title: The Neuronal Pentraxin-2 Pathway Is an Unrecognized Target in Human Neuroblastoma, Which Also Offers Prognostic Value in Patients.
abstract: Neuronal pentraxins (NPTX) and their corresponding receptors (NPTXR) have been studied as synapse-associated proteins in the nervous system, but their role in cancer is largely unknown. By applying a multidisciplinary, high-throughput proteomic approach, we have recently identified a peptide ligand motif for targeted drug delivery to neuroblastoma. Here, we report the sequence similarity between this peptide and a conserved portion of the pentraxin domain that is involved in the homo- and hetero-oligomerization of NPTX2 and NPTXR. We show that, in comparison with normal tissues, NPTX2 and NPTXR are overexpressed in vivo in mouse models, as well as in human Schwannian stroma-poor, stage IV neuroblastoma. Both proteins are concentrated in the vicinity of tumor blood vessels, with NPTXR also present on neuroblastic tumor cells. In vivo targeting of NPTX2 and NPTXR with the selected peptide or with specific antibodies reduces tumor burden in orthotopic mouse models of human neuroblastoma. In vitro interference with this ligand/receptor system inhibits the organization of neuroblastoma cells in tumor-like masses in close contact with vascular cells, as well as their adhesion to normal microenvironment-derived cells, suggesting a role in the cross-talk between tumor and normal cells in the early steps of neuroblastoma development. Finally, we show that NPTX2 is a marker of poor prognosis for neuroblastoma patients.
authors: Laboratory of Tumor Microenvironment, Candiolo Cancer Institute-IRCCS, Candiolo, Italy.
authors: Alice
authors: A
authors: Bartolini
authors: Laboratory of Oncology, Istituto G Gaslini, Genova, Italy.
authors: Daniela
authors: D
authors: Di Paolo
authors: Laboratory of Vascular Oncology, Candiolo Cancer Institute-IRCCS, Candiolo, Italy.
authors: Alessio
authors: A
authors: Noghero
authors: Department of Pathology, Istituto G Gaslini, Genova, Italy.
authors: Daniele
authors: D
authors: Murgia
authors: Department of Pathology, Istituto G Gaslini, Genova, Italy.
authors: Angela R
authors: AR
authors: Sementa
authors: Animal Facility, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
authors: Michele
authors: M
authors: Cilli
authors: University of New Mexico Cancer Center, Albuquerque, New Mexico. Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico.
authors: Renata
authors: R
authors: Pasqualini
authors: University of New Mexico Cancer Center, Albuquerque, New Mexico. Division of Hematology/Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico.
authors: Wadih
authors: W
authors: Arap
authors: Laboratory of Vascular Oncology, Candiolo Cancer Institute-IRCCS, Candiolo, Italy. Department of Oncology, University of Torino, Candiolo, Italy.
authors: Federico
authors: F
authors: Bussolino
authors: Laboratory of Oncology, Istituto G Gaslini, Genova, Italy.
authors: Mirco
authors: M
authors: Ponzoni
authors: Laboratory of Oncology, Istituto G Gaslini, Genova, Italy. serena.marchio@unito.it fabiopastorino@ospedale-gaslini.ge.it.
authors: Fabio
authors: F
authors: Pastorino
authors: Laboratory of Tumor Microenvironment, Candiolo Cancer Institute-IRCCS, Candiolo, Italy. Department of Oncology, University of Torino, Candiolo, Italy. serena.marchio@unito.it fabiopastorino@ospedale-gaslini.ge.it.
authors: Serena
authors: S
authors: Marchiò
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002097:C-Reactive Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D008024:Ligands; D051379:Mice; D058990:Molecular Targeted Therapy; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011379:Prognosis; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000099153:Pentraxins
chemical_list: D000911:Antibodies, Monoclonal; D002097:C-Reactive Protein; D008024:Ligands; D009419:Nerve Tissue Proteins; D010455:Peptides; D000099153:Pentraxins