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Updated: Dec 2, 2025
In Vitro Assay to Study Tumor-macrophage Interaction
Published on: August 1, 2019
Tumor-derived adenosine promotes macrophage proliferation in human hepatocellular carcinoma
Junfeng Wang1, Yongchun Wang1, Yifan Chu1
1Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China.
Background & Aims:
Macrophages (Mϕ) represent a major component of tumor tissues and play an important role in both tumor progression and therapeutic response. Although tumor Mϕ are generally considered to be derived from circulating monocytes, emerging evidence indicates that tissue Mϕ pools can be maintained by self-renewal. We aimed to elucidate the contribution, phenotype, and regulatory mechanisms of proliferating Mϕ in human hepatocellular carcinoma (HCC).
Methods:
Flow cytometry analyses were performed to examine the presence and phenotype of proliferating Mϕ in fresh HCC tissues. Dual immunofluorescence staining was applied to analyze the prognostic value of proliferating Mϕ. The underlying regulatory mechanisms were examined using human monocyte-derived Mϕ.
Results:
Tumor-infiltrating Mϕ exhibited a significantly higher proliferative capacity than Mϕ in non-tumor tissues. A higher level of Mϕ proliferation was positively correlated with Mϕ density in the tumor and a poor prognosis in patients with HCC. Proliferating Mϕ were less differentiated (with increased CD206 expression) and were induced by the tumor cell-derived soluble small molecule, adenosine, but not proteins, lipids, or large peptides. Mechanistic studies demonstrated that autocrine granulocyte-macrophage colony-stimulating factor (GM-CSF) released by tumor-stimulated Mϕ could enhance A2A receptor expression on Mϕ and function synergistically with adenosine to elicit Mϕ proliferation in HCC.
Conclusions:
Local Mϕ proliferation is an important mechanism for Mϕ accumulation in HCC tissues. Tumor-derived adenosine functions synergistically with autocrine GM-CSF released from activated Mϕ, which promotes Mϕ proliferation. Thus, selective modulation of Mϕ accumulation at the source may provide a novel strategy for cancer therapy.
Lay Summary:
Tumor-associated macrophages (TAMs) have been reported to play an essential role in both tumor progression and therapeutic response. A fundamental understanding of the mechanisms that regulate macrophage accumulation in tumors will undoubtedly lead to the development of strategies to target macrophages with high specificity and efficiency. The current study unveils a novel mechanism by which local proliferation is linked to macrophage accumulation in the tumor milieu, identifying potential targets for future immune-based anticancer therapies.
Insights
Local macrophage proliferation fuels hepatocellular carcinoma (HCC) growth. Tumor-derived adenosine and macrophage-released GM-CSF promote this proliferation, offering new therapeutic targets for HCC.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Macrophages (Mϕ) are key players in tumor progression and treatment response.
- While often considered monocyte-derived, tissue Mϕ can self-renew.
- Understanding Mϕ proliferation in hepatocellular carcinoma (HCC) is crucial.
Purpose of the Study:
- To investigate the contribution, phenotype, and regulation of proliferating Mϕ in human HCC.
- To determine the role of Mϕ self-renewal in HCC.
- To identify mechanisms driving Mϕ accumulation in HCC.
Main Methods:
- Flow cytometry to analyze Mϕ phenotype and proliferation in HCC tissues.
- Dual immunofluorescence staining for prognostic analysis.
- In vitro studies using human monocyte-derived Mϕ to explore regulatory mechanisms.
Main Results:
- Proliferating Mϕ were more abundant in tumors than non-tumor tissues.
- Higher Mϕ proliferation correlated with increased Mϕ density and poorer HCC prognosis.
- Proliferating Mϕ were less differentiated (CD206+) and induced by tumor-derived adenosine.
Conclusions:
- Local Mϕ proliferation is a significant factor in HCC Mϕ accumulation.
- Tumor adenosine and autocrine GM-CSF synergize to drive Mϕ proliferation in HCC.
- Targeting Mϕ accumulation offers a potential novel cancer therapy strategy.
