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Oncotarget. 2016 May 31;7(22):32100-12. doi: 10.18632/oncotarget.8527.

Lysyl oxidase family activity promotes resistance of pancreatic ductal adenocarcinoma to chemotherapy by limiting the intratumoral anticancer drug distribution.

Le Calvé B1,2,3,4,5, Griveau A1,2,3,4, Vindrieux D1,2,3,4, Maréchal R6, Wiel C1,2,3,4, Svrcek M7,8, Gout J1,2,3,4, Azzi L9, Payen L1,2,3,4,10, Cros J11,12, de la Fouchardière C3, Dubus P9, Guitton J4,10, Bartholin L1,2,3,4, Bachet JB13,14, Bernard D1,2,3,4.

Author information

1
Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
2
CNRS UMR5286, Lyon, France.
3
Centre Léon Bérard, Lyon, France.
4
Université de Lyon, Lyon, France.
5
Present address: URBC-NARILIS, University of Namur, Namur, Belgium.
6
Department of Gastroenterology and Gastrointestinal Cancer Unit, Erasme Hospital, Université Libre de Bruxelles, Belgium.
7
Department of Pathology, AP-HP, Hôpitaux Universitaires Est Parisien, Saint-Antoine Hospital, Paris, France.
8
Sorbonne University, UPMC University, Paris, France.
9
Service de Biologie des Tumeurs, CHU de Bordeaux Hôpital du Haut Lévêque, Pessac, France.
10
Hospices Civils de Lyon, Université de Lyon, Lyon, France.
11
AP-HP, Hôpitaux Universitaires Paris Nord Val de Seine, Beaujon, France.
12
Paris Diderot University, Paris, France.
13
Sorbonne University, UPMC University and INSERM, UMRS 1147, Paris Descrates University, Paris, France.
14
Gastroenterology Department, APHP, Pitié Salpêtrière Hospital, Paris, France.

Abstract

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.

KEYWORDS:

biomarker; chemoresistance; collagen; lysyl oxidase; survival

PMID:
27050073
PMCID:
PMC5078000
DOI:
10.18632/oncotarget.8527
[Indexed for MEDLINE]
Free PMC Article

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