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Role of Annexin A1 in the Tumor Microenvironment

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A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 16070

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Special Issue Editor

Prof. Dr. Antonello Petrella

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Guest Editor

Department of Pharmacy, University of Salerno, via Giovanni Paolo II 132, 84084 Fisciano (SA), Italy
Interests: annexin; cancer therapy; cancer biology; metastasis; cellular signaling; endothelial and epithelial-to-mesenchymal transition; extracellular vesicles; tumor microenvironment; biomarkers; skin wound healing
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Special Issue Information

Dear Colleagues,

This Special Issue highlights the role of the protein Annexin A1 (ANXA1) in cancer progression, particularly its role in the tumor microenvironment. Cancer progression is closely associated with growth, differentiation, angiogenesis, cell motility, metastasis, and inflammatory responses. The microenvironment surrounding tumor cells plays a critical role in their development, revealing a strong relationship between cancer organization and metastasis. It is well known that this kind of tissue complex is made up of the same tumor cells, stromal and immune ones and extracellular components, such as extracellular vesicles (EVs), which maintain the sustenance of the primary tumor, in an autocrine and paracrine way. ANXA1 participates in many physiopathological processes, including cell proliferation, motility, differentiation and death, and inflammation. In tumor development, this protein can be considered as an oncogene or oncosuppressor, operating in a tissue-specific manner. Furthermore, it is able to contribute to cell behavior both as extra- and intracellular element, mainly inducing the acquisition of a mesenchymal phenotype of tumor cells, essential for their diffusion into distant sites. Earlier studies highlighted that ANXA1, as a secreted protein, may be identified as a component of tumor-deriving EVs, which favor cell-to-cell and cell-to-matrix communication and the generation of pre-metastatic niches. Uncovering the mechanisms by which ANXA1 contributes to the sustenance of the tumor microenvironment and its interaction with cellular components may uncover interesting cues for the study of novel therapeutic strategies against cancer.

We invite investigators to contribute original research articles as well as review articles that will stimulate continuing efforts to understand the role of ANXA1 in the tumor microenvironment and provide valuable insights that may translate to therapeutic opportunities.

Prof. Dr. Antonello Petrella
Guest Editor

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Keywords

ANXA1
tumor microenvironment
tumor progression
extracellular vesicles
therapeutic target

Published Papers (4 papers)

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Research

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22 pages, 8910 KiB

Open AccessArticle

Interleukin-6 Signaling in Triple Negative Breast Cancer Cells Elicits the Annexin A1/Formyl Peptide Receptor 1 Axis and Affects the Tumor Microenvironment

by Lara Vecchi, Sara Teixeira Soares Mota, Mariana Alves Pereira Zóia, Isabella Castro Martins, Jessica Brito de Souza, Tiago Góss Santos, Adriano de Oliveira Beserra, Victor Piana de Andrade, Luiz Ricardo Goulart and Thaise Gonçalves Araújo

Cells 2022, 11(10), 1705; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11101705 - 20 May 2022

Cited by 10 | Viewed by 2405

Abstract

Annexin A1 (AnxA1) is a pleiotropic protein that exerts essential roles in breast cancer (BC) growth and aggressiveness. In our previous work, we described the autocrine signaling of AnxA1 through formyl peptide receptor 1 (FPR1) in the triple-negative (TN) BC cell line, MDA-MB-231. Here, we aimed to describe the interaction between the AnxA1/FPR1 and the Interleukin-6 (IL-6) signaling pathways and their role in the tumor microenvironment (TME). First, we demonstrated that AnxA1 and IL-6 expression levels are correlated in BC tissue samples. In three TNBC cell lines, overexpression of both AnxA1 and IL-6 was also identified. Next, we inhibited FPR1, the IL-6 receptor and STAT3 in both MDA-MB-231 and MDA-MB-157 cells. The FPR1 inhibition led to increased levels of IL-6 and secreted AnxA1 in both cell lines. On the other side, inhibition of the IL-6 receptor or STAT3 led to the impairment of AnxA1 secretion, suggesting the essential role of the IL-6 signaling cascade in the activation of the AnxA1/FPR1 autocrine axis. Finally, we described the interaction between IL-6 and the AnxA1/FPR1 pathways and their role on the TME by analyzing the effect of supernatants derived from MDA-MB-231 and MDA-MB-157 cells under the inhibition of FPR1 or IL-6 signaling on fibroblast cell motility. Full article

(This article belongs to the Special Issue Role of Annexin A1 in the Tumor Microenvironment)

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15 pages, 2062 KiB

Open AccessArticle

Annexin A1 Expression Is Associated with Epithelial–Mesenchymal Transition (EMT), Cell Proliferation, Prognosis, and Drug Response in Pancreatic Cancer

by Masanori Oshi, Yoshihisa Tokumaru, Swagoto Mukhopadhyay, Li Yan, Ryusei Matsuyama, Itaru Endo and Kazuaki Takabe

Cells 2021, 10(3), 653; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10030653 - 15 Mar 2021

