M2-Type Macrophages and Cancer-Associated Fibroblasts Combine to Promote Colorectal Cancer Liver Metastases

Abstract

Purpose

This research explored the association between CD163-labeled M2-type macrophages and cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) of 38 colorectal cancer (CRC) liver metastases. In addition, we investigated the correlation differences between M2-type macrophages and CAFs in the tumor microenvironments of 38 primary colorectal cancer patients with confirmed liver metastases and 946 colorectal cancer patients, as well as possible mechanisms of action between the two cells.

Methods

The Immunohistochemistry (IHC) method was applied to detect the expression levels of M2-type macrophages and CAFs in the tissues of 984 cases of CRC and to analyze the correlation between M2-type macrophages and CAFs in colorectal cancer tissues. The IHC method was also applied to detect the expression levels of M2-type macrophages and CAFs in the liver metastases of 38 cases of CRC in the experimental group and to analyze the correlation between the two cells in liver metastases.

Results

1. M2-type macrophages and CAFs expression were significantly higher in 38 primary colorectal cancer patients compared to 946 controls, and the expression of M2-type macrophages was significantly positively correlated with CAFs. 2. In 984 CRC cases, M2-type macrophages and CAFs expression levels were significantly higher in the cancer tissues than in the paired paracancerous tissues. 3. The expression levels of M2-type macrophages and CAFs in primary colorectal cancer were significantly higher in the experimental group than in colorectal cancer tissues without distant metastasis.

Conclusion

M2-type macrophages and CAFs are involved in the development of the colorectal cancer tumor microenvironment, and their interaction influences the initiation and progression of liver metastasis in colorectal cancer. It may provide new clinical ideas for early diagnosis of CRC liver metastases and searching for immune targets.

Keywords:

• M2-type macrophages
• cancer-associated fibroblasts
• colorectal cancer
• liver metastasis

Abbreviations

CRC, colorectal carcinoma; CAFs, cancer-associated fibroblasts; TME, tumor microenvironment; IHC, immunohistochemical; TAMs, tumor-associated macrophages; TGF-β, transforming growth factor-β; EMT, epithelial-mesenchymal-transition; VEGF, vascular endothelial growth factor; α-SMA, α-Smooth muscle actin; FSP-1, fibroblast-specific protein 1; CXCL12, C-X-C motif chemokine ligand 12; CEA, Carcinoembryonic antigen; CA19-9, Glycated antigen 19-9; CA72-4, glycan antigen 72-4.

Data Sharing Statement

The analyzed data sets generated during the study are available from the corresponding author upon reasonable request. Inquiries for data access may be sent to the following e-mail address: [email protected].

Statement of Ethics

The samples were obtained from the First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China. The study was conducted following the Ethics Committee of the First Affiliated Hospital of Jinzhou Medical University(2023103) and the 1964 Helsinki Declaration. Informed consent was obtained from all participants included in the study. The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Acknowledgments

The authors sincerely appreciate the assistance of The First Affiliated Hospital of Jinzhou Medical University.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors have declared that no competing interest exists.

Additional information

Funding

There is no funding to report.