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Role of chemokines in the crosstalk between tumor and tumor-associated macrophages.

ABSTRACT: Tumor microenvironment (TME) consists of a dynamic network of non-tumoral stromal cells, including cancer-associated fibroblasts, endothelial cells, tumor-associated macrophages (TAMs), B and T cells. In the TME, TAMs support tumor initiation, progression, invasion and metastasis by promoting angiogenesis and immunosuppression of the tumor cells. There is close crosstalk between TAMs and tumor cells. Notably, chemokines are a significant messenger mediating the crosstalk between tumor cells and TAMs. TAMs can promote tumor progression via secretion of chemokines. Various chemokines secreted by tumors are involved in the generation and polarization of TAMs, the infiltration of TAMs in tumors, and the development of TAMs' suppressive function. This paper reviews CCL2-CCR2, CCL3/5-CCR5, CCL15-CCR1, CCL18-CCR8, CX3CL1/CCL26-CX3CR1, CXCL8-CXCR1/2, CXCL12-CXCR4/CXCR7 signaling pathways, their role in the recruitment, polarization and exertion of TAMs, and their correlation with tumor development, metastasis and prognosis. Furthermore, we present the current research progress on modulating the effects of TAMs with chemokine antagonists and discuss the prospects and potential challenges of using chemokine antagonists as therapeutic tools for cancer treatment. The TAMs targeting by chemokine receptor antagonists in combination with chemotherapy drugs, immune checkpoint inhibitors or radiotherapy appears to be a promising approach.

SUBMITTER: Qin R

PROVIDER: S-EPMC10460746 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Role of chemokines in the crosstalk between tumor and tumor-associated macrophages.

Qin Rui R Ren Weihong W Ya Guoqi G Wang Bei B He Jiao J Ren Shaoxin S Jiang Lu L Zhao Shuo S

Clinical and experimental medicine 20220929 5

Tumor microenvironment (TME) consists of a dynamic network of non-tumoral stromal cells, including cancer-associated fibroblasts, endothelial cells, tumor-associated macrophages (TAMs), B and T cells. In the TME, TAMs support tumor initiation, progression, invasion and metastasis by promoting angiogenesis and immunosuppression of the tumor cells. There is close crosstalk between TAMs and tumor cells. Notably, chemokines are a significant messenger mediating the crosstalk between tumor cells and ...[more]

PMID: 36173487

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Project description:Background5-fluorouracil (5-FU)-based chemotherapy regimen has been widely used for the treatment of gastric cancer, but meanwhile the development of chemotherapeutic resistance remains a major clinical challenge. Tumor microenvironment (TME) frequently correlates with the development of chemoresistance in human cancer. As a major component of TME, the role of tumor-associated macrophages (TAMs) in the chemoresistance of gastric cancer has not been fully elucidated.MethodsImmunohistochemistry (IHC) was applied to detect the density of TAMs in clinical samples of 103 patients with gastric cancer who had undergone 5-FU-based neoadjuvant chemotherapy. 5-FU-resistant gastric cell lines MKN45-R and HGC27-R were established, macrophages were then separately co-cultured with MKN45-R, HGC27-R cells and their parental cells. The effect of gastric cancer cells on the polarization of macrophages, the biological function of M2-polaried macrophages and the mechanism for promoting 5-FU-resistance were investigated. Then the correlation between the expression of CXC motif chemokine ligand 5 (CXCL5) and the infiltration of hemoglobin scavenger receptor (CD163) positive and mannose receptor (CD206) positive macrophages was analyzed, the prognostic value of CXCL5 expression in clinical samples was further explored.ResultsThe high infiltration of macrophages marked by CD68 in gastric cancer samples was significantly associated with the resistance of gastric cancer to chemotherapy. Gastric cancer cells could modulate macrophages to M2-like polarization through indirect co-culture, and chemoresistant cells were more efficient in inducing macrophages polarization to M2 phenotype. Co-culturing M2-polarized macrophages in turn enhanced 5-FU-resistance of gastric cancer cells, and it was further verified that CXCL5 derived from M2-polarized macrophages promoted chemoresistance through activing the PI3K/AKT/mTOR pathway. Besides, high level of CXCL5 could recruit monocytes to form more M2-polarized macrophages. Clinically, high expression of CXCL5 in gastric cancer samples was associated with the high infiltration of CD163 positive macrophages and CD206 positive macrophages, and patients with high expression of CXCL5 presented lower overall survival (OS) rates than those with low expression of CXCL5.ConclusionInteraction between TAMs and gastric cancer cells promoted chemoresistance in gastric cancer via CXCL5/PI3K/AKT/mTOR pathway. Thus, targeting TAMs and blocking the cell-cell crosstalk between TAMs and gastric cancer cells may represent prospective therapeutic strategies for patients with gastric cancer.

Project description:BackgroundTumor-associated macrophages (TAMs) are major components of tumor microenvironment that frequently associated with tumor metastasis in human cancers. Circulating tumor cell (CTC), originating from primary tumor sites, is considered to be the precursors of tumor metastasis. However, the regulatory mechanism of TAMs in CTC-mediated tumor metastasis still remains unclear.MethodsImmunohistochemical staining was used to detect the macrophages infiltration (CD68 and CD163), epithelial-mesenchymal transition (EMT) markers (E-cadherin and Vimentin) expression in serial sections of human colorectal cancer (CRC) specimens. Then, the correlations between macrophages infiltration and clinicopathologic features, mesenchymal CTC ratio, and patients' prognosis were analyzed. A co-culture assay in vitro was used to evaluate the role of TAMs on CRC EMT, migration and invasion, and ELISA, luciferase reporter assay and CHIP were performed to uncover the underlying mechanism. Furthermore, an in vivo model was carried out to confirm the effect of TAMs on mesenchymal CTC-mediated metastasis.ResultsClinically, CD163+ TAMs infiltrated in invasive front was associated with EMT, mesenchymal CTC ratio, and poor prognosis in patients with CRC. CRC-conditioned macrophages regulated EMT program to enhance CRC cells migration and invasion by secreting IL6. TAMs-derived IL6 activated the JAK2/STAT3 pathway, and activated STAT3 transcriptionally inhibited the tumor suppressor miR-506-3p in CRC cells. miR-506-3p, a key miRNA regulating FoxQ1, was downregulated in CRC cells, resulting in increased FoxQ1 expression, which in turn led to the production of CCL2 that promoted macrophage recruitment. Inhibition of CCL2 or IL6 broke this loop and reduced macrophage migration and mesenchymal CTC-mediated metastasis, respectively.ConclusionsOur data indicates that TAMs induce EMT program to enhance CRC migration, invasion, and CTC-mediated metastasis by regulating the JAK2/STAT3/miR-506-3p/FoxQ1 axis, which in turn leads to the production of CCL2 that promote macrophage recruitment, revealing a new cross-talk between immune cells and tumor cells in CRC microenvironment.

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Role of chemokines in the crosstalk between tumor and tumor-associated macrophages.

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Role of chemokines in the crosstalk between tumor and tumor-associated macrophages.

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