Annexin A1 (ANXA1) is a Ca2+-regulated phospholipid-binding protein involved in various cell processes. ANXA1 was initially widely studied in inflammation resolution, but its overexpression was later reported in a large number of cancers. Further in-depth investigations have revealed that this protein could have many roles in cancer progression and act at different levels (from cancer initiation to metastasis). This is partly due to the location of ANXA1 in different cell compartments. ANXA1 can be nuclear, cytoplasmic and/or membrane associated. This last location allows ANXA1 to be proteolytically cleaved and/or to become accessible to its cognate partners, the formyl-peptide receptors. Indeed, in some cancers, ANXA1 is found at the cell surface, where it stimulates formyl-peptide receptors to trigger oncogenic pathways. In the present review, we look at the different locations of ANXA1 and their association with the deregulated pathways often observed in cancers. We have specifically detailed the non-classic pathways of ANXA1 externalization, the significance of its cleavage and the role of the ANXA1–formyl-peptide receptor complex in cancer progression.

INTRODUCTION

Annexin A1 (ANXA1) is a Ca2+-regulated phospholipid-binding protein. It was initially studied in neutrophils, where it represents 2–4% of total cytosolic proteins [1]. It was characterized as a glucocorticoid-regulated anti-inflammatory protein [2]. Subsequently, studies showed that ANXA1 is expressed in several tissues and involved in different cell processes including cell survival, proliferation, apoptosis, differentiation and migration [3]. Consequently, its deregulation often correlates with cancer, and its role in tumour initiation, proliferation and metastases has been established [4,5].

Several groups have reported the existence of three subcellular localizations of ANXA1: one cytoplasmic, the second nuclear and the third attached, loosely or closely, to the plasma membrane [68]. In relation to these different locations, ANXA1 participates in tumorigenesis in different ways. Once formyl-peptide receptors (FPRs) were identified as cognate partners of ANXA1 [9], several studies focused on externalized ANXA1 and found that the ANXA1/FPR complex was involved in inflammation [2], neuroendocrine system regulation [10], skeletal muscle differentiation [11] and cancer progression [4]. To date, FPRs are the only known receptors of externalized ANXA1. As these receptors can be activated or silenced by a variety of synthesized ligands they are a very attractive family of pharmacological targets [12]. FPRs can be activated by the full-length ANXA1 as well as by synthetic peptides derived from its N-terminal region [9]. Although ANXA1 is often cleaved in its N-terminal domain in cells (Table 1), the significance of this cleavage is still being debated.

Table 1
Features of ANXA1 cleavage sites

Depending on the studied human tissue/cell line, ANXA1 can be cleaved at different positions by different protease. Note that the last cleavage site was determined using recombinant calpain.

Protease (family)Cell line/tissueCleavage site P2–P1 position/P1′–P2′Reference
Plasmin (serine proteinase) Seminal plasma Ser–Lys29/Gly–Gly [87
ADAM-10 (metalloproteinase) Jurkat cells (lymphoma) Glu–Phe7/Leu–Lys [105
PR3 (serine proteinase) Neutrophils Gln–Ala11/Trp–Phe, Tyr–Val22/Gln–Thr, Ala–Val36/Ser–Pro [88
Cathepsin D (aspartic proteinase) Keratinocytes Ala–Trp12/Phe–Ile [63
Uncharacterized (serine proteinase) Melanoma Ser–Ser28/Lys–Gly [89
Recombinant calpain (cysteine proteinase) Recombinant ANXA1 Val–Lys26/Ser–Ser [104
Protease (family)Cell line/tissueCleavage site P2–P1 position/P1′–P2′Reference
Plasmin (serine proteinase) Seminal plasma Ser–Lys29/Gly–Gly [87
ADAM-10 (metalloproteinase) Jurkat cells (lymphoma) Glu–Phe7/Leu–Lys [105
PR3 (serine proteinase) Neutrophils Gln–Ala11/Trp–Phe, Tyr–Val22/Gln–Thr, Ala–Val36/Ser–Pro [88
Cathepsin D (aspartic proteinase) Keratinocytes Ala–Trp12/Phe–Ile [63
Uncharacterized (serine proteinase) Melanoma Ser–Ser28/Lys–Gly [89
Recombinant calpain (cysteine proteinase) Recombinant ANXA1 Val–Lys26/Ser–Ser [104

In the present review we report on the main structural characteristics of ANXA1 and its interaction with protein partners. We then describe the molecular mechanisms deployed by nuclear and cytoplasmic ANXA1 in cancer. Finally, we discuss the non-classic pathways of ANXA1 externalization, the significance of its cleavage and the role of the ANXA1/FPR complex in cancer progression.

ANXA1 STRUCTURE AND MEMBRANE BINDING

Human ANXA1 is composed of 346 amino acids (37 kDa). In its N-terminus, Met1 is removed and Ala2 is N-acetylated [13]. ANXA1 consists of two different regions, the singular N-terminal domain (from Ala2 to Asp43), also called the tail, and the C-terminal domain (from Pro44 to Gly344), named the core domain [14].

The core domain

The core domain, which is shared by all annexin members, contains four similar repeats (eight for ANXA6), each about 70 amino acids long. Each repeat is made up of five helices and usually contains characteristic motifs for Ca2+ binding with the sequence GxGT[38 residues]D/E [15]. The four repeats are arranged in a cyclical manner, repeat I followed by repeat IV, repeat II then repeat III, thereby forming a compact structure that is stabilized by hydrophobic interactions and resistant to proteolysis (Figure 1A) [1517]. This structure resembles a flattened disc with a slightly convex surface. The convex side contains types of Ca2+-binding sites, the so-called type 2 and type 3 sites, and faces the membrane when an annexin is associated peripherally with negatively charged phospholipids, preferentially phosphatidic acid, phosphatidylserine and phosphatidylinositol (Figure 1B). The Ca2+ concentration required for maximal membrane binding varies largely between annexins. Essentially it depends on the annexin involved and its affinity for a given phospholipid [6]. However, it was reported that ANXA1 can cross a phospholipidic membrane and establish a pH-dependent and Ca2+-independent interaction with phospholipids [18]. This is consistent with the observation that a pool of ANXA1 is insensitive to EGTA treatment and can be solubilized only by zwitterionic detergents [19]. The concave side of ANXA1 points away from the membrane and thus appears accessible for interactions with the N-terminal domain and/or possibly for binding partners [6,20,21].

ANXA1 structure and membrane binding

Figure 1
ANXA1 structure and membrane binding

(A) In the absence of Ca2+, ANXA1 is present as a core domain (the four repeats arranged in a cyclical manner, repeat I followed by repeat IV, repeat II and repeat III) and an N-terminal domain (orange) buried near repeat III. On Ca2+ and membrane binding, (B), the N-terminal domain is exposed, allowing its amphipathic α-helix (Ala2–Asn16) to interact with (C) a second phospholipidic site causing membrane aggregation or with (D) a proteinaceous partner (green) to establish a cellular response.

