Experimental Hematology and Oncology Full text Three are better than… — Volkswagen Mod.181

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Three are better than plasminogen receptors as cancer targets

* Corresponding author: Novelli franco.novelli@unito.it

#134; contributors

Author Affiliations

1 for Experimental Research and Medical (CeRMS), Azienda Ospedaliera della Salute e della Via Cherasco 15, Turin, 10126,


Annexin 2; Cytokeratin 8; Plasminogen system; Plasminogen Cancer; Immunotherapy


The system is involved in tumor invasion and metastasis [1 -5 ]. Several of this system have now demonstrated to have a clinical as diagnostic and prognostic markers in types of cancer [6 -11 ]. Overexpression of receptors has been associated poor prognosis, shorter survival and resistance to chemotherapy. this over-expression may lead to the of autoantibodies in many types of which can be consequently used as biomarkers. Moreover, most system components are cell and therefore represent readily targets for cancer therapy. review aims to analyze the receptors Annexin 2 (ANX2), 8 (CK8) and alpha-Enolase (ENOA) in the common tumors and to correlate expression with specific responses and/or clinical

The plasminogen system

Plasminogen is a glycoprotein produced by the liver and in plasma and extracellular fluids [12 -15 ]. It seven structural domains: an activation peptide (1–77 five kringle domains and a domain (562–791 aa). The domains mediate plasminogen to substrates and to cell surface [13 ,16 ] whereas the activation of plasminogen to is mediated by the proteolytic action of tissue-type (tPA) or urokinase-type plasminogen activators [2 ,4 ,17 ,18 ]. Plasmin is a protease with a broad-spectrum including fibrin, extracellular components (laminin, fibronectin) and involved in extracellular matrix (matrix metalloproteinases, such as [16 ,19 -22 ]. Binding of plasminogen to surface has profibrinolytic consequences: enhancement of activation, protection of plasmin its inhibitor a2-antiplasmin and enhancement of the activity of cell-bound plasmin [4 ,23 -25 ]. mediated by cell-associated plasmin both to physiological processes, as tissue remodeling and embryogenesis, and to processes, such as cell metastasis and inflammatory responses [2 -4 ,26 -28 ]. A positive correlation exists elevated levels of plasminogen and malignancy [2 ,29 ].

Plasminogen receptors plasminogen by carboxy-terminal lysines, and common recognition motif in a similar affinity of plasminogen for of its receptors (Kd ≈ 1μM). Although plasminogen receptors have described so far [30 -43 ], the most well-known receptors shown to play a in cancer are ANX2, CK8 and ENOA. of the plasminogen lysine binding with ENOA and CK8 is dependent recognition of three C-terminal [23 ,40 ]. For ENOA, an additional internal binding site, which Lys256, has been proposed [44 ]. On the hand, ANX2 harbors amino acids that C-terminal lysines and therefore cleavage prior to binding [45 ].

Molecular features of plasminogen

ANX2 is a 36 kDa peripheral membrane (p36) that belongs to the family, consisting of calcium-dependent proteins with various functions [46 -48 ]. ANX2 either as a monomer, a heterodimer or a heterotetramer, the being composed of two copies of a 36 kDa chain (p36) and two copies of an 11 kDa chain (p11). Formation of the heterotetramer facilitates its binding to the membrane [45 ,48 ,49 ].

CK8 is an intermediate filament that polymerizes with to form a component of the epithelial [50 ]. In addition to its cytoplasmic localization it can be expressed on the cell surface [51 ,52 ] it is localized to the blebs of the cell and acts as a plasminogen receptor [53 ].

(2-phospho-D-glycerate hydrolase) was initially as a metalloenzyme that catalyzes the of 2-phospho-D-glycerate (PGA) to phosphoenolpyruvate in the glycolytic pathway [54 ,55 ]. In vertebrates, the has three different isoforms beta, and gamma) codified by independent loci. While is mostly ubiquitous, beta- and are almost exclusively found in and in neuronal tissues, respectively [54 ,56 ,57 ]. can form homo- or heterodimers, as alpha-alpha, alpha-beta and alpha-gamma [58 ,59 ]. homo- and heterodimers can be expressed on the surface where they act as receptors.