Cited by 32 | Viewed by 3556

Abstract

Annexin A1 (ANXA1) is a calcium-dependent phospholipid-binding protein overexpressed in pancreatic cancer (PC). ANXA1 expression has been shown to take part in a wide variety of cancer biology, including carcinogenesis, cell proliferation, invasion, apoptosis, and metastasis, in addition to the initially identified anti-inflammatory effect in experimental settings. We hypothesized that ANXA1 expression is associated with cell proliferation and survival in PC patients. To test this hypothesis, we analyzed 239 PC patients in The Cancer Genome Atlas (TCGA) and GSE57495 cohorts. ANXA1 expression correlated with epithelial–mesenchymal transition (EMT) but weakly with angiogenesis in PC patients. ANXA1-high PC was significantly associated with a high fraction of fibroblasts and keratinocytes in the tumor microenvironment. ANXA1 high PC enriched multiple malignant gene sets, including hypoxia, tumor necrosis factor (TNF)-α signaling via nuclear factor-kappa B (NF-kB), and MTORC1, as well as apoptosis, protein secretion, glycolysis, and the androgen response gene sets consistently in both cohorts. ANXA1 expression was associated with TP53 mutation alone but associated with all KRAS, p53, E2F, and transforming growth factor (TGF)-β signaling pathways and also associated with homologous recombination deficiency in the TCGA cohort. ANXA1 high PC was associated with a high infiltration of T-helper type 2 cells in the TME, with advanced histological grade and MKI67 expression, as well as with a worse prognosis regardless of the grade. ANXA1 expression correlated with a sensitivity to gemcitabine, doxorubicin, and 5-fluorouracil in PC cell lines. In conclusion, ANXA1 expression is associated with EMT, cell proliferation, survival, and the drug response in PC. Full article

(This article belongs to the Special Issue Role of Annexin A1 in the Tumor Microenvironment)

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18 pages, 5608 KiB

Open AccessFeature PaperArticle

Annexin A1 Released in Extracellular Vesicles by Pancreatic Cancer Cells Activates Components of the Tumor Microenvironment, through Interaction with the Formyl-Peptide Receptors

by Nunzia Novizio, Raffaella Belvedere, Emanuela Pessolano, Alessandra Tosco, Amalia Porta, Mauro Perretti, Pietro Campiglia, Amelia Filippelli and Antonello Petrella

Cells 2020, 9(12), 2719; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9122719 - 18 Dec 2020

Cited by 26 | Viewed by 3332

Abstract

Pancreatic cancer (PC) is one of the most aggressive cancers in the world. Several extracellular factors are involved in its development and metastasis to distant organs. In PC, the protein Annexin A1 (ANXA1) appears to be overexpressed and may be identified as an oncogenic factor, also because it is a component in tumor-deriving extracellular vesicles (EVs). Indeed, these microvesicles are known to nourish the tumor microenvironment. Once we evaluated the autocrine role of ANXA1-containing EVs on PC MIA PaCa-2 cells and their pro-angiogenic action, we investigated the ANXA1 paracrine effect on stromal cells like fibroblasts and endothelial ones. Concerning the analysis of fibroblasts, cell migration/invasion, cytoskeleton remodeling, and the different expression of specific protein markers, all features of the cell switching into myofibroblasts, were assessed after administration of wild type more than ANXA1 Knock-Out EVs. Interestingly, we demonstrated a mechanism by which the ANXA1-EVs complex can stimulate the activation of formyl peptide receptors (FPRs), triggering mesenchymal switches and cell motility on both fibroblasts and endothelial cells. Therefore, we highlighted the importance of ANXA1/EVs-FPR axes in PC progression as a vehicle of intercommunication tumor cells-stroma, suggesting a specific potential prognostic/diagnostic role of ANXA1, whether in soluble form or even if EVs are captured in PC. Full article

(This article belongs to the Special Issue Role of Annexin A1 in the Tumor Microenvironment)

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Review

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24 pages, 4721 KiB

Open AccessReview

Annexin A1 as a Regulator of Immune Response in Cancer

by Thaise Gonçalves Araújo, Sara Teixeira Soares Mota, Helen Soares Valença Ferreira, Matheus Alves Ribeiro, Luiz Ricardo Goulart and Lara Vecchi

Cells 2021, 10(9), 2245; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10092245 - 30 Aug 2021

Cited by 37 | Viewed by 6057

Abstract

Annexin A1 is a 37 kDa phospholipid-binding protein that is expressed in many tissues and cell types, including leukocytes, lymphocytes and epithelial cells. Although Annexin A1 has been extensively studied for its anti-inflammatory activity, it has been shown that, in the cancer context, its activity switches from anti-inflammatory to pro-inflammatory. Remarkably, Annexin A1 shows pro-invasive and pro-tumoral properties in several cancers either by eliciting autocrine signaling in cancer cells or by inducing a favorable tumor microenvironment. Indeed, the signaling of the N-terminal peptide of AnxA1 has been described to promote the switching of macrophages to the pro-tumoral M2 phenotype. Moreover, AnxA1 has been described to prevent the induction of antigen-specific cytotoxic T cell response and to play an essential role in the induction of regulatory T lymphocytes. In this way, Annexin A1 inhibits the anti-tumor immunity and supports the formation of an immunosuppressed tumor microenvironment that promotes tumor growth and metastasis. For these reasons, in this review we aim to describe the role of Annexin A1 in the establishment of the tumor microenvironment, focusing on the immunosuppressive and immunomodulatory activities of Annexin A1 and on its interaction with the epidermal growth factor receptor. Full article

(This article belongs to the Special Issue Role of Annexin A1 in the Tumor Microenvironment)

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