Elevated CD163 + /CD68 + Ratio at Tumor Invasive Front is Closely Associated with Aggressive Phenotype and Poor Prognosis in Colorectal Cancer

• Published in: International journal of biological sciences 2019-01, Vol.15 (5), p.984-998
• Main Authors: Yang, Chaogang, Wei, Chen, Wang, Shuyi, Shi, Dongdong, Zhang, Chunxiao, Lin, Xiaobin, Dou, Rongzhang, Xiong, Bin
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD - metabolism; Antigens, Differentiation, Myelomonocytic - metabolism; Biological effects; Blood circulation; Cancer; CD163 antigen; Cell culture; Cell Differentiation - genetics; Cell Differentiation - physiology; Cell Line; Cell proliferation; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - metabolism; Crosstalk; E-cadherin; Epithelial-Mesenchymal Transition - genetics; Epithelial-Mesenchymal Transition - physiology; Female; Hazards; Humans; Immunohistochemistry; In vivo methods and tests; Infiltration; Invasiveness; Leukocyte migration; Macrophages; Male; Markers; Medical prognosis; Mesenchyme; Metastases; Mice; Mice, Nude; Middle Aged; Peripheral blood; Phenotypes; Prognosis; Receptors, Cell Surface - metabolism; Regression analysis; Research Paper; Survival; Tumor cells; Tumors; Vimentin; Wound Healing - genetics; Wound Healing - physiology
• ISSN: 1449-2288; 1449-2288
• DOI: 10.7150/ijbs.29836

The interaction and crosstalk between tumor-associated macrophages (TAMs) and epithelial-mesenchymal transition (EMT) has been demonstrated to play a critical role in the progression and metastasis of multiple cancers. However, the roles of the M2-polarized TAMs in different tumor location in EMT and prognosis of colorectal cancer (CRC) have not been elucidated. Therefore, the present study was designed to set up a reliable ratio of CD163 /CD68 to assess M2-polarized TAMs infiltration in the tumor center (TC) and tumor invasive front (TF) and to further evaluate their prognostic value and biological effects on tumor cells in CRC. TAMs markers (CD68 and CD163) and EMT markers (E-cadherin and Vimentin) expression were evaluated by immunohistochemistry in 81 patients with CRC. Circulating tumor cells (CTCs) of peripheral blood from above patients was also isolated. The correlation of CD163 /CD68 ratio in different locations, EMT and CTCs counts were further analyses. Kaplan-Meier and the model analyses of univariate Cox proportional hazards were utilized to compare the survival of patients with high CD163 /CD68 ratio with those with low CD163 /CD68 ratio. Furthermore, the effects of the M2-polarized TAMs on growth, migration and invasion of CRC cells were explored and co-culture system. : The results showed that the level of CD163 /CD68 ratio in TF was significant higher than that in TC, and higher CD163 /CD68 ratio were closely correlated with enhanced lymphovascular invasion, tumor invasion and TNM stage. Interestingly, higher CD163 /CD68 ratio were also significantly associated with EMT program and CTCs counts. Meanwhile, Kaplan-Meier analysis showed that CD163 /CD68 was associated with both recurrence-free survival (RFS) and overall survival (OS) of patients with CRC. Multivariate Cox regression analyses demonstrated that CD163 /CD68 remained an independent prognostic factor for RFS and OS. Further receiver operating characteristic (ROC) curve analysis found that CD163 /CD68 was a better prognosticator compared with CD68 and CD163 for CRC patients. What's more, M2-polarized TAMs secreted TGF-β to facilitate the EMT, growth, proliferation and invasion of CRC cells by and experiments. Our studies preliminarily elucidated the prognostic value of CD163 /CD68 ratio in different tumor locations and the biological functions of M2-polarized TAMs in CRC progression via TGF-β.