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Cancer Microenviron. Aug 2011; 4(2): 199–208.
Published online Mar 5, 2011. doi:  10.1007/s12307-011-0064-9
PMCID: PMC3170418

The Role of Annexin A2 in Tumorigenesis and Cancer Progression

Abstract

Annexin A2 is a calcium-dependent, phospholipid-binding protein found on various cell types. It is up-regulated in various tumor types and plays multiple roles in regulating cellular functions, including angiogenesis, proliferation, apoptosis, cell migration, invasion and adhesion. Annexin A2 binds with plasminogen and tissue plasminogen activator on the cell surface, which leads to the conversion of plasminogen to plasmin. Plasmin is a serine protease which plays a key role in the activation of metalloproteinases and degradation of extracellular matrix components essential for metastatic progression. We have recently found that both annexin A2 and plasmin are increased in conditioned media of co cultured ovarian cancer and peritoneal cells. Our studies suggest that annexin A2 is part of a tumor-host signal pathway between ovarian cancer and peritoneal cells which promotes ovarian cancer metastasis. Accumulating evidence suggest that interactions between annexin A2 and its binding proteins play an important role in the tumor microenvironment and act together to enhance cancer metastasis. This article reviews the current knowledge on the biological role of annexin A2 and its binding proteins in solid malignancies including ovarian cancer.

Keywords: Annexin A2, p11 protein, t-PA, Plasmin and metastasis

Introduction

The plasminogen activation system known to be involved in thrombolysis and wound healing plays a major role in cancer progression. The inactive enzyme plasminogen is converted to the active serine protease plasmin by plasminogen activators; tissue plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA). Plasmin is involved in many biological processes besides vascular thrombolysis including angiogenesis, tissue remodeling and also activates metalloproteinases (MMPs) and latent growth factors and the degradation of extracellular matrix (ECM), processes which all contribute to tumor development and metastasis [1]. A well studied protein which is an important mediator in the plasminogen activator system is annexin A2 [2]. The interaction between annexin A2 and t-PA mediates the conversion of plasminogen to plasmin and increases the catalytic efficiency of plasmin generation by up to 60-fold [3].

Annexin A2, a calcium-binding cytoskeletal protein is localized at the extracellular surface of endothelial cells and various types of tumor cells [4, 5]. The increased expression of annexin A2 has been reported in cancers of the breast, liver, prostate and pancreas [69]. Additionally, annexin A2 has also been demonstrated to play a role in cancer cell migration, invasion [7, 10] and adhesion [11, 12], processes which are essential for cancer metastasis. This article reviews the current knowledge on annexin A2 expression in various malignancies including ovarian cancer and its role in regulating cancer cell behavior.

The Structure and Function of Annexin A2

Annexin A2 belongs to the annexin family of calcium binding proteins which consists of 12 members (A1-A11 & A13). Each family member shares the conserved calcium binding motif in the carboxyl domain. However, the individual annexin members have diverse functions due to the highly variable amino-terminal domain [13]. Annexin family members have been reported to play multiple roles in cancer, including signal transduction, angiogenesis, tumour invasion and metastasis and apoptosis (reviewed in [14]). Studies have shown annexin A1, A2, A3, A4, A6, A8 and A11 to be up- regulated whilst annexin A1, A2, A7, A8, A10 and A11 are decreased in different cancer types [14]. Moreover, annexins have also been associated with chemo resistance in breast and ovarian cancer cells [1518].

The human annexin A2 gene spans approximately 40 kb on the long arm of chromosome 15 (15q21) [19]. This region has been shown to be associated with allelic imbalance in advanced breast cancer [20]. However, no annexin A2 mutations have been described to date in cancer or other diseases. Annexin A2 has a functional N-terminal domain with p11 proteins and t-PA binding sites and a C-terminal domain consist of binding sites for calcium, phospholipids and actin filaments (Fig. 1). Annexin A2 exits both as a monomer and a heterotetramer. The annexin A2 monomer is an intracellular 38 kDa protein whilst, the annexin A2 heterotetramer consisting of two subunits of annexin A2 monomers and two subunits of p11 proteins (also known as S100A10) localized to the plasma membrane [21]. The translocation of annexin A2 monomers from the cytoplasm to the cell surface occurs as a result of heat stress [22], tyrosine phosphorylation [23], and interaction with heat shock protein 90 alpha [24, 25]. In endothelial cells, translocation of annexin A2 to the plasma membrane due to heat stress is dependent on the expression of p11 proteins and phosphorylation of tyrosine 23 [22]. Annexin A2 also assists in the rearrangement of the actin cytoskeleton, maintaining the plasticity of the actin cytoskeleton and regulating membrane trafficking events including endocytosis and exocytosis [2628].

