期刊
IMMUNOBIOLOGY
卷 223, 期 2, 页码 151-161出版社
ELSEVIER GMBH
DOI: 10.1016/j.imbio.2017.10.031
关键词
CCL2; CCL5; CCL22; Th1-Th2 ratio; TGF-beta; Breast cancer
类别
资金
- DST, Government of India [DST/INT/South Africa/P-06/2014, INT/RFBR/P82]
- UGC [F.101-5/2014(IC), F117.1/201415/RGNF201415SCWES57973]
- CSIR [SRF/NET- 9/028(842)/2011- EMR-I]
We investigated expressions of -CC chemokine ligand 2 (CCL2) and CCL5 in tumor samples from 147 breast cancer (BCa) patients and correlated with transforming growth factor-beta (TGF-beta) expression. We observed an inverse correlation of TGF-beta expression with CCL2, CCL5 expression in early stages of BCa. On contrary, in late stages, CCL2, not CCL5, expression was found to be directly proportional with TGF-beta expression. TGF-beta stimulated MDA-MB-231 cells to express CCL2, however, downregulated both CCL2 and CCL5 in MCF-7. Interestingly, a significant swing of Th1-Th2 ratio towards Th2 is seen within the primary tumors expressing moderate/high-CCL2-low/negative-CCL5. We observed that CCL2-CCR2 interaction induces monocytes/macrophages to secrete Th2-attracting chemokine CCL22 in vitro. Therefore, CCL2 secreted from the tumor micro environment may attract and interact with monocytes/macrophages, and favor Th2 accumulation by inducing CCL22 secretion. Study in 4T1-BALB/c BCa mouse model demonstrated significant (p < 0.05) decrease in CCL2, CCL5 and CCL22 levels and reduction in lung metastatic nodule numbers upon administering TGF-beta inhibitor. These findings collectively indicate that TGF-beta regulates CCL2 and CCL5 expression in a stage-dependent manner during BCa progression, which in turn, determines Th1-Th2 balance within the tumor microenvironment.
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