Lysyl oxidase family activity promotes resistance of pancreatic ductal adenocarcinoma to chemotherapy by limiting the intratumoral anticancer drug distribution
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Benjamin Le Calvé1,2,3,4,14, Audrey Griveau1,2,3,4,*, David Vindrieux1,2,3,4,*, Raphaël Maréchal5, Clotilde Wiel1,2,3,4, Magali Svrcek6,7, Johann Gout1,2,3,4, Lamia Azzi8, Léa Payen1,2,3,4,9, Jérôme Cros10,11, Christelle de la Fouchardière3, Pierre Dubus8, Jérôme Guitton4,9, Laurent Bartholin1,2,3,4, Jean-Baptiste Bachet12,13, David Bernard1,2,3,4
1Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France
2CNRS UMR5286, Lyon, France
3Centre Léon Bérard, Lyon, France
4Université de Lyon, Lyon, France
5Department of Gastroenterology and Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Belgium
6Department of Pathology, AP-HP, Hôpitaux Universitaires Est Parisien, Saint-Antoine Hospital, Paris, France
7Sorbonne University, UPMC University, Paris, France
8Service de Biologie des Tumeurs, CHU de Bordeaux Hôpital du Haut Lévêque, Pessac, France
9Hospices Civils de Lyon, Université de Lyon, Lyon, France
10AP-HP, Hôpitaux Universitaires Paris Nord Val de Seine, Beaujon, France
11Paris Diderot University, Paris, France
12Sorbonne University, UPMC University and INSERM, UMRS 1147, Paris Descrates University, Paris, France
13Gastroenterology Department, APHP, Pitié Salpêtrière Hospital, Paris, France
14Present address: URBC-NARILIS, University of Namur, Namur, Belgium
*These authors have contributed equally to this work
David Bernard, email: [email protected]
Keywords: chemoresistance, collagen, survival, biomarker, lysyl oxidase
Received: December 07, 2015 Accepted: March 18, 2016 Published: April 01, 2016
Solid tumors often display chemotherapy resistance. Pancreatic ductal adenocarcinoma (PDAC) is the archetype of resistant tumors as current chemotherapies are inefficient. The tumor stroma and extracellular matrix (ECM) are key contributors to PDAC aggressiveness and to limiting the efficacy of chemotherapy. Lysyl oxidase (LOX) family members mediate collagen cross-linking and thus promote ECM stiffening. Our data demonstrate increased LOX, LOXL1, and LOXL2 expression in PDAC, and that the level of fibrillar collagen, which is directly dependent of LOX family activity, is an independent predictive biomarker of adjuvant “Gemcitabine-based chemotherapy” benefit. Experimentally in mice, increased LOX family activity through LOXL2 promotes chemoresistance. This effect of LOX family activity seems to be due to decreased gemcitabine intra-tumoral diffusion. This observation might be explained by increased fibrillar collagen and decreased vessel size observed in tumors with increased LOX family activity. In conclusion, our data support that LOX family activity is both a novel target to improve chemotherapy as well as a novel biomarker to predict gemcitabine benefit in PDAC. Beyond the PDAC, it is possible that targeting LOX family activity might improve efficacy of chemotherapies against different kinds of solid tumors.
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