Fig. 1
Annexin A2 domain structure. The N-terminal domain consists of the p11 proteins and tissue plasminogen activator (t-PA) binding sites. The C-terminal domain consists of four repeating domains which each contains annexin A2 consensus sequence and the biding ...

Expression of Annexin A2 in Cancer

Many studies have reported increased expression of annexin A2 in cancer tissues compared with normal tissues [6, 7, 2931] (Table 1). The up-regulation of annexin A2 expression in pancreatic, colorectal, and brain tumors was directly correlated with advanced clinical stage [3133]. Higher annexin A2 expression was also observed in metastatic breast cancer and colon cancer cells compared with the non-metastatic cells [7, 34]. In prostate cancer however, reports regarding annexin A2 have been conflicting. Whilst several studies reported a reduction of annexin A2 expression in prostate cancer tissues [3538], a study by Banerjee et al. (2003) showed high focal membrane staining of annexin A2 in high grade prostate cancers and the prostate carcinoma cell lines, PC3 and DU145 [39]. Furthermore, a more recent study demonstrated a correlation between high annexin A2 levels and a more aggressive prostate cancer phenotype [9].

Table 1
Annexin A2 expression in cancer

Conflicting results on annexin A2 expression have also been observed in head and neck cancers. A study by Wu et al. (2002) using 2D gel-electrophoresis of two head and neck squamous cell carcinoma cell lines derived from primary and metastatic tumors from the same patient, found annexin A2 to be up-regulated in the cell line established from the metastatic cancer cell line [40]. In contrast, Pena-Alonso et al. (2008) observed a significant down-regulation of annexin A2 mRNA and protein levels in poorly differentiated carcinomas of the head and neck by real time-PCR and immunohistochemistry [41]. These contradictory findings may be explained by different experimental techniques utilised to examine annexin A2 expression or differences between primary tumors and metastatic lesions. The different annexin A2 levels identified by Wu et al. (2002) may reflect annexin A2 protein modifications detected by mass spectrometry which are not detectable by real-time PCR or immunohistochemistry [40]. Despite various studies having confirmed either an up or down regulation of annexin A2 in various tumour types, the exact mechanism that regulate annexin A2 expression at both gene and protein level are poorly understood.

Annexin A2 apart from being a cell surface protein, has also been shown to be secreted. Deora et al. (2003) reported that annexin A2 is secreted via a non-classical secretory pathway as it does not have a signal secretion sequence [22]. Secreted annexin A2 was also found in the conditioned media of co-cultured human keratinocytes and fibroblasts [42]. Annexin A2 secretion has been also reported for various tumor types. Davis et al. (1995) demonstrated high levels of secreted annexin A2 in a human pancreatic adenocarcinoma cell line (Capan-2) [43]. Zhao et al. (2003) have reported that annexin A2 secretion by rat adrenal pheochromocytoma (PC12) cells in vitro is induced by activation of both the insulin and insulin like growth factor receptor followed by reduction of intracellular annexin A2 [44]. A study by Ji et al. (2009) reported that annexin A2 was up-regulated in the serum of hepatocellular carcinoma patients compared with the serum of healthy patients by ELISA [45]. A recent study using a proteomic approach investigating the secretome of the gastric cancer cell line, SGC7901 identified annexin A2 as a secreted phosphoprotein [46]. Together these studies suggest that annexin A2 has potential diagnostic and prognostic value for several different carcinomas which needs to be further examined.

