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.
Highlights
Neoplastic transformation and progression encompass multiple unknown or poorly described events
Hanahan and Weinberg proposed different hallmarks that, despite being interrelated, define the principles of tumorigenesis. These hallmarks include the resistance to cell death mechanisms, uncontrolled proliferation, induction of angiogenesis, invasion potential, metastasis formation and immune escape [1]. Cancer cells acquire these hallmarks by modifying the extracellular matrix (ECM) and modulating the behavior of different cell types that surround the tumor
It is important to unravel the immunomodulatory role of the protein Annexin A1 (AnxA1), which is the purpose of this review
Summary
Neoplastic transformation and progression encompass multiple unknown or poorly described events. 2. Anticancer Immune Response and Cancer Immune Escape The immune system recognizes antigens expressed on the surface of transformed cells, leading to their destruction, hampering tumor progression. Cancer cells can modulate gene expression and signaling pathways of the immune system, inducing an immune-suppressive phenotype that supports tumor growth and metastasis [6] In this regard, cancer cells produce several factors that trigger a persistent inflammation that contributes to suppressing anti-tumor immunity [7]. Two types of DCs are involved in the maintenance of self-tolerance in physiological conditions, the tolerogenic DCs (tDCs) and immature DCs (iDCs) Both hamper the immune response by expressing low levels of co-stimulatory molecules and producing IL-10 and TGF-β [36,37]. Understanding the mechanisms and the molecules involved in this microenvironment, including immune cells, is essential in controlling the evolution of the tumor and its impact on the outcomes of patients
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