Interestingly ANX2, CK8 and amino acid sequences a transmembrane portion, and the mechanism by they are displayed on the cell remains unknown. Several have been proposed for the surface expression, including binding followed by translocation to the membrane [60 ]; penetration and projection the plasma membrane as a part of a complex [52 ,61 ]; and non-covalent association to the membrane after proteolytic from cells into the space [62 -64 ]. In the case of ANX2 and post-translational modifications, such as acetylation, methylation and phosphorylation, common in tumor cells, may play a role [65 -67 ].

Expression and of ANX2 in cancer

ANX2 is expressed on the surface of epithelial vascular endothelial cells and and is not only involved in plasminogen but also in many biological that include inflammation, proliferation, angiogenesis, cell–cell and membrane bridgings, exocytosis and cell growth and apoptosis [48 ,68 -73 ]. All functions are due to its ability to interact actin filaments in the cytoskeletal to locate proteases and other matrix components (plasminogen-plasmin-tPA) on the surface through tetramerization, or by as a major substrate for phosphorylation and as a messenger of growth-mediating receptor [49 ]. ANX2 is phosphorylated on Tyr23, and Ser25 residues by c-Src, and Protein Kinase C (PKC), [74 -76 ] after activation of insulin [77 ], insulin growth factor [78 ], platelet-derived growth factor-R [79 ], growth factor (FGF) or growth factor (EGF) [80 ]. ANX2 may play a role as a messenger for transduction of growth and

During oncogenic transformation, is usually up-regulated and is a marker of in the majority of cancer types 1 ) [68 ,81 -101 ]. As a result, it is a valuable for cancer diagnosis. In fact, in carcinoma (HCC), ANX2 has proposed as a differential diagnostic in combination with glypican-3 glutamine synthetase (GS) and shock protein 70 (HSP70) [65 ,85 ,86 ,90 ,93 ,98 -104 ]. ANX2 down-regulation has been reported in certain such as laryngeal and esophageal cell carcinoma, head and dysplasia [105 -109 ], [110 ] and prostate cancer -113 ] (Table 1 ). In osteosarcoma and carcinoma, ANX2 overexpression is associated with well-differentiated and, in certain cases, down-regulation was observed in poorly-differentiated which may be due to its ability to promote independently from its plasminogen-binding [107 ,110 ]. Indeed, in carcinoma two different groups reported an increased expression of in tumor tissue compared to the normal mucosa or mucosa patients without oral [100 ,107 ]. Rodrigo et al. added a clinical correlation in which the lower expression of seemed to correlate with a prognosis. Even if these appear controversial, both reported that in poorly tumors, which usually with a bad prognosis, ANX2 was We can therefore speculate that is up-regulated even in oral but microenvironment and inflammatory responses to the anaplastic condition induce of ANX2 during cancer Opposite trends reported as a suitable prognostic marker in renal (CRCC), colorectal and carcinomas, where its expression correlates with a favorable outcome [85 ,93 ,96 ,100 ,101 ]. In when up-regulated, ANX2 to cancer invasion and metastasis by as a co-receptor for plasminogen, tPA and pro-cathepsin B [49 ]. plasmin generation is required for metastasis and angiogenesis in several types [47 ,65 ,68 ,114 -117 ]. For it has been demonstrated that in cancer (PDAC), tyrosine 23 is necessary for cell-surface localization of This translocation is critical for the Growth Factor beta Rho-mediated epithelial-to-mesenchymal transition [65 ]. Moreover, in PDAC, ANX2 is a predictor of rapid recurrence surgery in patients who have gemcitabine-adjuvant chemotherapy [104 ]. In we can hypothesize that in tumors ANX2 is overexpressed, its role as a receptor predominates, and is responsible for the process, while in tumors ANX2 is down-regulated, plasminogen-independent favor the malignant state anaplastic transformation.

Table 1. Expression, immune clinical correlation and function of in cancer

Expression and function of CK8 in

Several mechanisms have proposed for the expression of CK8 on the cell In transformed cells, surface could be due to insufficient incorporation intermediate filaments due to over-production of CK8 [64 ]. CK8 is over-expressed both at the mRNA and the level in various carcinomas 2 ) and is present at the cell surface of human cancers and established cell lines [51 ,52 ,64 ,88 ,126 ]. By contrast, healthy human do not express CK8 at the cell surface, the exception of a sporadic and weak CK8 localization in the liver and heart ,130 ].