Role of Annexin A2 and Its Binding Proteins in Cancer

The co-localization of annexin A2 with its binding proteins including t-PA, p11 protein, tenascin C and cathepsin B facilitates the proteolytic cascade leading to the activation of pro-enzymes and selective degradation of ECM components which regulate cancer cell properties and enhance metastasis (reviewed in [5]). Several studies have demonstrated the co-expression of annexin A2 and p11 protein in tumor and endothelial cells. Annexin A2 co-localizes with p11 protein at the surface of tumor cells where plasminogen activation occurs [47]. Puisieux et al. (1996) showed a co-expression of annexin A2 and p11 protein in colon, renal and liver carcinoma cell lines [48]. Moreover, over-expression of annexin A2 and p11 protein was observed in renal cell carcinoma tissues when compared with normal kidney [31]. Zhang et al. (2010) also reported over-expression of annexin A2 and p11 protein in the invasive breast cancer cell lines compared with the non-invasive breast cancer cell lines [47].

Annexin A2 also binds to tenascin C (reviewed in [5]), a large ECM molecule which is expressed in the tumor microenvironment and plays an important role in tumorigenesis (reviewed in [49]). Esposito et al. (2006) reported annexin A2 and tenascin C to be over-expressed at both the mRNA and protein levels in pancreatic cancers compared with normal pancreas tissues [50]. Moreover, the interaction between annexin A2 and tenascin C has been shown to regulate cell migration and to enhance cell proliferation of endothelial cells [51]. Tenascin C has also been shown to be over-expressed in malignant ovarian tumor and to regulate adhesion and migration of ovarian cancer cells [52].

Cathepsin B, a lysosomal cysteine protease on the cell surface of various tumor cells (reviewed in [5]) also binds to annexin A2. Mai et al. (2000) reported that human pro-cathepsin B interacts with the annexin A2 heterotetramer which is co-localized on the surface of human breast carcinoma and glioma cells [53]. Cavallo-Medved et al. (2009) recently reported that the co-localization of cathepsin B and annexin A2 heterotetramer were involved in ECM degradation in endothelial cells during in vitro tube formation [54].

There are also other proteins which have been reported in the literature to bind to annexin A2. Annexin A2 receptor protein which has been characterized in osteoclasts [55] plays an important role in promoting prostate cancer progression [11]. Annexin A2 binds to collagen I in epithelial cells in a calcium dependent manner [56] and annexin A2 also interacts with the transcription factor, STAT6 in the metastatic prostate cancer cells [57]. Annexin A2 also binds to progastrin in colon cancer cells [58] and the interaction between annexin A2 and progastrin mediate growth effects of progastrin in gastrointestinal cancers (reviewed in [59]). Furthermore, annexin A2 has also been reported to form complexes with other S100 proteins such as S100A4 in endothelial cells [60] and S100A6 in pancreatic cancer cells [61].

Role of Annexin A2 in the Plasminogen Activator System

Emerging evidence indicates that annexin A2 plays an important role in the plasminogen activator system which regulates cancer metastasis and angiogenesis (reviewed in [62, 63]). The interaction between annexin A2 and t-PA mediates the conversion of plasminogen to plasmin [3, 64, 65] which facilitates MMP activation and ECM degradation leading to enhanced cancer cell migration and invasion [10, 66]. These findings suggest that annexin A2 is likely to play an important role in the early dissemination model which has been recently described by Coghlin and Murray [67].

Kinetic studies have demonstrated that binding of annexin A2 to t-PA on the cell surface of endothelial cells increases the catalytic efficiency of plasmin generation by up to 60-fold [3]. The co-localization of annexin A2 and t-PA has been demonstrated in breast and pancreatic cancer cells [10, 66, 68]. Roda et al. (2003) reported that the annexin A2 binding site for t-PA, the LCKLSL peptide motif (amino acid 8–13), is vital for the interaction between annexin A2 and t-PA to mediate plasmin production [69]. This was confirmed by Diaz et al. (2004) who reported activation of plasminogen via specific interaction of t-PA and annexin A2 in pancreatic cancer cells using the LCKLSL annexin A2 peptide [10].

Over-expression of annexin A2 resulted in higher levels of plasmin production in acute promyelocytic leukaemia cells [70] and increased plasmin levels were also observed in invasive breast cancer cell lines when compared with non-invasive cell lines [47, 66]. Recently, the interaction between heat shock protein 90 alpha (Hsp90a), annexin A2, t-PA and plasminogen in the exosomes of human breast, glioma and fibrosarcoma cancer cell lines resulted in increased cancer cell motility due to increased plasmin production [24]. Thus, these studies suggest increased annexin A2 expression enhances plasmin generation in the cancer cells via the t-PA dependent plasminogen activation pathway.

