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Review
. 2024 May;64(5):51.
doi: 10.3892/ijo.2024.5639. Epub 2024 Mar 22.

An overview of the regulatory role of annexin A1 in the tumor microenvironment and its prospective clinical application (Review)

Kuan Gao  1 , Xinyang Li  1 , Shuya Luo  2 , Limei Zhao  1
Affiliations
Review

An overview of the regulatory role of annexin A1 in the tumor microenvironment and its prospective clinical application (Review)

Kuan Gao et al. Int J Oncol. 2024 May.

Abstract

Although annexin A1 (ANXA1), a 37 kDa phospholipid‑binding anti‑inflammatory protein expressed in various tissues and cell types, has been investigated extensively for its regulatory role in cancer biology, studies have mainly focused on its intracellular role. However, cancer cells and stromal cells expressing ANXA1 have the ability to transmit signals within the tumor microenvironment (TME) through autocrine, juxtacrine, or paracrine signaling. This bidirectional crosstalk between cancer cells and their environment is also crucial for cancer progression, contributing to uncontrolled tumor proliferation, invasion, metastasis and resistance to therapy. The present review explored the important role of ANXA1 in regulating the cell‑specific crosstalk between various compartments of the TME and analyzed the guiding significance of the crosstalk effects in promotion or suppressing cancer progression in the development of cancer treatments. The literature shows that ANXA1 is critical for the regulation of the TME, indicating that ANXA1 signaling between cancer cells and the TME is a potential therapeutic target for the development of novel therapeutic approaches for impeding cancer development.

Keywords: annexin A1; cancer; formyl peptide receptor; immune response; tumor microenvironment.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Model of ANXA1 regulating different compartments of the TME. (A) Cancer cells produce ANXA1 to activate NFs into CAFs. CAFs secrete ANXA1 to promote angiogenesis and maintain stem cell stemness properties of cancer cells. (B) ANXA1 released by cancer cells reaches infiltration of M2 macrophages, Tregs, MDSCs and iDCs and inhibits T cells to mediate tumor immune escape. (C) Cancer cells release ANXA1 to promote transendothelial migration and increase angiogenesis, supporting cancer progression. (D) ANXA1 produced by cancer cells enter blood vessels, contributing to colonization in distant organs of cancer cells. ANXA1, annexin A1; TME, tumor microenvironment; NF, normal fibroblast; CAF, cancer-associated fibroblasts; Treg, T regulatory lymphocyte; MDSC, myeloid-derived suppressor cell; iDC, immature dendritic cell.
Figure 2
Figure 2
Expression and externalization mechanisms of ANXA1. Expression mechanisms, including glucocorticoids, indirectly induce ANXA1 expression by activating MAPK and cAMP, subsequently upregulating CREB to bind to the ANXA1 promoter; ANXA1 upregulation by glucocorticoids that induce the combination GILZ with PU.1. IL-6 induces ANXA1 expression by activating the transcription factors STAT3 and C/EBP-β. miR-196a binds to the 3′UTR of ANXA1 mRNA to downregulate ANXA1 expression. Externalization mechanisms are: ① Activation of the ATP-binding (ABC) transporter; fusion of ANXA1-containing granules to the plasma membrane; ② phosphorylation of ANXA1 of Ser27 by PKC; secretion of ANXA1-loaded EVs. Externalized ANXA1 interact with FPRs in an autocrine, juxtacrine, or paracrine manner. ANXA1, annexin A1; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding protein; GILZ, glucocorticoid-induced ③ leucine zipper; miR, microRNA; FPRs, ④ formyl peptide receptors; PKC, protein kinase C; p, phosphorylated.
Figure 3
Figure 3
Bidirectional crosstalk of ANXA1 between cancer cells and macrophages. The release of ANXA1 mediated by the HIF1A/FOSL2 and JMJD6 signaling pathways in ERα-positive breast cancer and GBM, respectively. ANXA1 released by cancer cells can bind to the FPRs of macrophages, subsequently activating the JAK/STAT3, PI3K/AKT, ERK and NF-κB signaling pathways to induce macrophage polarization towards the M2 phenotype. ANXA1 released by M2 macrophages can communicate with FPRs of cancer cells, which enhances the PI3K/AKT, MEK/ERK axis to promote cancer progression. ANXA1, annexin A1; ERα, estrogen receptor alpha; GBM, glioblastoma; FPRs, formyl peptide receptors.
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Grants and funding

The present study was supported by the National Natural Science Foundation of China (grant nos. 81673510 and 82073936) and the Outstanding Scientific Fund of Shengjing Hospital (grant no. M0779).