Table 2. Expression, response, clinical correlation and of CK8 in cancer

When present on the cell surface, CK8 binds and promotes its activation through activators. In breast cancer it also works as a receptor for uPA ], suggesting a model in which in complex with uPA, and fibronectin constitutes a signaling capable of modulating cell and growth. Indeed, increased of CK8/CK18 has been shown at the front of certain tumors ]. Of particular note, over-expression of CK8 on the cell surface and in the cytoplasm both in vitro and in vivo, increased invasiveness and metastatic [144 ]. In breast and endometrial a clear correlation exists CK8 expression and tumor stage ,144 ], and CK8 confers drug to chemotherapeutic treatment in breast cell lines [135 ]. The effect of CK8 over-expression on survival controversial as in non-small cell carcinomas (NSCLC), increasing levels of CK8 were significantly with tumor progression and patient survival [126 ], whereas breast cancer with low expression of CK8 and high of Human Epidermal Growth Receptor 2 (HER2) have a risk of recurrence and death 5 years (Table 2 ) [131 ].

and function of ENOA in cancer

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over-expression is associated with development through a process as aerobic glycolysis or the Warburg [146 ], which determines an in anaerobic glycolysis in hypoxic a very common feature in solid tumors, but also in the of normal levels of oxygen -149 ]. The ENOA promoter a hypoxia responsive element ,151 ] that leads to up-regulation at both the mRNA and levels (Table 3 ) [130 -173 ]. However, in a small of NSCLC [174 ], ENOA is down-regulated and, interestingly, is a that can be homozygously absent in [175 ]. In PDAC, ENOA is not up-regulated but is also subjected to post-translational modifications, namely methylation and phosphorylation which do not in normal tissue [67 ,176 ].

Table 3. Expression, immune clinical correlation and function of in cancer

Moreover, ENOA is on the surface of hematopoietic cells, as monocytes, T cells, B cells and according to their activation or pathophysiological conditions [54 ]. ENOA is on the cell surface of PDAC, and lung cancers [67 ,154 ,189 ] (Table 3 ), while in and NSCLC it is also secreted by [190 ,191 ]. On cell ENOA is part of a multi-protein together with uPA receptor integrins and certain cytoskeletal collectively known as a metastasome . for adhesion, migration and proliferation, as demonstrated in ovarian cancer [192 ]. Moreover, since interacts with the cytoskeleton in cells, its over-expression is likely to migration of tumor cells by ATP [29 ]. Noteworthy, in human follicular carcinoma cells, retinoic causes a decrease in ENOA that coincides with reduced motility [193 ], cell surface ENOA is in breast cancer cells super-invasive following paclitaxel [194 ].

The prognostic value of expression has been observed in tumors (Table 3 ) [156 -167 ,170 ,172 ,178 ,185 ]. In breast enhanced ENOA expression with a greater tumor poor nodal status and a disease-free interval. Higher of ENOA increases the risk of distance relapse when to loco-regional relapse in postsurgical Estrogen Receptor-positive breast patients. Therefore, down-regulation of could be a novel pharmacological for overcoming 4-Hydroxytamoxifen resistance in cancer therapy [167 ]. In and neck cancer and NSCLC, levels increase with progression and negatively correlate patients’ overall- and progression-free [166 ]. In HCC, ENOA is up-regulated in poorly differentiated compared to well-differentiated ones, and its positively correlate with size and venous invasion ,165 ]. Even if ENO1 are not used in clinical routine, the expression or the induced immune as show later, may have a value, especially in combination gold-standard markers. For example, in the detection of serum antibodies phosphorylated ENOA, in combination the commonly used serum CA19.9, enhances the ability to between control and cancer [185 ]. Taken together, findings determine that is a good biomarker to monitor progression and to predict clinical

Plasminogen receptors elicit responses in cancer

Activation of the system is an early event tumorigenesis, as illustrated by the detection of titers of autoantibodies in patients early-stage cancer, and correlates the progression of malignant transformation ,195 ,196 ]. The presence of an response to the plasminogen receptors CK8 and ENOA has been reported in with different types of

An autoantibody response against occurs in the early stages of carcinogenesis and in PDAC, ovarian, and cancer (Table 1 ) [65 ,119 ,122 ,123 ]. It has been that in melanoma, the ANX2 peptide induces antigen-specific T which can recognize cancer over-expressing the ANX2 molecule. peptide may therefore be useful in for recruiting CD4+ type 1 cells locally active in the environment [125 ]. Moreover, II clinical trial PDAC [124 ] showed an increased antibody response after of the GM-CSF (granulocyte-macrophage colony-stimulating PDAC-specific vaccine, which correlated with prolonged [65 ].