Figure 1
ANXA1 structure and membrane binding

(A) In the absence of Ca2+, ANXA1 is present as a core domain (the four repeats arranged in a cyclical manner, repeat I followed by repeat IV, repeat II and repeat III) and an N-terminal domain (orange) buried near repeat III. On Ca2+ and membrane binding, (B), the N-terminal domain is exposed, allowing its amphipathic α-helix (Ala2–Asn16) to interact with (C) a second phospholipidic site causing membrane aggregation or with (D) a proteinaceous partner (green) to establish a cellular response.

The N-terminal domain

In contrast to the core domain, which is shared by the annexin family members, the sequence of the N-terminal domain is extremely variable in length and sequence. This domain confers specificity and physiological activity to each annexin [22]. A crystallographic study of full-length ANXA1 revealed that the first 26 amino acids of the N-terminal domain form two α-helices, Ala2–Asn16 and Glu18–Lys26, which are reciprocally inclined (60°) at Glu17. The unstructured peptide Ser27–Asn43 plays the role of a linker between the N-terminal and core domains [15]. In the absence of Ca2+, the N-terminal domain is located within the concave side of the protein, opposite Ca2+-binding sites, near the third repeat (Figure 1A). In the presence of Ca2+, ANXA1 undergoes a conformational change allowing it to be bound to phospholipids via the core region and exposure of the N-terminal motif (Figure 1B) [14]. Depending on the cellular context, this process allows its amphipathic α-helix (Ala2–Asn16) to interact with a second phospholipidic site, which causes membrane aggregation (Figure 1C) or leads to the interaction of ANXA1 with its intra-/extra-cellular partners (Figure 1D) [14,15].

ANXA1 PARTNERS

Cytosolic phospholipase A2

Phospholipases A2 (PLA2s) are divided, according to their enzymatic characteristics (subcellular localization, Ca2+ requirement and substrate specificity), into various groups named secretory (sPLA2), cytosolic (cPLA2), Ca2+-independent (iPLA2), platelet-activating factor–acyl hydrolase (PAF-AH), lysosomal PLA2 (LPLA2) and adipose-specific PLA2 (AdPLA2) [23]. Cytosolic PLA2 requires Ca2+ for its activity. It specifically hydrolyses membrane phospholipids at the sn-2 position to release arachidonic acid (AA). AA is then processed by cyclooxygenase, lipoxygenase and cytochrome P450s to produce a wide spectrum of eicosanoid metabolites, second lipid messengers that play a fundamental role in inflammation and cancer [24,25]. As the released bioactive lipids induce potent cellular responses, cPLA2 (AA supplier) deregulation is involved in several diseases, ranging from chronic inflammation (and associated diseases) to cancer [26,27]. One of the anti-inflammatory roles of ANXA1 is due to its ability to interact directly with cPLA2 to inhibit its proinflammatory effect [28]. This interaction was initially demonstrated by immunoprecipitation and mammalian two-hybrid methods with truncated ANXA1 mutants [29]. Although full-length ANXA1 and its C-terminal region ANXA1275–346 were shown to interact with cPLA2, the N-terminal domain ANXA11–274 has no affinity for cPLA2 [29]. This is consistent with the observation that: (i) endogenous full-length ANXA1 interacted with and inhibited the activity (phosphorylation) of cPLA2 in the cytoplasm of resting mast cells; and (ii) on activation ANXA1 was cleaved and, together with cPLA2, translocated to the plasma membrane [30]. Although cleaved ANXA1 maintained its ability to interact with cPLA2, it lost its ability to inhibit the activity (phosphorylation [31]) of cPLA2 that leads to the release of AA. This was confirmed by the use of mutant ANXA1 (resistant to cleavage in activated mast cells), which exhibited inhibitory effects on both the phosphorylation of cPLA2 and the production of eicosanoids [30]. Another study investigating the role of cPLA2 in keratinocyte proliferation showed that the interaction of ANXA1 with cPLA2 required prior formation of a S100A11/ANXA1 complex in which the ANXA1 N-terminal domain was crucial [32]. After proteolytic cleavage, ANXA1 lost its binding capacity to S100A11, which resulted in maintenance of cPLA2 in an active state; this, in turn, promoted keratinocyte proliferation [32]. This study demonstrated that, although not involved in the direct ANXA1/cPLA2 interaction, the ANXA1 N-terminal domain plays an important role in cPLA2 activity.

S100A11

S100A11 belongs to the family of S100 proteins, which are dimeric EF-hand Ca2+-binding proteins. The biological function of S100A11 was evidenced in the processes of endo- and exocytosis, regulation of enzyme activity, cell growth regulation, apoptosis and inflammation [33]. After Ca2+ binding, S100A11 undergoes a conformational change leading to the exposure of hydrophobic residues at its surface, on each side of the dimer [34], and to the recognition of different biological targets such as RAGE (receptor for advanced glycation end products), PKCα, actin filaments and ANXA1. As S100A11 has a very broad range of partners it is a key mediator of several cellular responses [33]. In the presence of ANXA1 and Ca2+, S100A11 can interact with the first 14 amino acids of the ANXA N-terminus. As the N-terminal domain of ANXA1 is exposed when the protein is associated with phospholipidic membrane, it was speculated that the S100A11 dimer bridges two membrane-bound ANXA1 molecules [35,36]. This mechanism was thought to be crucial for membrane aggregation/invagination and vesicle trafficking, especially in the process of epidermal growth factor receptor (EGFR) internalization [20]. It has been shown in Hela and A431 cells that ectopic expression of the ANXA1 core domain (lacking the N-terminal peptide) had different outcomes from that of the full-length protein. This was attributed to the disruption of the ANXA1/S100A11 complex, which delayed the transport of the EGFR to the late endosomal/lysosomal compartment for degradation. EGFR stabilization was associated with prolonged mitogen-activated protein kinase (MAPK) signalling, which therefore conferred a more aggressive phenotype on Hela and A431 cells (enhanced migration and colony formation abilities) [37]. It is noteworthy that ANXA1 loss or depletion did not significantly affect EGFR degradation [38]; this may result in compensatory mechanisms possibly involving other annexin family members, especially ANXA2, which is an S100A11 ligand [39] overexpressed after the inactivation of the ANXA1 gene [40]. In some cancers, ANXA1 undergoes a proteolytic cleavage in its N-terminal domain (see below). One possible consequence of this cleavage could be the disruption of the ANXA1/S100A11 complex and the constitutive activation of EGFR and the downstream signalling pathways.

