3%. Breast cancer estimations and predictions indicated 704 instances in Alexandria in 2020, with a continuous increase in cases.
Neutrophils are the most prominent type of granulocyte and play an important role in inflammatory reactions. These leukocytes were discovered to be capable of a unique immunological response in which they eject their DNA and internal components such as myeloperoxidase, metalloproteinases, and elastase in a web-like structure known as neutrophil extracellular traps (NETs). NETosis was found as a new immunological response to bacterial infection, but it has now been revealed to occur improperly in a range of other inflammatory disease states, including cancer.
NETs have been found in the blood and tumors of both animal models and patients, where they may serve as pro- or anti-tumoral factors depending on the immune system’s or tumor microenvironment’s condition. NETosis has been associated to increased disease progression and metastasis in breast cancer. Furthermore, NETosis focused treatments have demonstrated efficacy in preclinical cancer models and may represent useful therapeutic targets in slowing or stopping tumor development in breast cancer patients. In vitro mechanistic studies revealed that mouse neutrophil-derived NETs triggered Toll-like
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receptor 9 (TLR9) dependent pathways in cancer cells, promoting adhesion, proliferation, migration, and invasion.
TLR9 is a cellular DNA receptor of the innate immune system that recognizes DNA and causes an inflammatory response. TLR9 mRNA is expressed in a variety of cancer cells, including breast, brain, stomach, and renal cell carcinomas. TLR9 binding has been demonstrated to activate numerous pathways in tumor cells, including the NF-kB, MAPK, and STAT3 pathways, resulting in increased cancer cell proliferation and survival. More significantly, TLR9 suppression might effectively block these pathways, offering a potential preclinical signal for novel treatment in certain malignancies.
So, we aimed in this study to determine the effect of TLR9-inhibitors on NETosis interactions among patients with different stages of breast cancer. In addition, all parameters were correlated with one another as well as with the disease’s clinicopathological features.
The current study included 45 females who were divided into 30 breast cancer patients in different stages of disease and 15 age-matched healthy females as a control group. All patients were recruited from the Medical Research Institute Alexandria University’s surgery Department outpatient clinic or ward, as well as Cancer Management and Research Department. Venous blood samples in heparin vacutainers were obtained from each female under study for the isolation of peripheral blood polymorphonuclear neutrophils and the quantification of myeloperoxidase (MPO) and neutrophil elastase (NE) in cultured neutrophils with and without TLR9-inhibitor using an enzyme-linked immunosorbent assay (ELISA) and for biochemical investigations.
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The results showed that there was no statistically significant difference in tumor grade, tumor types, vascular invasion, and the hormonal receptors status (ER and PR) or HER2 expression between early and late stages in breast cancer patients. While there was a statistically significant difference regarding tumor size and lymph node involvement in different stages of breast cancer patients.
The present study revealed a statistical significant increase in the means of both NE and MPO concentrations in untreated neutrophils of late stage compared to both early stage and healthy individuals where these concentrations were markedly increased in early stage compared to healthy individuals. In addition, there was a significant decrease in the means of both NE and MPO concentrations in neutrophils treated with anti-TLR9 in the early stages compared to the late stages as well as in healthy individuals compared to both the early and late stages.
In both untreated and treated neutrophils, a significant association was demonstrated between both NE and MPO concentrations and different clinicopathological parameters including tumor grade, lymph node involvement, vascular invasion, and HER2 expression in different stages of breast cancer patients. On the other hand, no statistical significant association was observed between both NE and MPO concentrations and other parameters (age, tumor type, and hormonal receptors status) in breast cancer patients.
Finally, a significant positive correlation was observed between NE and MPO concentrations in untreated and treated neutrophils with TLR9- inhibitor in all patients as well as in early and late stages in breast cancer patients.