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Review Open Access

CCL2/CCR2 signaling pathway in tumorigenesis and metastasis (Review)

  • Authors:
    • Ya Zhang
    • Bin Fan
    • Hang Yang
    • Gangxian Chen
    • Zhou Huang
    • Ying Li
    • Xiang Ma
    • Tiying Wang
    • Weiquan Wang
    • Linhao Cai
    • Lei Han
    • Yan Liu
    • Dongqi Li
    • Xianwei Chen
    • Yihao Yang
    • Zuozhang Yang
  • View Affiliations / Copyright

    Affiliations: Bone and Soft Tissue Tumors Research Centre of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital), Kunming, Yunnan 650118, P.R. China, Department of Rehabilitation Medicine, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China, Bone and Soft Tissue Tumors Research Centre of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital), Kunming, Yunnan 650118, P.R. China
    Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 598
    |
    Published online on: October 17, 2025
       https://doi.org/10.3892/ol.2025.15344
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Abstract

C‑C motif chemokine ligand 2 (CCL2) is associated with tumorigenesis and cancer progression. C‑C motif chemokine receptor 2 (CCR2) is the main receptor of CCL2. The present review aimed to summarize the role of the CCL2/CCR2 signaling axis in tumorigenesis and metastasis. The CCL2/CCR2 signaling axis exerts antitumor activities by activating the immune response and immunosurveillance, recruiting neutrophils to destroy cancer cells, inducing tumor‑infiltrating lymphocytes to infiltrate tumor tissue, and interfering with the function of T lymphocytes and dendritic cells. In addition, it promotes tumor progression by enhancing cell proliferation, migration and invasion, inducing epithelial‑mesenchymal transition, stimulating the production of vascular endothelial growth factor and tumor angiogenesis, recruiting tumor‑related cells to the tumor niche and remodeling the tumor microenvironment to render it immunosuppressive. The dual effect of the CCL2/CCR2 signaling axis depends on the specific conditions and stage of tumor metastasis.
View Figures

Figure 1

Role of CCL2/CCR2 axis in tumor
cells. CCL2, C-C motif chemokine ligand 2; CCR2, C-C motif
chemokine receptor 2; PKC, protein kinase C.

Figure 2

Signaling pathways associated with
CCL2/CCR2. CCL2, C-C motif chemokine ligand 2; CCR2, C-C motif
chemokine receptor 2; PKC, protein kinase C; EMT,
epithelial-mesenchymal transition.

Figure 3

Interaction between the CCL2/CCR2
signaling axis and CAFs in the TME. CAFs secreting CCL2 promote the
migration of CCR2-expressing monocytes from the blood circulation
to the TME and directly interact with them to promote their
differentiation into MDSCs. CAF-induced MDSCs inhibit T-cell
proliferation by upregulating NOX2 and IDO1 to generate excess ROS.
CCL2, C-C motif chemokine ligand 2; CCR2, C-C motif chemokine
receptor 2; CAF, cancer-associated fibroblast; TME, tumor
microenvironment; MDSC, myeloid-derived suppressor cell; NOX2,
NADPH oxidase 2; IDO1, indoleamine 2,3-dioxygenase 1; ROS, reactive
oxygen species.