Role of Annexin A2 in Cancer Cell Adhesion, Invasion, and Migration

Several studies suggest that annexin A2 plays an essential role in regulating cancer cell adhesion, invasion, proliferation and migration [10, 36, 66, 71]. The effects of annexin A2 on different cancer cells are summarised in Table 2. Sharma et al. (2006) demonstrated that the highly invasive breast cancer cell line, MDA-MB231 expressed high annexin A2 levels and in the presence of plasminogen resulted in plasmin generation which could be blocked by a monoclonal antibody to annexin A2 [7]. However, neither plasmin production nor annexin A2 expression was observed in the non-metastatic MCF-7, breast cancer cell line [7]. Additionally, annexin A2 expression was shown to be up-regulated in MDA-MB231 breast cancer cells by basic fibroblast growth factor (bFGF) which is known to accelerate tumor growth and angiogenesis [7]. A later study by Sharma et al. (2009) confirmed the importance of annexin A2 and t-PA interactions on the cell surface of MDA-MB231 cells and demonstrated that the t-PA dependent plasmin generation was essential for cancer cell migration and neo-angiogenesis [66]. In contrast, Gillette et al. (2004) showed that over-expression of annexin A2 in osteosarcoma cells did not alter their metastatic properties such as motility, adhesion, or proliferation. This study suggested however that annexin A2 decreases osteosarcoma aggressiveness by inducing a more differentiated state [72]. Furthermore, Jung et al. (2007) demonstrated using both in vivo and in vitro studies that the annexin A2 heterotetramer regulates adhesion of hematopoietic stem cells to osteoblasts and bone marrow endothelial cells [73]. Recently, Shiozawa et al. (2008) also reported that annexin A2 regulates adhesion and migration of prostate cancer cells to osteoblasts and endothelial cells [11].

Table 2
Summary of the effects of annexin A2 on cancer cells

Annexin A2 has also been demonstrated to play an important role in regulating cytoskeleton structures and actin remodeling which both are essential for cancer cell migration [74, 75]. A recent study by Pu et al. (2009) reported that annexin A2 interaction with HAb18G/CD187 (a member of immunoglobulin family) promotes invasion and migration of human hepatocellular carcinoma cells (FHCC-98 cells) in vitro [76]. siRNA studies have also confirmed that knockdown of annexin A2 expression decreases cell migration in human glioma cells [77] and decreases the invasive ability of multiple myeloma cells [71]. The silencing of annexin A2 expression in hepatocellular carcinoma cells results in a significant decrease of both MMP-2 and MMP-9 levels which decreases cancer cell invasiveness [76]. Bao et al. (2009) also showed that the loss of annexin A2 expression leads to reduced levels of pro-angiogenic molecules including MMP-2, MMP-9, MTI-MMP, and TIMP2 in multiple myeloma cell lines (U266 and RPMI18226) [71]. These pro-angiogenic molecules are essential for tumor cell properties such as angiogenesis, proliferation and invasion [71]. Annexin A2 and Hsp90alpha released in the exosomes of the tumor cells activates plasminogen and pro-MMP2 which increase plasmin production to enhance ECM remodeling and increased tumor cell motility and invasion in the tumor microenvironment [24]. These studies demonstrate that annexin A2 is a key factor in regulating MMP secretion and activation which are essential for ECM degradation and metastatic progression.

Hou et al. (2008) reported that annexin A2 regulates p11 protein and plasmin levels in a mouse lymphoma (L5178Y) cell line [78]. Annexin A2 knockout in L5178Y cells exhibited reduced cell motility and invasion in vitro and in vivo [78]. In a recent study by Zhang et al. (2010) showed that the silencing of annexin A2 expression resulted in an inhibition of breast cancer cell proliferation and invasion which was also associated with a down-regulation of p11 protein and plasmin levels [47]. Together these studies indicate that annexin A2 plays an important role in promoting adhesion, migration and subsequent metastasis of cancer cells.

