Aminopeptidase N/CD13 induces angiogenesis through interaction with a pro-angiogenic protein, galectin-3

Yang, Eun-Ju; Shim, Joong Sup; Woo, Hee Jong; Kim, Kyu Won; Kwon, Ho Jeong

doi:10.1016/j.bbrc.2007.08.179

Cited by 44 publications

(34 citation statements)

References 18 publications

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“…Some papers suggested that CD13 could be exploited as a diagnostic and prognostic marker in certain tumors, such as lung squamous cell carcinoma and other non-small-cell lung cancer, gastric and colon carcinoma, hepatocellular and pancreatic carcinoma, ovarian and cervical cancer (Hashida et al 2002;Ikeda et al 2003;Rocken et al 2005;Ichimura et al 2006;Surowiak et al 2006;Tokuhara et al 2006;Kawamura et al 2007;Terauchi et al 2007;Yamashita et al 2007;Tsukamoto 2008;Ito et al 2009). More recently, other papers showed that CD13 plays multiple roles in angiogenesis (Pasqualini et al 2000;Bhagwat et al 2001;Bhagwat et al 2003;Bauvois 2004;Bauvois and Dauzonne 2006;Fukasawa et al 2006;Mahoney et al 2007;Rangel et al 2007;Yang et al 2007;Mina Osorio 2008). Consistently, we observed that angiogenic/activated (CD105 + ) exponentially growing HUVEC overexpressed CD13 and stained positive to the three anti-CD13 mAbs (data not shown), which in contrast did not stain CD31 + CD45…”

Section: Discussionsupporting

confidence: 91%

Enhanced Expression of CD13 in Vessels of Inflammatory and Neoplastic Tissues

Matteo

Arrigoni

Alberici

et al. 2011

J Histochem Cytochem.

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Aminopeptidase-N (CD13) is an important target of tumor vasculature-targeting drugs. The authors investigated its expression by immunohistochemistry with three anti-CD13 monoclonal antibodies (WM15, 3D8, and BF10) in normal and pathological human tissues, including 58 normal, 32 inflammatory, and 149 tumor tissue specimens. The three antibodies stained vessels in most neoplastic tissues, interestingly with different patterns. As a matter of fact, WM15 stained almost all intratumor and peritumor capillaries and only partially large vessels, whereas BF10 and 3D8 reacted with arteries and venules and to a lesser extent with capillaries. These antibodies also stained the stroma in about half of neoplastic tissues. In inflammatory lesions, the three antibodies stained vessels and stroma, whereas in normal tissues, they stained a small percentage of blood vessels. Finally, the three antibodies failed to stain endothelial cells of normal colon, whereas they reacted with activated human umbilical vein endothelial cells and with endothelial cells of colon adenocarcinoma vessels. Overall, WM15 was the most specific antibody for angiogenic tumor vessels, suggesting that it may be a good tool for detecting the CD13 form associated with the tumor vasculature. This finding may be relevant for CD13-mediated vascular targeting therapies.

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Section: Discussionsupporting

confidence: 91%

Enhanced Expression of CD13 in Vessels of Inflammatory and Neoplastic Tissues

Matteo

Arrigoni

Alberici

et al. 2011

J Histochem Cytochem.

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“…A study demonstrated that APN/CD13 could enhance invasive ability through interacting with tumor-associated surface antigen L6 [27]. Additionally, a number of studies [28, 29] have provided evidence that APN/CD13 plays a role in tumor progression by regulating cell–cell adhesion and angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Serum APN/CD13 as a novel diagnostic and prognostic biomarker of pancreatic cancer

et al. 2016

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Aminopeptidase N, also known as CD13, has been reported to be overexpressed in several cancers and may contribute to tumor metastasis and angiogenesis. The aim of this study was to evaluate whether serum APN/CD13 could be a potential biomarker for the diagnosis and prognosis of pancreatic cancer (PC). Serum APN/CD13 and carbohydrate antigen 19-9 (CA19-9) levels were measured from 382 participants, which comprised of 204 participants with PC, 48 participants with benign pancreatic tumors (BPT), 43 participants with chronic pancreatitis (CP) and 87 healthy controls (HC). We used receiver operating characteristic (ROC) analysis to calculate diagnostic accuracy. The association of serum APN/CD13 levels with the clinicopathological characteristics of PC patients and their survival was investigated. Serum APN/CD13 levels were substantially higher in PC patients than in controls. ROC analysis revealed that APN/CD13 was significantly better than CA19-9 in differentiating patients with PC from controls. Similar results were noted for early-stage PC. Moreover, the combined use of APN/CD13 and CA19-9 data improved the diagnostic accuracy for PC vs. controls, compared with either test alone. High serum APN/CD13 levels were associated with tumor size, lymph nodes, and metastasis (TNM) stage. Multivariate and ROC curve analyses revealed that high serum APN/CD13 level is an independent factor for predicting mortality and overall survival (OS). Moreover, Kaplan–Meier analysis demonstrated an inverse correlation between increased serum APN/CD13 level and OS. Our study established that serum APN/CD13 may be a novel diagnostic and prognostic biomarker for PC.