Formyl-peptide receptors

Human FPRs are a family of seven transmembrane G-protein-coupled receptors composed of three members: FPR1, FPR2 and FPR3. They bind to a large number of agonists and antagonists including structurally distinct peptides (N-formyl-hexapeptides, ANXA12–26, SAA, MMWLL, WRWWWW, LL-37), proteins (ANXA1, cathepsin G, CCL23β) and lipid mediators (including Lipoxin A4, Resolvin D1 and D5, and BML-111) [12,41,42]. These receptors have been extensively studied in inflammation and it was shown that FPR activation was involved in different stages of immune responses including leukocyte attraction [43,44], pathogen clearance [45] and inflammation resolution [46]. This activation results in potent opposite effects depending on the ligand. It was recently shown that FPR2 could be present as a monomer or a homo-/hetero-dimer (with FPR1 or FPR3) and, depending on the FPR complex, FPR2 ligands could stimulate different pathways [47]. This could partly explain how one specific FPR ligand (e.g. ANXA1) could have pleiotropic roles and transduce different signalling pathways (see below). FPRs have been found in several human tissues including astrocytes, hepatocytes, and human lung and skin fibroblasts, suggesting that FPR might be involved in processes other than inflammatory reactions [48,49]. As FPRs catalyse the activation of coupled G-proteins, which involves multiple processes such as intracellular signalling transduction, transcription and Ca2+ mobilization [12,50,51], they are associated with several diseases including cancer, amyloidosis and neurodegenerative disorders, host defence and acquired immune deficiency syndrome, diabetes and obesity [42].

CYTOPLASMIC ANXA1

Cytoplasmic ANXA1 is mostly associated with vesicular structures [early and multivesicular endosomes, phagosomes and, occasionally, endoplasmic reticulum (ER)], and is distributed throughout the cell and at the inner leaflet of the plasma membrane [5254]. The overexpression of ANXA1 in the cytoplasm of tumour cells has been observed in several cancers (for a review, see Mussunoor and Murray [55]). In this section we focus on breast cancer and malignant squamous epithelial cells in which the pro-tumoral role of ANXA1 was investigated at the molecular level.

Breast cancer

De Graauw et al. [56] showed that depletion of ANXA1 in a panel of basal-like breast cancer cells (BLBCs) resulted in attenuation of their migratory phenotype and inhibition of lung metastasis formation in mice. In BLBC cells, ANXA1 expression mediates an epithelial–mesenchymal transition (EMT)-like switch via transforming growth factor β (TGF-β) signalling, which subsequently induces Smad2 phosphorylation, Smad4 nuclear translocation and stimulation of Smad3/Smad4 transcriptional activity [56]. To strengthen this finding, the authors performed an ectopic expression of ANXA1 in luminal-like breast tumour cells that do not express ANXA1. ANXA1 expression resulted in a clear EMT-like switch and enhanced TGF-β signalling. As TGF-β receptor endocytosis results in Smad2 phosphorylation and Smad-mediated gene transcription [57,58], it was speculated that ANXA1, as observed for EGFR internalization [59], might influence TGF-β signalling by stimulating TGF-β receptor endocytosis. In addition to its direct effect on endocytosis, the authors suggested that ANXA1 might also influence the internalization of TGF-β receptors indirectly through regulation of the actin cytoskeleton. Decreased actin cytoskeletal dynamics were observed in ANXA1 knockdown cells, which could stiffen the cell membrane, thereby impeding TGF-β receptor internalization [56]. Later studies focused on the role of ANXA1 in breast cancer cell invasion and metastasis formation. It was shown that ANXA1 could activate nuclear factor κB (NF-κB) in two different ways: either directly by interacting with and stabilizing the NEMO–RIP1–IKK complex, which is important for NF-κB phosphorylation and its nuclear translocation [60], or indirectly by inhibiting miR-26b* and miR-562, which directly silence the NF-κB pathway by recognizing, respectively, Rel A (p65) and NF-κB1 (p105) mRNAs at the 3′-UTR [61]. Once activated, NF-κB stimulates breast cancer cell invasion via matrix metalloproteinase 9 (MMP9), chemokine receptor 4 (CXCR4) and urokinase plasminogen activator (uPA) expression [60,62].

Squamous cancer cells

Cytosolic PLA2 is an initiator enzyme of the AA cascade and thus plays a critical role in the regulation of growth of many different cell types [25]. In keratinocytes, ANXA1 associates, via its N-terminal region and in a Ca2+-dependent manner [35], with S100A11 to inhibit the activity of cPLA2 and limit cell proliferation [63,32]. During squamous cell transformation and after EGF exposure, ANXA1 is phosphorylated at Tyr21 by the EGFR and cleaved at Trp12 by cathepsin D. The truncation of ANXA1 at its N-terminal region leads to the dissociation of S100A11 and cPLA2 activation, thereby allowing cell growth and proliferation [63]. In another study, it was shown that dissociated S100A11 is actively secreted. The secreted form of S100A11 enhances the production of EGF and thereby stimulates keratinocyte growth [32]. The disruption of the ANXA1–S100A11 complex was also shown to inhibit EGFR internalization in Hela and A431 cells [37]. This was associated with a prolonged stimulation of this receptor and the activation of oncogenic pathways. Altogether, these data point out that ANXA1/S100A11 complex disruption (possibly by ANXA1 cleavage) may induce cell proliferation by at least three mechanisms involving EGFR stabilization, EGF production and cPLA2 activation.

NUCLEAR ANXA1

Although none of the annexins contains nuclear targeting sequences, different reports have indicated the nuclear location of ANXA1 [64,65]. To date, the precise mechanism leading to ANXA1 translocation from the cytoplasm to the nucleus and the functional relevance of this location are not fully understood. However, some reports have attempted to address these issues and have identified certain elements that argue for the role of nuclear ANXA1 in cell transformation and cancer.