Post Translational Modifications and Proteolytic Cleavage of Annexin A2 in Cancer Cells

Several studies have reported post-translational modification and proteolysis of annexin A2 in cancer. Multiple isoforms of annexin A2 were identified by 2D gel electrophoresis and mass spectrometry in colorectal and oral carcinomas [79, 80]. Phosphorylation at tyrosine 23 in the N-terminal domain of annexin A2, has been shown to be present in liver [8] and pancreatic cancer tissues but not in corresponding normal tissues [32]. Takano et al. (2008) also observed post-translational modifications of annexin A2 in a chemotherapy-resistant pancreatic cancer cell line compared with chemo-sensitive cells [81]. Zheng et al. (2009) recently reported that phosphorylation of annexin A2 at tyrosine 23 was essential for localisation of annexin A2 at the cell surface and its contribution to the invasive properties of pancreatic cancer cells [32]. Eustace et al. (2011) recently reported increased phosphorylated forms of annexin A2 in dasatinib sensitive melanoma cell lines (WM-115) compared with the dasatinib resistant cell line (WM-2660-4) [82].

Annexin A2 can also undergo proteolysis. N-terminal processing of annexin A2 in human peripheral monocytes [83] and endothelial cells [84] induced by plasmin resulted in the loss of the first 27 amino acid residues. Tomonaga et al. (2007) reported cleavage of annexin A2 in the C-terminal end of annexin A2 in the healthy bowel mucosa but not in the colorectal cancer samples [80]. Tsunezumi et al. (2008) demonstrated that treatment of human colon cancer and breast cancer cell lines with MMP-7 (matrilysin) can result in specific cleavage of annexin A2 at the N-terminal region between Lys9 and Leu10 within the t-PA binding motif [85]. This study additionally demonstrated that the first nine amino acid residues in the N-terminal domain of annexin A2 bound preferentially to t-PA over intact annexin A2 on the surface of colon cancer cells [85]. Annexin A2 cleavage induced by glycogen synthase-3 was also observed in a time-dependent manner in serum-free conditioned media of human lung epithelial cells and human epidermoid cells [86]. Whilst several studies have demonstrated post-translational modifications of annexin A2, including phosphorylation changes and annexin A2 cleavage by cancer cells, the regulation of these modifications is poorly understood. Further studies are required to evaluate the significance of these modified forms of annexin A2 in cancer.

Annexin A2 and Ovarian Cancer

To date, there is limited knowledge about the importance of annexin A2 in ovarian cancer. A proteomic ovarian cancer biomarker study by Wang et al. (2004) using 2D liquid phase separation followed by reverse-phase high performance liquid chromatography (RP-HPLC) and matrix-assisted laser desorption or ionisation-time of flight (MALDI-TOF) mass spectrometry, identified annexin A2, amongst other proteins at three different pI values. Annexin A2 at pI 7.10, was markedly elevated in ovarian cancer cell lines when compared with normal ovarian surface epithelial cells, suggesting that a post-translational modification of annexin A2 occurs in ovarian cancer cells [87]. Furthermore, Gagne et al. (2007) also found annexin A2 to be up-regulated in the highly metastatic, TOV-112D epithelial ovarian cancer cell line compared with the TOV-81D ovarian cancer cells with low malignant potential, using iTRAQ (isobaric tag for relative and absolute quantitation) and 2D gel electrophoresis coupled with liquid chromatography and tandem mass spectrometry [88]. A more recent microarray study by Tchagang et al. (2008) reveal increased annexin A2 gene expression in ovarian cancer tissues when compared with normal ovarian tissue [89]. Moreover, several proteomic studies have also identified annexin A2 in the secretome of human ovarian cancer cell lines [90, 91].

