The Mechanisms Of Triggering Of TLR4on Metastasis Breast Cancer Cells Promotes Invasion And TGF-β/TNF-α Accentuate The EMT Of Non-metastasis Breast Cancer Cells

Metastasis was the main reason for the tumor recurrence and death. The metastasis of breast cancer has been the leading course of death in patients. In recent years, the role of tumor microenvironment in tumor metastasis has been increasingly important. The tumor microenvironment consists of the vasculature, stomal cells, immune cells and the extracellular matrix, together with abnomal physiological environment, such as hypoxia and acidic extracellular PH, influences a range of phenotypic traits of cancer, including invasion, metastasis and response to therapy. It has become increasingly clear that the chronic inflammation of tumor environment is tightly correlated with tumorigenesis. As cancer has been viewed as a "a wound that never heals". Mounting evidence from various clinical and experimental studies has demonstrated that the inflammatory tumor microenvironment contributes a pivotal role not only to tumor development but also to the metastasis. The inflammation of tumor microenvironment contains cytokines, chemokines and enzymes which mediate the inflammation process. The molecules released from the tumor cells necrosis (DTC-Ms) can active the immune cells to reconstitute response and promotes the metastasis of tumor. Simultaneously, the inflammation cytokine in tumor microenvironment can promote the malignant of the tumor. Here, we will find out how do the DTC-Ms and inflammation cytokines promote the malignant of tumor.Part I The mechanisms of triggering of TLR4on metastasis breast cancer cells promotes invasion and metastasis by extracellular molecular from tumor microenvironment. Because of the high metabolize and hypoxia of the tumor, many tumor cells necrosis in the tumor tissue. There are many molecules released from the necrosis tumor cells, which include the ligand of Toll like receptor4(TLR4), such as HSP70, HMGB1et al. And the bacterial in the tumor tissue also include the ligand of TLR4. As the TLR4is broadly expressed on the tumor cells, these ligands can active the TLR4on the tumor cells. Now, researchers have found that triggering the TLR4on the tumor cells can promote the proliferation and apoptosis resistant. Consistantly, triggering TLR4can promote the immune escape of tumor cells. All of these can promote the progression of tumor. At the same time, silencing TLR4could reduce the metastasis potential of metastatic tumor cells, implying that TLR4signaling might be able to regulate the expression of the gene with functional relevance to invasion capacity of metastatic tumor cells. However, the effect of TLR4signaling on tumor metastasis has not been well elucidated. In this study, we use frezze-thaw of tumor cell to acquire the DTC-Ms. We also use lipoplysaccharide (LPS) as a positive control of TLR4ligand. We found that the DTC-Ms or LPS can promotes the invasion and metastasis of metastatic breast cancer cells. Further more, we show that both LPS and DTC-Ms could promote aVP3-mediated adhesion and invasion migration of metastatic breast cancer cells by up-regulation the expression of integrinaV(33and down-regulating the expressions of metastasis-suppressor TPM1and maspin through NF-kB signaling pathway.PartⅡ The mechanism of the synergistic effect between TGF-β1and TNF-a in induced EMT and invasion of breast cancer cells. Tumor cells undergo EMT can facilitate the metastasis of tumor. EMT can promote the dissociation of tumor cells from the primary tumor. EMT cells are responsible for degrading the surrounding matrix to ennable invasion and intravasation of both EMT and non-EMT cells. Both of TGF-β1and TNF-a are the inflammation related cytokine. Interestingly, both of them can induce tumor epithelial cells EMT, which can potentiate the metastsis ability of the tumor cells, In this study, we will wonder to know if co-stimulate with TGF-β or TNF-a can induce EMT of breast cancer cell and whether they have synergistic...