ANXA1-nuclear translocation

ANXA1 translocates to the nucleus by mitogenic/proliferative and DNA-damaging stimuli such as EGF, heat, hydrogen peroxide, sodium arsenite and phorbol 12-myristate 13-acetate (PMA) [66,67]. One study with human embryonic kidney HEK293 cells focused on ANXA1 cellular location during a PMA-induced mitogenic signal [67]. The authors observed that nuclear translocation occurred in about 20–30% of treated cells, which suggests that ANXA1 translocation may be a cell cycle-dependent event [67]. Using inhibitors of different signalling kinases such as extracellular signal-related kinase (ERK), p38, phosphoinositide 3-kinase (PI3K) and protein kinase C (PKC), they identified PKCδ as the kinase responsible for ANXA1-nuclear translocation [67]. Given that PKCδ can phosphorylate ANXA1 at Thr24, Ser27 and/or Ser28 residues [68], it would be interesting to know whether nuclear translocation of ANXA1 depends on its phosphorylation by PKCδ. Once in the nucleus, ANXA1 is mostly modified by SUMO [69]. A recent structural study of ANXA1 revealed that the sumoylation site (Lys257) was located in a hot spot where several overlapping modulation sites, including a Ca2+-binding site (Asp253, Leu256 and Glu261) and a nuclear export signal (NES), from Leu254 to Asp259, were co-located [70]. The overlap of the NES region and the sumoylation site suggests that sumoylation could prevent the binding of nuclear export factors to NES, with the result that sumoylated ANXA1 is retained in the nucleus. Two independent studies showed that, after EGF treatment, ANXA1 was phosphorylated in the cytoplasm by EGFR at Tyr21 [63] and translocated to the nucleus [66]. This is in accordance with the observations that Tyr21 mutation led to a decreased sumoylation of ANXA1 whereas EGF treatment increased the sumoylation signal [70]. Altogether, these data suggest that nuclear translocation of ANXA1 is associated with a phosphorylation process (tyrosine and possibly threonine and serine phosphorylations) and regulated via cross-talk between its N-terminal and C-terminal domains (Figure 2).

Involvement of nuclear ANXA1 in cancer

Figure 2
Involvement of nuclear ANXA1 in cancer

The translocation of ANXA1 from cytoplasm to nucleus is initiated by mitogenic/proliferative signals (black arrows) or after DNA damage (red arrows). PMA treatment induces PKCδ activation, which allows ANXA1 phosphorylation and its relocalization to the nucleus. Similarly, the activation of EGFR by its cognate ligand (EGF) induces phosphorylation (of the Tyr21 residue) and nuclear translocation of ANXA1. Once in the nucleus, ANXA1 is sumoylated (within its third repeat at Lys257) and stimulates DNA replication via its helicase activity (black arrows). After DNA damage, ANXA1 is translocated from the cytoplasm to the nucleus where it is desumoylated and monoubiquitinated. By its helicase activity and in the presence of heavy metals (As3+ and Cr6+), monoubiquitinated ANXA1 allows translesion synthesis and mutagenesis (red arrows).

Figure 2
Involvement of nuclear ANXA1 in cancer

The translocation of ANXA1 from cytoplasm to nucleus is initiated by mitogenic/proliferative signals (black arrows) or after DNA damage (red arrows). PMA treatment induces PKCδ activation, which allows ANXA1 phosphorylation and its relocalization to the nucleus. Similarly, the activation of EGFR by its cognate ligand (EGF) induces phosphorylation (of the Tyr21 residue) and nuclear translocation of ANXA1. Once in the nucleus, ANXA1 is sumoylated (within its third repeat at Lys257) and stimulates DNA replication via its helicase activity (black arrows). After DNA damage, ANXA1 is translocated from the cytoplasm to the nucleus where it is desumoylated and monoubiquitinated. By its helicase activity and in the presence of heavy metals (As3+ and Cr6+), monoubiquitinated ANXA1 allows translesion synthesis and mutagenesis (red arrows).

Nuclear ANXA1 and cancer

The presence of ANXA1 in nuclei is now proposed as a significant predictor of poor overall survival in oral and oesophageal squamous cell carcinoma [64,71] and peritoneal dissemination in patients with gastric cancer (GC) [65]. More interestingly, it was reported in oesophageal cancer that, although ANXA1 expression was decreased in the cytosol and membranes, it was increased in the nuclei [72]. This suggests that, apart from its expression level, ANXA1’s subcellular location may play an important role in tumorigenesis.

ANXA1 contains sequence and structural motifs for binding to DNA and/or RNA [73]. It can bind dsDNA and ssDNA in Mg2+- and Ca2+-dependent manners, respectively [74]. Furthermore, this protein is present in DNA synthesomes [75] and exerts helicase activity. In the presence of ATP and Mg2+, ANXA1 binds and unwinds dsDNA by hydrolysing ATP into ADP, but in the presence of Ca2+ it binds two ssDNA molecules and mediates their annealing [74].

As DNA replication and repair require helicase activity, it is now recognized that nuclear ANXA1 participates in tumorigenesis by introducing mutations into DNA. DNA damage is a major cause of mutation. It can be induced by exposure of cells to physical (UV, radiation, heat) or chemical agents, but it can also arise spontaneously owing to the inherent instability of DNA or attacks by intermediates of cellular metabolism [76]. One category of damage-induced mutagenesis is thought to involve insertion of an incorrect nucleotide(s) at the lesion site during DNA polymerization. After this translesion synthesis (TLS), a second round of replication using the nascent strand as a template fixes the mutation in both strands of a DNA duplex. TLS, therefore, allows the cell to tolerate the presence of DNA damage and avoids potentially fatal replicative arrest. However, this may occur at the expense of replication accuracy and give rise to mutations [77]. Clearly, tolerance of DNA damage via TLS may account for a significant fraction of damage-induced mutations linked to the development of cancer [78]. TLS is catalysed by error-prone DNA polymerases (with reduced fidelity), which are recruited via ubiquitination of nuclear proteins such as proliferating cell nuclear antigen [79].

Nuclear ANXA1 can also be monoubiquitinated in the nucleus by the ubiquitin-conjugating enzymes UbcH2A and UbcH2A (Rad6 homologues), together with E3 ubiquitin ligase, Rad18 [69]. As the Rad6–Rad18 system is closely associated with DNA damage bypass [77,80], it has been speculated that ANXA1 is involved in TLS and mutagenesis. In fact, it has been shown, in mouse L5178Y tk+/− lymphoma cells treated with DNA-damaging agents, that the amount of nuclear ANXA1 increased whereas the cytoplasmic counterpart decreased. Accordingly, the authors suggested that nuclear translocation of ANXA1 occurs in response to DNA damage signalling [69]. In addition, analysis of the nuclear pool of ANXA1 showed that, after treatment with a DNA-damaging agent, the proportion of ubiquitinated ANXA1 increased at the expense of the sumoylated form.

Sumoylation and monoubiquitination stimulated the helicase activity of ANXA1 by approximately 3.5- and 6-fold, respectively, compared with the native protein [69]. Furthermore, monoubiquitinated ANXA1 exhibited higher affinity and enhanced annealing activity for damaged ssDNA, whereas sumoylated ANXA1 had a greater affinity for undamaged oligonucleotides [81]. These observations suggest that ubiquitinated ANXA1 is involved in DNA damage response [69].