We have recently explored the interaction between ovarian cancer and peritoneal cells using an in vitro co culture system [92]. We compared proteins in the secretome of ovarian cancer (OVCAR-5) and peritoneal cells (LP-9) cultured separately (Fig. 2a) and co-cultured together (Fig. 2b). We identified annexin A2 to be up-regulated in the secretome of co-cultured ovarian cancer and peritoneal cells by 2D-gel electrophoresis and mass spectrometry (Fig. 2b). Furthermore, we have recently reported increased plasmin levels during the co culture of ovarian cancer and peritoneal mesothelial cells in vitro [92]. Preliminary findings have demonstrated high annexin A2 immunostaining in serous ovarian cancer tissues compared with benign serous cystadenomas (Fig. 3). Our studies suggest that increased plasmin production and increased annexin A2 secretion is part of a tumor-host signal pathway between ovarian cancer and peritoneal cells which promotes ovarian cancer metastasis. Ongoing studies in our laboratory are currently investigating the importance of annexin A2 in ovarian cancer metastasis and its potential as a novel therapeutic target for this malignancy.

Fig. 2
A. 2D-gel electrophoresis of proteins in the secretome of ovarian cancer (OVCAR-5) and peritoneal cells (LP-9) cultured separately. B. 2D-gel electrophoresis gel of proteins in the secretome of OVCAR-5 and LP-9 co culture. Circled spots that were up-regulated ...
Fig. 3
Annexin A2 expression in human ovarian tumor tissues. a. Benign serous cystadenoma b. Serous ovarian carcinoma. Annexin A2 immunohistochemistry using mouse anti-annexin A2 (BD Biosciences, 1: 500), with a citrate buffer microwave retrieval. Bar = 100 μm ...

Annexin A2 as a Potential Therapeutic Target in Cancer

Several research groups have targeted annexin A2 to inhibit cancer progression and metastasis. Monoclonal antibodies against annexin A2 have been reported to be an effective therapeutic approach against Lewis lung carcinoma xenografts [93]. Jacovina et al. (2001) reported that a polyclonal antibody against the N-terminal domain of annexin A2 was able to block plasmin production in rat adrenal pheochromocytoma (PC-12) cells in vitro [94]. Annexin A2 has also been shown to bind to angiostatin, a powerful anti-angiogenic molecule that is generated from plasminogen processing [95]. Tuszynski et al. (2002) reported that angiostatin binding to the lysine binding domain of annexin A2 in endothelial cells results in an anti-angiogenic effect [95]. Moreover, the interaction between annexin A2 and angiostatin resulted in reduced plasmin generation in Lewis lung carcinoma cells [93]. These findings indicate that plasminogen and angiostatin may bind to the same annexin A2 binding site and the anti-angiogenic action of angiostatin is mediated via interactions with annexin A2 [95]. These studies suggest angiostatin-like compounds that block annexin A2 binding to plasminogen could be promising cancer therapeutics. More recently, Braden et al. (2009) showed that polymeric nanoparticles combined with annexin A2 siRNA vector to allow long term annexin A2 silencing could inhibit prostate cancer growth in mice [96]. Annexin A2 has also been identified as a molecular target for TM601 (a peptide with tumor-targeting and anti-angiogenic effects) in glioma, lung and pancreatic cancer cells [97]. Together these studies indicate that annexin A2 has a great potential as therapeutic target to inhibit cancer progression and metastasis.

Conclusions and Future Directions

In conclusion, annexin A2 has been shown to play an important role in cancer cell migration, invasion, adhesion and angiogenesis processes which are essential for cancer metastasis. Emerging evidence indicates that annexin A2 plays an important role in the plasminogen activator system. The interaction between annexin A2 and t-PA mediates the conversion of plasminogen to plasmin which facilitates ECM degradation leading to enhanced cancer cell migration and invasion (Fig. 4). Annexin A2 over-expression and proteolytic cleavage has also been demonstrated in different malignancies. The processing of annexin A2 by MMPs and other proteases results in several annexin A2 isoforms but no studies so far have investigated the significance of these isoforms in tumor progression. Additional studies are needed to further explore the interactions between annexin A2 and its binding proteins and the importance of post-translational modifications of annexin A2 to promote tumor invasion and metastasis. A greater understanding of these mechanisms could potentially lead to the development of novel therapeutics to inhibit annexin A2 function and tumor progression.

Fig. 4
Proposed mechanism of annexin A2 promoting cancer metastasis in the plasminogen activation system. Annexin A2 heterotetramer on the cell surface binds to t-PA and activates plasminogen conversion to plasmin. Plasmin results in activation of MMPs and lead ...

Acknowledgement

This research was supported by the Ovarian Cancer Research Foundation (OCRF).

References

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