The Study Of The Tumor Associated Macrophage And Semaphorin 4D In Triple-negative Breast Cancer

ObjectiveTriple negative breast cancer(TNBC)is a special type of breast cancer with high heterogeneity that the expression of endocrine receptors(ER),progesterone receptors(PR)and human epidermal growth factor receptor-2(HER2)are negative.Accounting for approximately 20 percent of all types of breast cancer,it is characterized by a young age of onset,high histological grade,high metastatic recurrence rate and poor prognosis.Due to the lack of endocrine therapy and anti-HER2 receptor targets,there is no targeted treatment currently.Therefore,it is the fundamental solution that finding the right molecular target as the treatment of TNBC to improve its prognosis.Tumor associated macrophages(TAMs)is an important component of the tumor microenvironment and account for about 80% of all stromal cells.Macrophages have a series of unique cell surface markers that secrete cytokines to modulate immunity.They exist in both the perivascular and avascular regions and often accumulate in the hypoxic regions of tissues.Secreting a variety of tumor-promoting factors such as vascular endothelial growth factor(VEGF),thereby TAMs in tumor tissues play a role in promoting the formation of peritumoral vascular and lymphatic vessels and promoting the progression of tumor invasion and metastasis.The invasiveness of tumor including breast cancer,stomach and colorectal cancer,pancreatic cancer,lung cancer,tongue squamous cell carcinoma,malignant glioma and prostate cancer was enhanced by TAMs through different molecular pathways.However,only a few studies have shown that tumor associated macrophages(TAMs)play an important role in the development of triple negative breast cancer.It is worth noting that TAMs play an important role in promoting tumorigenesis by promoting angiogenesis.Semaphorin4D(SEMA4D),also known as CD100,is a crucial member of the Semaporin IV subfamily and plays a significant biological role in promoting tumor angiogenesis and the development and metastasis of tumors.SEMA4 D is highly expressed on various solid tumor cells,including head and neck squamous cell carcinoma,soft tissue sarcoma,prostate cancer,gastric cancer,colon cancer,and ovarian cancer.Binding to its receptor Plexin B1,SEMA4 D is on the surface of endothelial cells and thereby plays a role in promoting the formation of blood vessels,stimulating the activation and migration of endothelial cells,and promoting the migration and invasion of tumor cells.SEMA4 D plays an important role in the intricate interactions between tumor cells and tumor-associated macrophages.Studies have shown that TAMs can influence the expression of SEMA4 D in tumor tissues.At present,although there are studies on tumor-associated macrophages and Semaphorin4 D,the expression and relationship between the two have not been reported in triple-negative breast cancer.In this study,the expression of TAMs and SEMA4 D in TNBC was detected by immunohistochemical staining,then the clinical pathological features of TNBC,the relationship between the expression of TAMs and SEMA4 D and the clinicopathological features of breast cancer,and the correlation of TAMs and SEMA4 D expression were analyzed.Thereby the expression and correlation of TAMs and SEMA4 D in triple negative breast cancer were preliminarily elucidated.Methods 110 cases of triple-negative breast cancer from January 2007 to December 2011 were randomly selected as the experimental group in the Department of Breast Cancer Pathology and Research Laboratory,Tianjin Medical University Cancer Hospital.106 cases of non-specific invasive ductal carcinoma(IDS-NOS)were used as controls selected in the same period.Immunohistochemical staining(IHC)was performed on all of the cases to detect the expression of Semaphorin4 D and VEGF in tumor cells and the expression of tumor-associated macrophages(TAMs)which was marked by CD68 at the histological levels.Both the expression and correlation of TAMs and SEMA4 D in the two groups,their correlations with each clinical pathological parameters were analyzed.Results1.Compared with non-triple negative breast cancer,triple negative breast cancer has higher lymph node metastasis rate(P = 0.001)and recurrence metastasis rate(P =0.023),and the expression levels of CD68 and SEMA4 D protein are higher(P = 0.015,P = 0.0131),the difference was statistically significant;2.The positive rate of CD68 in triple negative breast cancer was 72.17%,which was significantly higher than that of non-triple negative breast cancer(60%),?2=5.377,p<0.05,the difference was statistically significant.And the positive expression rate of SEMA4 D in triple negative breast cancer was 63.48%,which was significantly higher than that of non-triple negative breast cancer(49.52%),?2=5.838,p<0.05,the difference was statistically significant.3.The correlation between tumor-associated macrophage expression(CD68)and triple negative breast cancer was statistically significant(P<0.05),but there was no significant correlation between with other clinical pathological parameters such as age,tumor size,histological grade,the expression of three hormone receptors,lymph node metastasis,and recurrence or metastasis.The expression of SEMA4 D protein was related to age(P=0.008),ER receptor(P=0.041),triple negative or not(P=0.013),lymph node metastasis(P=0.049),and whether recurrence or metastasis(P=0.012).The differences were statistically significant;4.SEMA4 D expression in breast cancer tissues was positively correlated with tumor-associated macrophage(CD68 expression)in the tumor microenvironment(r=0.191,P=0.002),and the difference was statistically significant;5.The expression of SEMA4 D in breast cancer tissues was positively correlated with the expression of vascular endothelial growth factor(VEGF)(r=0.357,P<0.001),the difference was statistically significant;similarly,the TAMs expression of breast cancer tumor microenvironment was also positively correlated with vascular endothelial growth factor(VEGF)(r=0.217,P=0.001),and the difference was statistically significant.6.The expression of SEMA4 D and CD68 all had an impact on the prognosis of patients with triple negative breast cancer,but multivariate survival analysis showed that only the presence or absence of triple negative and SEMA4 D expression affected the patient's disease-free survival(DFS)and overall survival(OS).Conclusions1.Lymph node metastasis,recurrence and metastasis of triple-negative breast cancer are more likely than non-triple negative breast cancer.The expression of tumor-associated macrophages and SEMA4 D protein in triple-negative breast cancer is higher than in the non-triple negative breast cancer;2.The expression of tumor-associated macrophages was only related to whether it was triple-negative breast cancer,but the expression of SEMA4 D protein was related to age,ER receptor,triple negative or not,lymph node metastasis,and whether it was recurrence or metastasis;3.The expression of SEMA4 D in breast cancer tissues is related to tumor-associated macrophages in the tumor microenvironment.The tumor-associated macrophages may promote the expression of SEMA4 D through a certain pathway;4.The expression of SEMA4 D in breast cancer tissues and TAMs in the tumor microenvironment may promote the expression of vascular endothelial growth factor(VEGF),thereby promoting peritumoral angiogenesis and affecting the tumor progression;5.The effect of SEMA4 D expression on the prognosis of triple-negative breast cancer patients is significant,and the impact of tumor-associated macrophages on the prognosis of triple-negative breast cancer patients is not yet clear in this study.