Although the heavy metals As3+ and Cr6+ are not directly mutagenic by themselves they are carcinogenic and can promote mutagenic effects [82]. As they can replace Ca2+ in the DNA-annealing reaction by ANXA1 [69], it was suspected that nuclear ANXA1 was involved in heavy metal-induced mutagenesis. In fact, As3+ and Cr6+ increase the affinity and the annealing ability of nuclear ANXA1 for the oxidatively damaged DNA but not for undamaged oligonucleotides [81]. Moreover, when As3+ and Cr6+ are present, nuclear extracts of L5178Y tk+/− lymphoma cells promote TLS. The mutagenic effects of these heavy metals were due to ANXA1 because TLS was inhibited by anti-ANXA1 antibody [81]. Finally, when L5178Y tk+/− lymphoma cells were exposed to the alkylating agent methyl methanesulfonate (MMS) and AsCl3, tk gene mutations occurred. Such mutations can be suppressed by pretreatment of L5178Y tk+/− cells with an ANXA1 anti-sense oligonucleotide [83]. Altogether, these observations provide strong evidence that nuclear monoubiquitinated ANXA1 is involved in heavy metal-promoted translesion DNA synthesis and is able to increase the introduction of mutations into DNA (Figure 2).

EXTERNALIZED ANXA1

Protein externalization from eukaryotic cells follows a path named the classic, or ER/Golgi-dependent, secretory pathway. Briefly, secreted eukaryotic proteins use an N-terminal signal peptide to direct their co-translation on ER-bound ribosomes into the ER lumen, after which they progress to the Golgi apparatus, from where they are ultimately exported through secretory vesicles to the cell surface or the extracellular environment [84]. ANXA1 sequence analysis revealed the lack of an N-terminal signal peptide, which is required for classic externalization of the protein [85]. This is consistent with the observation that inhibitors such as brefeldin A, monensin and nocodazole (inhibitors of classic secretory pathway) had no effect on ANXA1 externalization [86], and suggests that ANXA1 could be externalized through non-classic secretory pathways. In addition, it was often observed that, after its externalization, ANXA1 undergoes a proteolytic cleavage on its N-terminal end, near the FPR-recognition motif [8789].

In the next section, we first describe the different processes of ANXA1 externalization, then discuss the significance of its cleavage and finally summarize the role of the ANXA1/FPR complex in cancer.

ANXA1 externalization

Different studies aiming to characterize the ANXA1 externalization process reported that the protein could be externalized through five mechanisms involving direct interaction with the plasma membrane, membrane transporters or vesicular trafficking.

Through lipidation and Ser27 phosphorylation

In the pituitary FS cell line, phosphorylation induced by PKC at residue Ser27 promotes ANXA1 externalization through a passage across the plasma membrane [90]. Although the molecular processes behind this mechanism have not been fully addressed, it seems that ANXA1 externalization depends on a myristoylation process. As the sequence of ANXA1 itself includes potential sites for this modification (mapped to ANXA1 within Gly30–Ala35, Gly59–Ile65, Gly215–Asn222 and Gly320–Gln325 peptides [90]) and that PKC targets its myristoylated substrate to the plasma membrane [91], ANXA1 lipidation could be a prerequisite step for membrane targeting and a process facilitating ANXA1 passage across the plasma membrane (Figure 3A).

Non-classic secretory pathways of ANXA1
Figure 3
Non-classic secretory pathways of ANXA1

Depending on the cell type, ANXA1 is externalized through one of five mechanisms: (A) myristoylation and phosphorylation of Ser27 by PKC followed by membrane crossing and localization at the outer leaflet of the PM; (B) the activation of the ABC-A1 transporter; (C) through fusion of ANXA1-containing granules with the PM, followed by ANXA1 release and association with the cell surface, where ANXA1-binding proteins are expressed; (D) MP formation, by PM budding (the lipid bilayer becomes inside-out oriented leading to the exposure of phosphatidylserine-associated ANXA1 to the outside), secretion and subsequent fusion with the PM of a recipient cell; or (E) MVE fusion with the PM, exosome secretion (ANXA1 being associated with the exosome surface) and PM docking.

Figure 3
Non-classic secretory pathways of ANXA1

Depending on the cell type, ANXA1 is externalized through one of five mechanisms: (A) myristoylation and phosphorylation of Ser27 by PKC followed by membrane crossing and localization at the outer leaflet of the PM; (B) the activation of the ABC-A1 transporter; (C) through fusion of ANXA1-containing granules with the PM, followed by ANXA1 release and association with the cell surface, where ANXA1-binding proteins are expressed; (D) MP formation, by PM budding (the lipid bilayer becomes inside-out oriented leading to the exposure of phosphatidylserine-associated ANXA1 to the outside), secretion and subsequent fusion with the PM of a recipient cell; or (E) MVE fusion with the PM, exosome secretion (ANXA1 being associated with the exosome surface) and PM docking.

Through an ATP-binding cassette transporter

A study using transporter inhibitors showed that in inflamed rat colonic mucosa ANXA1 is secreted by an ATP-binding cassette (ABC) [92]. Another study extended this line of enquiry and showed, with siRNA technology and fluorescence microscopy co-localization, that ABC-A1, a member of the ABC family, was particularly involved in ANXA1 secretion and association with the cell surface (Figure 3B). As the inhibition of this transporter did not completely abrogate ANXA1 externalization, the authors suggested that other non-classic mechanisms might contribute to ANXA1 release [93].

Through neutrophil degranulation

Perretti et al. [8] have shown that ANXA1 is localized in the matrix of gelatinase granules in resting polymorphonucleocytes (PMNs). On adhesion to endothelial cells, the granules translocate and fuse with the plasma membrane during a process called degranulation, leading to the release of ANXA1 in the extracellular compartment and its association with the cell surface [94]. Given that ANXA1 is present in punctuated localizations in the plasma membrane, the authors suggested that this process was controlled by ANXA1-binding proteins, which are also expressed on the cell surface [95] (Figure 3C).

Through microparticle secretion

Microparticles (MPs or ectosomes) are membrane-coated vesicles of varying size (50–200 nm) [96]. They originate from plasma membrane (PM) budding. After the activation of flippases and scramblases, the bud–lipid bilayer becomes inside-out oriented with phosphatidylserine being exposed to the outside [97]. This process occurs before membrane shedding and MP secretion [97,98]. As ANXA1 has a high affinity for acidic phospholipids (notably phosphatidylserine) [6], the hypothesis of MP surface-associated ANXA1 has been investigated. Dalli et al. [99] showed that, on PMN activation, neutrophil-derived MPs harbour functionally active ANXA1 that confers anti-inflammatory properties on them. A later study reported that, after the fusion of MPs (harbouring ANXA1 on their surface) with the PM of recipient cells, ANXA1 became associated with the external leaflet of the phospholipid bilayer and was able to exert anti-inflammatory activity (Figure 3D) [100]. Altogether, these findings provide evidence of another mechanism of ANXA1 externalization. However, it is not clear if free ANXA1-associated MPs alone can exert this anti-inflammatory effect or if the fusion with a recipient cell is a prerequisite to modulating leukocyte trafficking.