Figure 4

Role of CCL2/CCR2 signaling pathway
in the dynamic process of tumor metastasis. In the primary tumor
site, the CCL2/CCR2 signaling axis promotes tumor cell survival,
proliferation, invasion and migration. The CCL2/CCR2 signaling
pathway is involved in constructing the pre-metastatic niche, which
mainly involves inflammation, immune suppression,
angiogenesis/vascular permeability, lymphangiogenesis, organ
tropism and reprogramming. In the circulatory system, the CCL2/CCR2
signaling axis increases vascular permeability and enhances the
permeability of CTCs. In addition, this pathway can stimulate
lymphangiogenesis, induce lymphatic network expansion and promote
lymphatic metastasis. The CCL2/CCR2 signaling pathway can promote
EMT. The CCL2/CCR2 signaling pathway is involved in organ-specific
metastasis. After reaching the distant metastatic site, CTCs become
DTCs. The CCL2/CCR2 axis participates in host immune defense
response and exerts antitumor effects. The surviving DTCs enter
dormancy. Once a favorable post-metastatic microenvironment is
established, DTCs enter a proliferative state, forming
metastasis-initiating cells and subsequently developing into
metastasis through a series of complex processes. CCL2/CCR2
signaling recruits immune-related CAFs, TAMs, Tregs and MDSCs to
construct an immunosuppressive microenvironment, which serves a
role in promoting metastasis. CCL2, C-C motif chemokine ligand 2;
CCR2, C-C motif chemokine receptor 2; CTC, circulating tumor cell;
EMT, epithelial-mesenchymal transition; DTC, disseminated tumor
cell; TAM, tumor-associated macrophage; MDSC, myeloid-derived
suppressor cell; Treg, regulatory T cell; CAF, cancer-associated
fibroblast; LNM, lymph node metastasis.
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Copy and paste a formatted citation
Spandidos Publications style
Zhang Y, Fan B, Yang H, Chen G, Huang Z, Li Y, Ma X, Wang T, Wang W, Cai L, Cai L, et al: CCL2/CCR2 signaling pathway in tumorigenesis and metastasis (Review). Oncol Lett 30: 598, 2025.
APA
Zhang, Y., Fan, B., Yang, H., Chen, G., Huang, Z., Li, Y. ... Yang, Z. (2025). CCL2/CCR2 signaling pathway in tumorigenesis and metastasis (Review). Oncology Letters, 30, 598. https://doi.org/10.3892/ol.2025.15344
MLA
Zhang, Y., Fan, B., Yang, H., Chen, G., Huang, Z., Li, Y., Ma, X., Wang, T., Wang, W., Cai, L., Han, L., Liu, Y., Li, D., Chen, X., Yang, Y., Yang, Z."CCL2/CCR2 signaling pathway in tumorigenesis and metastasis (Review)". Oncology Letters 30.6 (2025): 598.
Chicago
Zhang, Y., Fan, B., Yang, H., Chen, G., Huang, Z., Li, Y., Ma, X., Wang, T., Wang, W., Cai, L., Han, L., Liu, Y., Li, D., Chen, X., Yang, Y., Yang, Z."CCL2/CCR2 signaling pathway in tumorigenesis and metastasis (Review)". Oncology Letters 30, no. 6 (2025): 598. https://doi.org/10.3892/ol.2025.15344
Copy and paste a formatted citation
x
Spandidos Publications style
Zhang Y, Fan B, Yang H, Chen G, Huang Z, Li Y, Ma X, Wang T, Wang W, Cai L, Cai L, et al: CCL2/CCR2 signaling pathway in tumorigenesis and metastasis (Review). Oncol Lett 30: 598, 2025.
APA
Zhang, Y., Fan, B., Yang, H., Chen, G., Huang, Z., Li, Y. ... Yang, Z. (2025). CCL2/CCR2 signaling pathway in tumorigenesis and metastasis (Review). Oncology Letters, 30, 598. https://doi.org/10.3892/ol.2025.15344
MLA
Zhang, Y., Fan, B., Yang, H., Chen, G., Huang, Z., Li, Y., Ma, X., Wang, T., Wang, W., Cai, L., Han, L., Liu, Y., Li, D., Chen, X., Yang, Y., Yang, Z."CCL2/CCR2 signaling pathway in tumorigenesis and metastasis (Review)". Oncology Letters 30.6 (2025): 598.
Chicago
Zhang, Y., Fan, B., Yang, H., Chen, G., Huang, Z., Li, Y., Ma, X., Wang, T., Wang, W., Cai, L., Han, L., Liu, Y., Li, D., Chen, X., Yang, Y., Yang, Z."CCL2/CCR2 signaling pathway in tumorigenesis and metastasis (Review)". Oncology Letters 30, no. 6 (2025): 598. https://doi.org/10.3892/ol.2025.15344
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