Aminopeptidase A is a functional target in angiogenic blood vessels

Marchiò, Serena; Lahdenranta, Johanna; Schlingemann, Reinier O.; Valdembri, Donatella; Wesseling, Pieter; Arap, Marco Antônio; Hajitou, Amin; Ozawa, Michael G.; Trepel, Martin; Giordano, Ricardo J.; Nanus, David M.; Dijkman, H.B.P.M.; Oosterwijk, Egbert; Sidman, Richard L.; Cooper, Max D.; Bussolino, Federico; Pasqualini, Renata; Arap, Wadih

doi:10.1016/s1535-6108(04)00025-x

Cited by 130 publications

(87 citation statements)

References 37 publications

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“…To determine the best homing, SKLMS1 cells were incubated with targeted phage displaying one of the following: RGD-4C (10,14,15), the interleukin-11 receptor (IL11R)-targeting peptide CGRRAGGSC (21), or the aminopeptidase A (APA)-targeting peptide CPRECES (22); insertless phage and phage displaying an unrelated peptides served as negative controls. RGD-4C had the highest binding to sarcoma cell surfaces (Fig.…”

Section: Resultsmentioning

confidence: 99%

A preclinical model for predicting drug response in soft-tissue sarcoma with targeted AAVP molecular imaging

Hajitou

Lev

Hannay

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Human sarcomas are rare but diverse malignant tumors derived from mesenchymal tissue. Clinical response to therapy is currently determined by the modified World Health Organization (WHO) criteria or the Response Evaluation Criteria in Solid Tumors (RECIST), but these standards correlate poorly with sarcoma patient outcome. We introduced ligand-directed particles with elements of AAV and phage (AAVP) to enable integration of tumor targeting to molecular imaging. We report drug-response monitoring and prediction in a nude rat model of human sarcoma by AAVP imaging. As a proof-of-concept, we imaged Herpes simplex thymidine kinase in a clinic-ready setting with PET to show that one can a priori predict tumor response to a systemic cytotoxic. Given the target expression in patient-derived sarcomas, this platform may be translated in clinical applications. Sarcoma-specific ligands and promoters may ultimately lead to an imaging transcriptome.H uman sarcomas are rare yet heterogeneous malignant tumors from mesenchymal tissues (1). Monitoring drug responses in soft-tissue sarcoma has long been clinically problematic. Currently, responses are determined by the modified World Health Organization (WHO) criteria (2-4) or the Response Evaluation Criteria in Solid Tumors (RECIST) (5-7), which require marked tumor size decrease for patients to be considered responding to therapy. A major assumption of these criteria is that a solid tumor volume is directly proportional to the cancer cell number. However, in soft-tissue sarcomas, there are reasons to challenge such an assumption (8). First, in addition to tumor cells, sarcomas contain nonmalignant stromal cells and extracellular matrix (ECM) that do not disappear, even if the malignant component is treated. Moreover, when cytotoxics are used against sarcomas, there is often associated necrosis resulting in reduced total cell number but not necessarily overall tumor size changes. Finally, even if a soft-tissue sarcoma is predominantly or entirely composed of cancer cells, its remnant composition may not be fully eliminated when tumor cells are destroyed by therapy, because myxoid-type degeneration is not always promptly removed. Ultimately, the modified WHO criteria and RECIST correlate poorly with drug response and outcome in patients with soft-tissue sarcomas; validation in this setting is sporadic and restricted. In another level of complexity, drug responses in patients with soft-tissue sarcoma are determined through standard methods, such as CT, MRI, or PET scans. However, because systematic quantitative measurements have not been established because of the rarity and diversity of soft-tissue sarcomas, decreases in tumor size and/or density are not accepted as unequivocal evidence of response. Consequently, many conventional soft-tissue sarcoma responses in individual patients are evaluated qualitatively. Thus, new or alternative quantitative imaging criteria to improve management and follow-up of responses were proposed in ref. 9.We have introduced a hybrid vector that ena...