Through an exosomal pathway

Exosomes are small endosome-derived vesicles, ranging in size from 40 nm to 100 nm in diameter [96]. They are formed, similar to the intraluminal vesicles, by budding into early endosomes and multivesicular endosomes (MVEs). In response to a cellular signal, exosomes are actively released by fusion of MVEs with the plasma membrane (exocytosis). The released exosomes may then dock at the plasma membrane of a target cell by either direct fusion or endocytosis [101]. It is not surprising, therefore, that after the fusion process proteins that were associated with the exosome bilayer membrane become localized at the cell surface of a targeted cell. Members of the annexin family, including ANXA1, are associated with the exosome surface [102,103]. By fractionation of the cell supernatant into exosome-free and exosome-associated fractions, it was shown in breast cancer cells that annexin externalization required exosome fusion with the plasma membrane (Figure 3E) [103]. To our knowledge this is the only mechanism attributed to annexin externalization in the field of cancer. This process has to be studied in further detail to improve our understanding of the ANXA1 action mode in cancer.

ANXA1 N-terminal cleavage

ANXA1 can undergo, in vitro and in vivo, proteolytic cleavage(s) in its N-terminal region [2,63,8789,104106]. Depending on the protease involved, this cleavage may occur at different positions (see Table 1). On the basis of these observations, three hypotheses were considered: (i) ANXA1 cleavage is a homoeostatic mechanism limiting the biological function of the protein; (ii) it is an activating stage leading to the release of bioactive N-terminus-derived peptide(s), which allows distant interaction with cells expressing ANXA1 targets; or (iii) ANXA1 and its derived peptide(s) have different targets allowing distinct biological effects.

ANXA1 cleavage is a process limiting the biological function of the protein

This hypothesis was validated in a neutrophil-extravasation process. Using a human recombinant ANXA1 or ANXA1-based peptide (ANXA12–50) resistant to PR3 cleavage (a protease partially involved in externalized ANXA1 cleavage in neutrophils [88]), the authors showed that PR3-resistant ANXA1/ANXA12–50 interacted with FPR2 and induced the same signalling cascade as the native protein/peptide. Nevertheless, PR3-resistant ANXA1/ANXA12–50 displayed a stronger and longer anti-inflammatory effect (inhibition of neutrophil rolling and adhesion to endothelial cells) [107,108]. As the crucial motif for FPR2 binding and activation was mapped to ANXA1 from Lys9 to Val25 [109] and PR3 cleaved ANXA1 after the residues Ala11, Val22 and Val36 [88], it is most likely that the released peptides would not have any effect on FPR2. This suggests that, indeed, in neutrophils ANXA1 cleavage is a process leading to limitation of its anti-inflammatory property. A later study showed that cleaved ANXA1 had a proinflammatory activity [104]: it acted on endothelial cells to increase intercellular adhesion molecule 1 (ICAM1) clustering around adherent neutrophils to anchor them to the endothelium and promote transmigration [104]. This suggests that two different fragments of the parent protein have opposite functions and pinpoints the pivotal role of ANXA1 cleavage in the regulation of the inflammatory response.

ANXA1 cleavage allows distant interaction with target cells through the release of bioactive peptide(s)

Different observations obtained from indirect in vitro studies argue in favour of this hypothesis. Blume et al. [105] reported that exposure of ANXA1 during secondary necrosis coincided with proteolytic processing at Phe7 by ADAM10 (A Disintegrin and metalloproteinase domain-containing protein 10). Most importantly, using the ANXA12–7 peptide, they demonstrated that the released peptide and culture supernatants of secondary necrotic ANXA1-externalizing cells induced chemoattraction of monocytes [105]. As the ANXA12–7 peptide does not contain the FPR recognition motif, this suggests the presence of a novel target for ANXA1 which still needs to be identified in future studies. In addition, the authors showed in a previous study that the cell-bound core fragment of cleaved ANXA1 is involved in the phagocytic removal of dead cells and the regulation of the postphagocytic cytokine response [110]. Thus, ANXA1 constitutes a multifunctional protein that acts on its fragment (core domain or released N-terminal peptide) at different stages of dying cell clearance.

Scannell et al. [111] reported the role of ANXA1 peptide in the phagocytosis of apoptotic cells. They showed that, in apoptotic PMNs, human mesangial and Jurkat T-cells, ANXA1 was externalized and cleaved. To demonstrate the presence of ANXA1 peptide, they fractionated the supernatant of apoptotic PMNs using a 10-kDa molecular mass cut-off membrane. They found that fractions containing small proteins (<10 kDa) stimulated the prophagocytic activity of monocyte-derived macrophages and differentiated THP-1 cells. More importantly, this effect can be abrogated by a neutralizing antibody for ANXA1. Finally, using an FPR inhibitor (tBoc2), the authors showed that the released peptide interacted in a paracrine manner with FPRs expressed by target cells to stimulate their phagocytic activity, which is responsible for apoptotic cell clearance.

Recently and for the first time, one ANXA1 peptide was detected in the secretome of human pancreatic cancer cells (MIA-PaCa-2) [112]. A full scan analysis of the secretome–peptide fraction was performed by LC/high-resolution MS/MS and, on the basis of collision-induced dissociation spectra, the authors were able to identify the ANXA14–26 peptide. This suggests that the released peptide was processed at its N-terminal part, while maintaining the FPR-recognizing motif (Lys9–Val25). Although the results regarding the functional significance of this peptide are only preliminary they offer a convenient method for detecting ANXA1 peptide in different contexts and also for validating, in future studies, the hypotheses mentioned above.

The biological effect of full-length ANXA1 differs from that of its N-terminal-derived peptide

Although activation of FPR2 with the full-length protein or its derived peptide shares some similarities with regard to the downstream-induced targets, a number of activated genes were specific to each molecule, suggesting distinct downstream biological outcomes [113]. Hayhoe et al. [114] have shown that, although ANXA12–26 bound both FPR1 and FPR2, ANXA1 bound only FPR2. Furthermore, they compared the role of the two molecules in PMN interaction with Human Umbilical Vein Endothelial Cells (HUVECs) under flow and it appeared that, by triggering FPR2, ANXA1 inhibited adhesion of human PMNs whereas ANXA12–26, by triggering FPR1, significantly attenuated capture and rolling without an effect on adhesion [114]. FPR1 was largely studied for its role in inflammation and human diseases [42,115]. More importantly it was shown that the ANXA1/FPR1 axis could be involved in fibroblast wound-healing deficiency [116] and the progression of GC [117,118] and glioma [119]. Both the use of ANXA12–26 for functional studies and the multiple observations of the ANXA1-truncated isoform provided arguments for the implication of ANXA1/FPR1 interaction in disease. However, ANXA1 cleavage and its released peptide are still poorly characterized.

