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Int J Biol Sci 2019; 15(5):984-998. doi:10.7150/ijbs.29836

Research Paper

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

Chaogang Yang1,2,3*, Chen Wei1,2,3*, Shuyi Wang1,2,3*, Dongdong Shi1,2,3, Chunxiao Zhang1,2,3, Xiaobin Lin1,2,3, Rongzhang Dou1,2,3, Bin Xiong1,2,3✉

1. Department of Gastrointestinal Surgery & Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China;
2. Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, China;
3. Hubei Cancer Clinical Study Center, Wuhan 430071, China.
*These authors contributed equally to this work.

Abstract

Background: 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.

Methods: 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 in vivo and in vitro co-culture system.

Results: The results showed that the level of CD163+/CD68+ ratio in TF was significant higher than that in TC, and higher CD163+/CD68+TF ratio were closely correlated with enhanced lymphovascular invasion, tumor invasion and TNM stage. Interestingly, higher CD163+/CD68+TF ratio were also significantly associated with EMT program and CTCs counts. Meanwhile, Kaplan-Meier analysis showed that CD163+/CD68+TF was associated with both recurrence-free survival (RFS) and overall survival (OS) of patients with CRC. Multivariate Cox regression analyses demonstrated that CD163+/CD68+TF remained an independent prognostic factor for RFS and OS. Further receiver operating characteristic (ROC) curve analysis found that CD163+/CD68+TF was a better prognosticator compared with CD68+TF and CD163+TF for CRC patients. What's more, M2-polarized TAMs secreted TGF-β to facilitate the EMT, growth, proliferation and invasion of CRC cells by in vivo and in vitro experiments.

Conclusions: 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.

Keywords: colorectal cancer, tumor-associated macrophage, CD163+/CD68+ ratio, epithelial-mesenchymal transition, prognosis

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
How to cite this article:
Yang C, Wei C, Wang S, Shi D, Zhang C, Lin X, Dou R, Xiong B. Elevated CD163+/CD68+ Ratio at Tumor Invasive Front is Closely Associated with Aggressive Phenotype and Poor Prognosis in Colorectal Cancer. Int J Biol Sci 2019; 15(5):984-998. doi:10.7150/ijbs.29836. Available from http://www.ijbs.com/v15p0984.htm