title: Nucleolin Targeting Impairs the Progression of Pancreatic Cancer and Promotes the Normalization of Tumor Vasculature.
abstract: Pancreatic cancer is a highly aggressive tumor, mostly resistant to the standard treatments. Nucleolin is overexpressed in cancers and its inhibition impairs tumor growth. Herein, we showed that nucleolin was overexpressed in human specimens of pancreatic ductal adenocarcinoma (PDAC) and that the overall survival significantly increased in patients with low levels of nucleolin. The nucleolin antagonist N6L strongly impaired the growth of primary tumors and liver metastasis in an orthotopic mouse model of PDAC (mPDAC). Similar antitumor effect of N6L has been observed in a highly angiogenic mouse model of pancreatic neuroendocrine tumor RIP-Tag2. N6L significantly inhibited both human and mouse pancreatic cell proliferation and invasion. Notably, the analysis of tumor vasculature revealed a strong increase of pericyte coverage and vessel perfusion both in mPDAC and RIP-Tag2 tumors, in parallel to an inhibition of tumor hypoxia. Nucleolin inhibition directly affected endothelial cell (EC) activation and changed a proangiogenic signature. Among the vascular activators, nucleolin inhibition significantly decreased angiopoietin-2 (Ang-2) secretion and expression in ECs, in the tumor and in the plasma of mPDAC mice. As a consequence of the observed N6L-induced tumor vessel normalization, pre-treatment with N6L efficiently improved chemotherapeutic drug delivery and increased the antitumor properties of gemcitabine in PDAC mice. In conclusion, nucleolin inhibition is a new anti-pancreatic cancer therapeutic strategy that dually blocks tumor progression and normalizes tumor vasculature, improving the delivery and efficacy of chemotherapeutic drugs. Moreover, we unveiled Ang-2 as a potential target and suitable response biomarker for N6L treatment in pancreatic cancer. Cancer Res; 76(24); 7181-93. ©2016 AACR.
authors.affiliation: University of Paris Est (UPEC), ERL-CNRS 9215, Laboratory of Growth, Reparation and Tissue Regeneration (CRRET), UPEC, Créteil, France.
authors.forename: Maud-Emmanuelle
authors.initials: ME
authors.lastname: Gilles
authors.affiliation: Laboratory of Transgenic Mouse Models, Candiolo Cancer Institute - FPO, IRCCS, Candiolo (TO), Italy.|Department of Science and Drug Technology, University of Torino, Torino, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Maione
authors.affiliation: University of Paris Est (UPEC), ERL-CNRS 9215, Laboratory of Growth, Reparation and Tissue Regeneration (CRRET), UPEC, Créteil, France.
authors.forename: Mélissande
authors.initials: M
authors.lastname: Cossutta
authors.affiliation: University of Paris Est (UPEC), ERL-CNRS 9215, Laboratory of Growth, Reparation and Tissue Regeneration (CRRET), UPEC, Créteil, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Carpentier
authors.affiliation: University of Paris Est (UPEC), ERL-CNRS 9215, Laboratory of Growth, Reparation and Tissue Regeneration (CRRET), UPEC, Créteil, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Caruana
authors.affiliation: University of Paris Est (UPEC), ERL-CNRS 9215, Laboratory of Growth, Reparation and Tissue Regeneration (CRRET), UPEC, Créteil, France.
authors.forename: Silvia
authors.initials: S
authors.lastname: Di Maria
authors.affiliation: University of Paris Est (UPEC), ERL-CNRS 9215, Laboratory of Growth, Reparation and Tissue Regeneration (CRRET), UPEC, Créteil, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Houppe
authors.affiliation: University of Paris Est (UPEC), ERL-CNRS 9215, Laboratory of Growth, Reparation and Tissue Regeneration (CRRET), UPEC, Créteil, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Destouches
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), EPFL SV ISREC, Station 19, Lausanne, Switzerland.
authors.forename: Ksenya
authors.initials: K
authors.lastname: Shchors
authors.affiliation: Department of Pathology, Bichat Hospital APHP DHU UNITY and University of Paris Diderot, Paris, France.
authors.forename: Christopher
authors.initials: C
authors.lastname: Prochasson
authors.affiliation: University of Lyon, Ecole normale Supérieure de Lyon, Cancer Research Center of Lyon, Cancer Cell Plasticity Department, UMR INSERM 1052 CNRS 5286, Centre Léon Bérard, Lyon, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Mongelard
authors.affiliation: Department of Oncology, University of Torino, Candiolo (TO), Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Lamba
authors.affiliation: Department of Oncology, University of Torino, Candiolo (TO), Italy.|Candiolo Cancer Institute-FPO, IRCCS, Candiolo (TO), Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.affiliation: University of Lyon, Ecole normale Supérieure de Lyon, Cancer Research Center of Lyon, Cancer Cell Plasticity Department, UMR INSERM 1052 CNRS 5286, Centre Léon Bérard, Lyon, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouvet
authors.affiliation: Department of Pathology, Bichat Hospital APHP DHU UNITY and University of Paris Diderot, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Couvelard
authors.affiliation: University of Paris Est (UPEC), ERL-CNRS 9215, Laboratory of Growth, Reparation and Tissue Regeneration (CRRET), UPEC, Créteil, France.
authors.forename: José
authors.initials: J
authors.lastname: Courty
authors.affiliation: Laboratory of Transgenic Mouse Models, Candiolo Cancer Institute - FPO, IRCCS, Candiolo (TO), Italy. ilaria.cascone@u-pec.fr enrico.giraudo@ircc.it.|Department of Science and Drug Technology, University of Torino, Torino, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Giraudo
authors.affiliation: University of Paris Est (UPEC), ERL-CNRS 9215, Laboratory of Growth, Reparation and Tissue Regeneration (CRRET), UPEC, Créteil, France. ilaria.cascone@u-pec.fr enrico.giraudo@ircc.it.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Cascone
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010455:Peptides / Q000494:pharmacology*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors*; D046888:Tissue Array Analysis; D000097796:Nucleolin
chemical_list: D010455:Peptides; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D000097796:Nucleolin; C580583:N6L peptide