ANXA1/FPRs axis and cancer

The ANXA1/FPRs axis has been extensively studied and discussed in the context of normal and abnormal inflammatory responses [2,120]. In general, by binding FPR1/FPR2, ANXA1 induces different pathways including PLA2, phospholipase D, MAPK and PI3K pathways [12,41]. Depending on the studied cells and the state of differentiation, activation of these pathways has opposite outcomes, e.g. the induced pathways lead to cell differentiation (from monocytes to macrophages and dendritic cells) and to proliferation (T-cells) but also to apoptosis and necrosis (neutrophils). ANXA1/FPR signalling pathways and their biological implications in inflammation (pro- and anti-inflammatory effects in innate and adaptive immunity) have already been reviewed [2,120]. The expression/deregulation of ANXA1 and FPRs has been observed in a variety of tumours. In the present review, we focus on studies in which a relationship between the ANXA1/FPR complex and oncogenic pathways was established (Figure 4).

ANXA1/FPR axis in cancer

Figure 4
ANXA1/FPR axis in cancer

Although externalized ANXA1 stimulates FPR2, the released peptide, obtained by a proteolytic cleavage in its N-terminal domain, stimulates FPR1 and FPR2. Depending on the cancer cell type, ANXA1 and its released peptide can stimulate MAPK, PI3K and STAT3 pathways to induce proliferation via cyclin D1, survival through BCL-2, angiogenesis through HIF-1α and VEGF, EMT through Snail and Twist, stemness through Oct 4, and invasion through MMP2 and Iβ1BP1.

Figure 4
ANXA1/FPR axis in cancer

Although externalized ANXA1 stimulates FPR2, the released peptide, obtained by a proteolytic cleavage in its N-terminal domain, stimulates FPR1 and FPR2. Depending on the cancer cell type, ANXA1 and its released peptide can stimulate MAPK, PI3K and STAT3 pathways to induce proliferation via cyclin D1, survival through BCL-2, angiogenesis through HIF-1α and VEGF, EMT through Snail and Twist, stemness through Oct 4, and invasion through MMP2 and Iβ1BP1.

Gastric cancer

ANXA1 expression is significantly associated with peritoneal metastasis and serosal invasion and is an independent risk factor for poor overall survival in patients with GC [117]. Furthermore, in vitro analyses showed that GC cells express FPR1, FPR2 and FPR3. By individual inhibition of these receptors, the authors showed that ANXA1 triggered the three FPRs and stimulated cell invasion by extracellular signal-related kinase (ERK) phosphorylation and subsequent integrin β1-binding protein 1 (Iβ1P1) expression [117]. It was of interest that it was recently reported that FPR1 expression (ANXA1 peptide target) correlated with the same clinical features and outcome of patients with GC who overexpressed ANXA1. Furthermore, a positive feedback regulation of FPR1 is involved in the ANXA1–FPR1 signal transduction [118].

Breast cancer

ANXA1 expression correlated significantly with poor disease-free survival (DFS) of breast cancer patients [121]. Although intracellular ANXA1 is involved in the invasion process by promoting TGF-β/Smad signalling, actin reorganization, NF-κB translocation and MMP9 expression [60,62], externalized ANXA1 is implicated in tumour growth. FPR1, FPR2 and FPR3 are expressed by breast cancer cells that harbour, at their surface, full-length as well as cleaved ANXA1. Using the ANXA12–26 peptide and by silencing the expression of the full-length protein, the authors showed that ANXA1 triggers FPR2 and to a lesser extent FPR1 (possibly through the released peptide). FPR stimulation promotes mitogenesis by increasing cyclin D1 levels via activation of the PI3K/protein kinase B (Akt)/p70S6K pathway [122].

Prostate cancer

Initially, zoledronic acid (ZA) was used in clinical practice, notably in patients with prostate cancer, to reduce skeletal-related events and pain associated with bone metastases. It was then shown that, besides its effect on osteoblasts, ZA had anti-tumour activity [123]. It inhibited farnesylpyrophosphate synthase, a pivotal enzyme in the mevalonate pathway, which had been involved in carcinogenesis [124,125]. ANXA1 was overexpressed in DU145R80 prostate cancer cells, which are resistant to ZA, compared with their DU145 parental ones [126]. It is interesting that, although DU145R80 cells harboured at their surface full-length and cleaved ANXA1, the parental cells expressed only the full-length protein [127]. Further investigations have shown that, apart from FPR1, which was expressed by both cell lines, FPR2 was present only in DU145R80 cells. Using selective antagonists for each receptor, it was shown that both receptors were functional and could be induced by ANXA12–26. Indeed, ANXA1/FRR interaction stimulated cell invasion, possibly through the expression of MMP2/MMP9, focal adhesion kinase (FAK), E-cadherin and vimentin. In addition, it was found that ANXA1 was involved in JAK/STAT3 and ERK1/2 pathway induction to confer stem cell-like properties on prostate cancer cells via the expression of NANOG, ALDH1A7 and ABCG2 [127].

Glioma

The FPRs/fMLP axis in glioblastoma cells stimulates the phosphorylation of different proteins in vitro including ERK, p38, JNK (c-Jun N-terminal kinase), Akt and STAT3 (at Tyr705 and Ser727). However, only the MAPK pathway seemed to be involved in glioblastoma progression [128]. In fact, it was shown that induction of the MAPK pathway by FPR stimulation promoted: (i) the expression of the anti-apoptotic protein, Bcl-2, and thus maintained cell survival; (ii) the nuclear translocation of hypoxia-inducible factor (HIF)-1α, which increased the expression of vascular endothelial growth factor (VEGF) to stimulate cell growth; and (iii) MMP2 expression, which enhanced cell invasion capacity [128,129]. FPR agonist activity was reported to be present in the supernatants of necrotic glioma cells [128]. This provides evidence that this receptor might interact ‘in a paracrine manner’ with host-derived agonists produced in the tumour microenvironment, presumably in the necrotic area frequently associated with highly malignant gliomas. On the basis of these findings and using neutralizing antibody, Yang et al. [119] thereafter identified that ANXA1 was the chemotactic agonist for FPR1, and accounted for most of the FPR1 agonist activity. ANXA1 was released by necrotic tumour cells and promoted tumour cell growth and invasion [119]. Finally, clinical studies confirmed the involvement of ANXA1 in glioma progression and its correlation with poor patient outcomes [119,130].