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Section: Resultsmentioning

confidence: 99%

A preclinical model for predicting drug response in soft-tissue sarcoma with targeted AAVP molecular imaging

Hajitou

Lev

Hannay

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…The cause of the premature death in the c-Maf null mouse has not been determined, but the relatively late stage mortality indicates that c-Maf is either compensated for by another large Maf or not involved in embryonic vasculogenesis. However, pathologic angiogenesis in the adult is believed to occur via processes distinct from those of normal developmental angiogenesis (Marchio et al, 2004,Marler et al, 2002,Becker et al, 2005 and thus formation of functional embryonic vasculature in the absence of c-Maf does not preclude its critical role in angiogenesis in the adult. An endothelial-specific c-Maf null animal model will be useful for addressing this question.…”

Section: Discussionmentioning

confidence: 99%

CD13/APN transcription is regulated by the proto-oncogene c-Maf via an atypical response element

Mahoney

Petrović

Schacke

et al. 2007

Gene

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Angiogenic growth factors induce the transcription of the cell surface peptidase CD13/APN in activated endothelial cells of the tumor vasculature. Inhibition of CD13/APN abrogates endothelial invasion and morphogenesis in vitro and tumor growth in vivo suggesting a critical functional role for CD13 in angiogenesis. Experiments to identify the transcription factors responsible for this regulation demonstrated that exogenous expression of the proto-oncogene c-Maf, but not other bZip family members tested, potently activates transcription from a critical regulatory region of the CD13 proximal promoter between −115 and −70 bp which is highly conserved among mammalian species. Using promoter mutation, EMSA and ChIP analyses we established that both endogenous and recombinant c-Maf directly interact with an atypical Maf response element contained within this active promoter region via its basic DNA/leucine zipper domain. However full activity of c-Maf requires the amino-terminal transactivation domain, and site-directed mutation of putative phosphorylation sites within the transactivation domain (serines 15 and 70) shows that these sites behave in a dramatic cell type-specific manner. Therefore, this atypical response element predicts a broader range of c-Maf target genes than previously appreciated and thus impacts its regulation of multiple myeloma as well as endothelial cell function and angiogenesis.

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Section: B Amentioning

confidence: 99%

“…Constitutively, APN is a membrane-bound metallopeptidase that plays multiple functions as a regulator of various hormones and cytokines, protein degradation, antigen presentation, cell proliferation, cell migration, and angiogenesis (Luan and Xu, 2007;Razak and Newland, 1992;Riemann, 1999). More recently, this technique allows the identification of the sequence CPRECES, specific for another aminopeptidase, the aminopeptidase A (APA), expressed on endothelial and perivascular tumour cells (Marchio, 2004).Various compounds, including cytotoxic drugs, cytokines, antiangiogenic agents, viral particles, fluorescent and contrast tracers, DNA complexes, and other biologic response modifiers have been coupled or synthetically added to NGR peptides in order to increase their vasculature-homing effects (Arap, 1998;Buehler, 2006;Corti and Ponzoni, 2004;Curnis, 2005;Curnis, 2000;Grifman, 2001;Pastorino, 2006;Pastorino, 2003a;Zarovni, 2004).Recently, we showed that liposomes are attractive for targeting drugs and other effectors to tumour vasculature because they can carry large payloads. Using nanoparticles of doxorubicin (DOX) targeted to tumour endothelial cells by coupling the liposomes with peptides containing the NGR sequence, we evaluated their efficacy in orthotopic model of human neuroblastoma (Pastorino, 2003a).…”

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confidence: 99%

“…Some of these determinants, including endoglin (Burrows, 1995;Seon, 2002), vascular endothelial growth factor (VEGF) receptors (Brekken and Thorpe, 2001;Veenendaal, 2002), a v b 3 -integrins (Arap, 1998;Brooks, 1994), the fibronectin EDB domain (Nilsson, 2001), the prostate-specific membrane antigen (Chang, 1999) and specific aminopeptidases (Arap, 1998;Marchio, 2004;Taylor, 1993) have been identified as targets for ligand-directed approaches involving VDAs. Preclinical investigations employing such liganddirected VDAs have shown not only the homing of the therapeutic moieties to tumour vessels but also the selective destruction of tumour vasculature (Pastorino, 2003a;Thorpe, 2004).…”

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confidence: 99%

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The use of the orthotopic model to validate antivascular therapies for cancer

Loi¹,

Paolo²,

Becherini³

et al. 2011

Int. J. Dev. Biol.