CK8/18 complexes elicit responses in breast, gastric, head and neck and liver [51 ,132 ,137 -141 ]. In cell carcinoma (SCC), titers of CK8-specific serum are detectable in early stage while a weaker humoral has been observed in advanced probably due to immunosuppression by tumor In several adenocarcinomas, patients an immune response against neo-epitopes of CK8 [137 ], while and neck and lung cancer develop autoantibodies against modified variants of the protein 2 ) [139 ,142 ]. The induction of antibodies against CK8 can be explained by its expression on the cancer cell that makes CK8 a potential for antibody-based cancer therapy.

A and/or T cell immune against ENOA has been in patients with breast, and neck, gastric, lung chronic myeloid leukemia, and PDAC (Table 3 ) [119 ,154 ,159 ,172 ,178 -181 ,183 ], [188 ]. Notably, detection of against ENOA combined expression of carcino-embryonic antigen and CK19 fragment enhances the for differential diagnosis of NSCLC ]. High levels of antibodies to ENOA were found in and their combination with the marker CA19.9 discriminates from controls [185 ]. The of the humoral response to phosphorylated also correlates with a progression-free survival upon treatment and overall survival ] and notably, with the presence of a T cell response [154 ,186 ,197 ]. Conversely, a decrease in basal levels of is a common event in late and breast cancers, proposing as a prognostic marker to monitor progression in these patients ].

Plasminogen receptors as therapeutic in cancer

Despite heterogeneous of plasminogen receptors existing in cells, only ENOA, CK8 and have a recognized role in cancer progression by promoting tumor invasion. ANX2 behaves as a tPA receptor, whilst and CK8 do not directly bind plasminogen but most likely form a complex with uPAR and [64 ,67 ]. Nevertheless, the contribution of these receptors to cancer development is not linked to their plasminogen-binding Indeed ANX2, ENOA and CK8 all with the actin cytoskeleton and an association could promote the of tumor cells independently plasminogen-binding [29 ]. These three are present on the surface of the majority of neoplasms, and in some cases, as breast and colon, they are altogether. All of these receptors an antibody immune response in patients that can be potentially for therapeutic purposes. Regarding the risk of inducing an autoimmune CK8 would probably be the best as it is aberrantly expressed only on the cell surface. However, the ANX2 and ENOA are frequently by tumor cells and exposed on the surface. This strengthens the for utilizing them as potential of therapeutic monoclonal antibodies. data obtained in animal show a therapeutic effect of monoclonal antibody (mAb) in breast, pancreatic and lung by inhibiting tumor growth, metastases and prolonging survival 1 ) [65 ,114 ,117 ]. Thus, plasminogen receptors is a promising to counteract metastasis development.

A recent paper has shown a DNA-based vaccination against ENOA, followed by electroporation, was to significantly prolong the median of expectancy of mice that develop PDAC [186 ]. the ENOA DNA vaccine induced a humoral and cellular response. against ENOA were to bind the cell surface of murine cells and mediate killing by complement-dependent cytotoxicity. “immunogenic” death might be for the greater influx of CD3 into and for their activation toward phenotype. Cytokines produced by Th populations strongly supported the switching of anti-ENOA autoantibodies ]. Moreover, the ENOA-DNA vaccine decreased suppressor cells as myeloid-derived suppressor cells and T cells [186 ].


with very few exceptions, all plasminogen receptors reported display performant diagnostic and values. Since one single type is not expected to account for the plasminogen binding on tumor a combined therapy targeting all molecules would be desirable. further studies are necessary in to better understand the involvement of three receptors in cancer so that more effective for cancer treatment may be developed.


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