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: Maud-Emmanuelle Gilles, Federica Maione, Mélissande Cossutta, Gilles Carpentier, Laure Caruana, Silvia Di Maria, Claire Houppe, Damien Destouches, Ksenya Shchors, Christopher Prochasson, Fabien Mongelard, Simona Lamba, Alberto Bardelli, Philippe Bouvet, Anne Couvelard, José Courty, Enrico Giraudo, Ilaria Cascone
• Journal: Cancer research (Cancer Res) Vol. 76 Issue 24 Pg. 7181-7193 (12 15 2016) ISSN: 1538-7445 [Electronic] United States
• PMID: 27754848 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• N6L peptide
• Peptides
• Phosphoproteins
• RNA-Binding Proteins
• nucleolin

Topics

• Animals
• Carcinoma, Pancreatic Ductal (pathology)
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Disease Progression
• Humans
• Mice
• Neovascularization, Pathologic (pathology)
• Pancreatic Neoplasms (pathology)
• Peptides (pharmacology)
• Phosphoproteins (antagonists & inhibitors)
• RNA-Binding Proteins (antagonists & inhibitors)
• Tissue Array Analysis