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The orthotopic model reproduces aspects of the tumour microenvironment and emulates a number of important biological features of cancer progression, angiogenesis, metastasis and resistance. Due to its parallels with human cancer, the model can be used to evaluate therapeutic responses to various therapies. This review outlines the importance of using the orthotopic implantation of tumour cells in mice models for evaluating the effectiveness of antivascular therapies. KEY WORDS: orthotopic model, vascular disrupting agent, antivascular therapy, cancer Tumour vasculature and antivascular therapiesA functioning and continuously expanding vascular network is essential for tumour development, growth, survival and metastasis (Hanahan and Folkman, 1996). Given its pivotal role in these processes, tumour vasculature is a highly attractive target in anticancer therapy. Compared with the vasculature in normal tissue, the tumour vasculature is strikingly disorganized and tortuous (Eberhard, 2000;Konerding, 2001;McDonald and Choyke, 2003), its wall is poorly developed, often with discontinuous endothelial-cell lining, has relatively poor investiture with vascular smooth muscle cells, poor connections between pericytes and endothelial cells (Dvorak, 1988;Eberhard, 2000;Hashizume, 2000;Kobayashi, 1993) and an irregular, structurally abnormal basement membrane (Baluk, 2003;Paku and Paweletz, 1991). Endothelial cells themselves are often irregularly shaped, forming an uneven luminal layer, with loose interconnections and focal intercellular openings (Hashizume, 2000). These features contribute to a high intrinsic vascular permeability of macromolecules into the vasculature (Dvorak, 1991;Jain, 1987) and the consequent development of high interstitial fluid pressure (Boucher, 1990), which is augmented by inadequate lymphatic drainage. Tumour vascular networks are chaotic, featuring complex branching patterns and lack of hierarchy (Gillies, 1999;Konerding, 1999;Less, 1991). Vessel diameters are irregular and lengths between branching points are often very long. The result is a high geometrical resistance to blood flow, that such as small decreases in perfusion pressure, which have little Int. J. Dev. Biol. 55: [547][548][549][550][551][552][553][554][555] doi: 10.1387/ijdb.103230ml www.intjdevbiol.com *Address correspondence to: Mirco Ponzoni or Fabio Pastorino. Experimental Therapies Unit, Laboratory of Oncology, G. Gaslini Children's Hospital, 16148-Genoa, Italy. Tel: +39-010-5636342. Fax: +39-010-3779820. e-mail: mircoponzoni@ospedale-gaslini.ge.it or fabiopastorino@ospedale-gaslini.ge.it # These Authors share the last co-authorship. effect in normal tissues, can be catastrophic in tumours (Sevick and Jain, 1989). Capillary blood contains abnormally high levels of deoxygenated blood (Mueller-Klieser, 1981), which, combined with heterogeneous blood flow and large intercapillary distances, contributes to micro-regional hypoxia in tumours (Vaupel and Hockel, 2000). The tumour is also starved of nutrient, under acidic cond...

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Aminopeptidase A is a functional target in angiogenic blood vessels

Cited by 130 publications

References 37 publications

A preclinical model for predicting drug response in soft-tissue sarcoma with targeted AAVP molecular imaging

A preclinical model for predicting drug response in soft-tissue sarcoma with targeted AAVP molecular imaging

CD13/APN transcription is regulated by the proto-oncogene c-Maf via an atypical response element

The use of the orthotopic model to validate antivascular therapies for cancer

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