الفهرس 
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Abstract
Breast cancer is the most frequently occurring cancer in women worldwide. In Egypt, breast cancer ranks the first among cancer affecting females with incidence of 38.8% among female cancers.
There are several evidences that tumor microenvironment (TME) is consisting of the tumor bulk plus supporting cells. It is becoming increasingly evident that these supporting cells which are recruited by cancer cells promote events such as tumor angiogenesis, proliferation, invasion and metastasis as well as mediating mechanisms of therapeutic resistance. Tumor growth and metastasis are promoted via secretion of cytokines and chemokines mainly IL-6.
Many human cancers are driven by CSCs which are a highly tumorigenic cells existing as a minority population within tumors and have been hypothesized to be key drivers of cancer. The inability of conventional therapies to target CSCs has been suggested as a reason for tumor recurrence.
CSCs are self-renewal under non-differentiation conditions and can differentiate into non-stem cancer cells (NSCCs). CSCs and NSCCs represent distinct stable cell types that co-propagate independently. The two cell types can switch from one type to the other under the effect of IL-6 in a dynamic equilibrium maintaining the proportion of CSCs.
So, the current study aimed at investigating the dynamic interactions between cancer stem cells (CSCs), non-stem cancer cells (NCSCs) and breast cancer cells within intact tumor microenvironment.
This study was conducted on 30 patients with pathologically proved breast carcinoma. Tumor samples were obtained and cultured in absence and presence of appropriate different concentrations of IL-6. CD24 and CD44 expression were immunohistochemically evaluated as CSCs and NSCCs markers.
Results of the study revealed that:
Statistical significant increase in CD24 expression was found in tumor tissue cultured samples incubated with IL-6 of concentration 10µg/50 mm3 tissue than those incubated without IL-6 (p1 = 0.043), while non-significant differences have been found between CD24 expression in tumor tissue cultured samples incubated with other different IL-6 concentrations (10,25, 50, 100µg/50 mm3 tissue)
Regarding CD44 expression, our results showed significant increase in tumor tissue cultured samples incubated with 25, 50, 100µg/50 mm3 tissue of IL-6 than untreated samples (p1=0.0233, 0.011, 0.0233 respectively), while non-significant differences have been found between CD44 expression in tumor tissue cultured samples incubated with other different IL-6 concentrations(10,25, 50, 100µg/50 mm3 tissue)
Our study also showed that statistical significant decrease in CD24 expression is found in breast normal tissue samples incubated without IL-6 than those treated with IL-6 of concentration 10, 25, 50, 100µg/50 mm3 tissue (p1 = 0.001, 0.005, 0.002, 0.037), also statistical significant decrease in CD24 expression is found in breast normal tissue samples
incubated with IL-6 of concentration 10µg/50 mm3 tissue than those treated with IL-6 of concentration 100µg/50 mm3 tissue (p2 = 0.022), while non-significant differences have been found between CD24 expression in normal tissue cultured samples incubated with other different IL-6 concentrations (10, 25, 50, 100µg/50 mm3 tissue)
CD 44 expression showed significant decrease in breast normal tissue incubated without IL-6 than those incubated with IL-6 of concentrations 25,100µg/50 mm3 samples (p1=0.037, 0.043 respectively), while non-significant differences have been found between CD44 expression in normal tissue cultured samples incubated with other different IL-6 concentrations (10,25, 50, 100µg/50 mm3 tissue).
As regard comparing between CD24 and CD44 expression in breast tumor tissue cultures ,our results revealed a significant difference between CD24 and CD44 expression in untreated breast tumor tissue culture samples (p=0.0042). Significant differences have been found in breast tumor tissue cultures treated with IL-6 of concentrations 10, 25, 50 and 100µg/50 mm3 tissue between the two studied markers (p= 0.002, 0.00001, 0.00001, 0.0001 respectively).
Regarding the correlation between the two studied cell surface markers CD24 and CD44 in breast normal tissue cultured samples, statistical significant correlation was recorded in cultured samples incubated without IL-6 (p=0.041). Non-significant differences have been found between CD24 and CD44 expression in breast normal tissue cultured samples incubated with IL-6 of concentrations 10, 50 and 100µg/50 mm3 tissue (p= 0.588, 0.925, 0.051 respectively). In addition, statistical significant difference has been found between CD24 and CD44 expression in breast normal tissue cultured samples incubated with IL-6 of concentration 25µg/50 mm3 tissue (p= 0.04)
No significant associations were found between expression of either CD24 or CD44 in untreated or treated breast tumor cultured tissues and their corresponding normal ones in our study.
Correlating the CD24 and CD44 expression in breast tumor cultured tissue with patients clinicopathological parameters in our study, results revealed that the only significant difference was found between CD24 expression in grade II and grade III in samples incubated without IL-6 (p=0.005). A significant difference was found between CD24 expression in -ve and +ve lymph node invasion in samples incubated with 100 µg/50 mm3 tissue (p= 0.029). Meanwhile, non-significant difference was recorded between CD24 expression in -ve and +ve vascular invasion in samples incubated either without or with IL-6.
Interestingly, no significant differences were recorded between CD44 expression and any of clinicopathological parameters of the patients under our current study.
Accordingly, we can conclude that there is an IL-6 dependent dynamic interaction between cancer stem cells (CSCs), non-stem cancer cells (NCSCs) and breast cancer cells within breast tumor tissue culture system simulating tumor microenvironment of the patients under the current study. Targeting this interaction could be a remarkable step for an effective breast cancer immunotherapeutic approach.
The Linear correlation chart which illustrates the different CD24 and CD44 expressions at different IL-6 concentrations signify the core of our current study which is confirming the dynamic interactions between CSCs and NSCCs at IL-6 of concentrations 50, 100 µg/50 mm3 tissue at which high degree of stemness appear .