Melanoma

We and others have recently reported in retrospective studies that DFS in patients with melanoma was inversely related to ANXA1 and FPR (FPR1 and FPR2) expression [131,132]. Consistent with these findings, full-length and cleaved ANXA1 levels (proteolytic cleavage occurring after full-length protein externalization) in human melanoma cell lines were found to positively correlate with cell invasion capacity. Further in vitro analyses showed that melanoma cell lines expressed FPR1 and FPR2, and that their stimulation by ANXA1 promoted cell invasion. This effect occurred at least partially through ERK and STAT3 phosphorylation, which in turn induced the expression of MMP2 and its release to the extracellular compartment [89,131].

FUTURE PERSPECTIVES

During the past decade, substantial progress has been made in understanding the molecular mechanisms of ANXA1 in cancer. However, further studies are needed to gain fuller knowledge of its mode of action and to assess its use in therapy.

Nuclear ANXA1

It was shown in vitro that monoubiquitinated ANXA1, together with error-prone DNA polymerases, was involved in alkylating agent (MMS)- and heavy metal-induced mutagenesis [83]. However, to date, there are no in vivo data showing the role of ANXA1 in oncogene mutation. Although it was reported that ANXA1 expression correlated with K-ras mutation in colorectal cancer [133], it is not clear whether K-ras mutation was induced by nuclear ANXA1 or whether ANXA1 expression was the consequence of the activation of the K-ras oncogenic pathways. Mutations caused by error-prone DNA polymerases can be potentiated after chemotherapy (e.g. cisplatin, MMS) and lead to treatment insensitivity [134]. The possibility that ANXA1 can operate with error-prone DNA polymerases to bypass lesions induced by chemotherapeutic agents is suggested by the association of ANXA1 expression and cancer resistance to chemotherapy [135,136] and more specifically the role of nuclear ANXA1 in protecting HeLa cells from cisplatin treatment [137]. It is therefore quite conceivable that efficient inhibitors of ANXA1 could potentiate cell response to chemotherapy. In fact, it was recently shown that the use of compounds targeting ANXA1 rendered lung cancer cells more sensitive to cisplatin [138].

ANXA1 and tumour microenvironment

It is assumed that solid cancers are not simple clusters of malignant tumour cells but rather represent complex organ-like structures encompassing endothelial, fibroblast and immune cells (stroma). The modulation of cancer cells by stroma and vice versa is one of the important processes that steers tumour progression [139]. This cross-talk involves secreted molecules such as peptides, chemoattractants and growth factors from each compartment [140]. Certain related observations argue for the participation of secreted ANXA1 in such a process. First, it was shown in a melanoma syngenic model that mice treated with the proinflammatory FPR agonist (WKYMVm) had a smaller number of myeloid-derived suppressor cells and greater natural killer cell infiltration, which significantly inhibited tumour growth [141]. It is thus conceivable that secreted ANXA1 and its derived peptide (FRP anti-inflammatory agonists [142]) could influence the tumour microenvironment to escape immune surveillance. Second, a study using ANXA1-knockout mice, to abolish exclusively the expression of stroma-derived ANXA1, showed that tumour growth, angiogenesis and metastasis were significantly reduced [143]. Finally, it was reported that prostate-derived cancer-associated fibroblasts secreted ANXA1 to confer stem cell-like properties on prostate cancer cells. Secreted ANXA1 increased the expression of TGF-β1, TGFβ receptor II, Oct4 (stem cell marker) and Snail and Twist (EMT markers) in prostate cancer cells, possibly via FPR activation [144]. Altogether, these studies suggest that ANXA1 could be a tumorigenic mediator between cancer cells and their microenvironment, and that more detailed investigations would be warranted.

ANXA1 and tumour vasculature

Caveolae, special types of lipid raft, are small (50–100 nm) invaginations of the plasma membrane in many cell types, especially in endothelial cells [145]. They are frequently associated with stress fibres to ensure molecule trafficking into, and more importantly across, the cell [146]. It was shown that targeting proteins expressed in caveolae from endothelial cells allowed specific pumping of intravenously injected antibodies into the lung [147]. Cleaved ANXA1 is expressed in caveolae from human tumours (breast, kidney, liver, lung, brain and prostate), at luminal surfaces of the microcirculation, but not in normal vessels. More interestingly, Alexa Fluor 488-conjugated anti-ANXA1 antibody injected intravenously into mice (bearing tumours) rapidly accumulated in tumours at an unprecedented speed for the binding kinetics of an antibody or any other probe [148]. Moreover, injecting 125I-labelled ANXA1 antibody intravenously into rats bearing lung tumours caused significant remission even in advanced disease [149]. These data demonstrate that ANXA1 is specifically expressed in tumour vasculature (at least in breast, kidney, liver, lung, brain and prostate cancers) and could be a promising target for human tumour imaging, drug delivery and internal radiotherapy.

CONCLUSIONS

ANXA1 exhibits tumour type-specific patterns of expression and localization. It plays important roles in tumour development, proliferation, invasion and metastasis. In some cancers, ANXA1 is translocated to the cell surface, where it stimulates FPRs to induce oncogenic pathways. This makes ANXA1 an accessible target that should be assessed in therapy. In addition to ANXA1, FPRs are singular in that they can be activated or silenced by specific ligands. Their potential roles in cancer make them an attractive family of pharmacological targets.

We thank Mehdi Boudhraa for careful and critical reading of the manuscript.

Abbreviations

     
  • AA

    arachidonic acid

  •  
  • ABC

    ATP-binding cassette

  •  
  • Akt

    protein kinase B

  •  
  • ANXA1

    annexin A1

  •  
  • BLBC

    basal-like breast cancer cell

  •  
  • DFS

    disease-free survival

  •  
  • EGFR

    epidermal growth factor receptor

  •  
  • EMT

    epithelial–mesenchymal transition

  •  
  • ER

    endoplasmic reticulum

  •  
  • ERK

    extracellular signal-related kinase

  •  
  • FPR

    formyl-peptide receptor

  •  
  • GC

    gastric cancer

  •  
  • HIF

    hypoxia-inducible transcription factor

  •  
  • Iβ1BP1

    integrin β1-binding protein 1

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • MMS

    methyl methanesulfonate

  •  
  • MP

    microparticle

  •  
  • MVE

    multivesicular endosome

  •  
  • NES

    nuclear export signal

  •  
  • PAF-AH

    platelet activating factor–acyl hydrolase

  •  
  • PKC

    protein kinase C

  •  
  • PLA2

    phospholipase A2

  •  
  • PM

    plasma membrane

  •  
  • PMA

    phorbol 12-myristate 13-acetate

  •  
  • PMN

    polymorphonucleocyte

  •  
  • TLS

    translesion synthesis

  •  
  • VEGF

    vascular endothelial growth factor

  •  
  • ZA

    zoledronic acid

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