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“…26 In endothelial cells CD13 specifically interacts with galectin-3, a proangiogenic protein, in a carbohydrate recognition-dependent manner. 27 It is possible that the selectivity of NGR peptides for endothelial CD13 is related to differential glycosylation or to conformational changes caused by complex formation with this or other unknown compounds. Selective accessibility due to the structurally abnormal architecture of angiogenic vasculature is also likely to play a role.…”

Section: The Ngr Receptor(s)mentioning

confidence: 99%

The neovasculature homing motif NGR: more than meets the eye

Corti

Curnis

Arap

et al. 2008

Blood

176

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IntroductionPhage display libraries are often used for discovering peptide sequences that interact with proteins differentially expressed in normal and pathologic tissues. 1,2 Indeed, in vivo panning of peptide-phage libraries in tumor-bearing animal models has proven useful for selecting peptides able to interact with proteins expressed within tumor-associated blood vessels and therefore to home to neoplastic tissues. 3 Among the ligands identified so far, cyclic and linear peptides containing the Asn-Gly-Arg (NGR) motif have been exploited for systemic, yet ligand-directed targeted delivery of therapeutic and imaging agents to angiogenic blood vessels, including cytotoxic drugs and cytokines, among other entities (such as viruses and nanoparticles). These findings highlight the value of NGR peptides in drug development. In this review we discuss the biochemical and biologic properties of NGR and NGR-derived compounds. Given that many native proteins contain the sequence NGR, we also address the emerging role of NGR as an unrecognized "molecular timer" due to the timedependent generation of isoAsp-Gly-Arg (isoDGR), a new integrinbinding motif that regulates a gain-of-function within the extracellular matrix protein fibronectin. 4 The discovery of the NGR motifIn vitro panning of several phage libraries against the ␣5␤1 integrin led to the selection of various RGD-containing peptides and also of the peptide NGRAHA. 5 These peptides (including NGRHA) inhibited cell attachment mediated by both ␣v␤3 and ␣v␤5 integrins. Moreover, 8 NGR-containing peptides were isolated upon screening of cyclic peptide libraries under similar experimental conditions. 6 Notably, one selected phage clone displayed the peptide CVLNGRMEC, which is similar to the sequence ALN-GREE found within the 9th type III repeat of human fibronectin. 7 Further studies based on in vitro selection of libraries on ␣v␤3, revealed several different peptides containing the NGR motif, such as NGRIPD, TNGRGP, NGRSFR, RSRNGR, NGRNTV. 8 In another line of investigation, in vivo phage-display screenings were performed to isolate tumor-homing peptides. Systemic administration of a phage library into nude mice bearing human breast carcinoma xenografts led to selection of a tumor vasculaturehoming phage carrying the sequence CNGRCVSGCAGRC. 3 Tumor homing was inhibited by co-injection with the CNGRC peptide (NGR-2C) indicating that this short cyclic loop is a functional tumor targeting peptide. Phage displaying the peptides NGRAHA or CVLNGRMEC, previously identified in vitro, also selectively localized to tumors. 3 The NGR receptor(s)In vivo phage display-based studies showed that also the peptide ACDCRGDCFC (RGD-4C), an ␣v␤3/␣v␤5 binding sequence, can bind to tumor neovasculature. 3,9 Cross-inhibition experiments of NGR-2C and RGD-4C-phage clones with synthetic RGD-4C and NGR-2C peptides showed that RGD-4C peptide does not compete the homing of NGR-2C-phage to tumors and vice versa. 3 This result suggests that NGR-2C and RGD-4C bind to distinct receptors in tumor ...

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Aminopeptidase N/CD13 induces angiogenesis through interaction with a pro-angiogenic protein, galectin-3

Cited by 44 publications

References 18 publications

Enhanced Expression of CD13 in Vessels of Inflammatory and Neoplastic Tissues

Enhanced Expression of CD13 in Vessels of Inflammatory and Neoplastic Tissues

Serum APN/CD13 as a novel diagnostic and prognostic biomarker of pancreatic cancer

The neovasculature homing motif NGR: more than meets the eye

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