Chitinase 3-like-1 and fibronectin in the cargo of extracellular vesicles shed by human macrophages influence pancreatic cancer cellular response to gemcitabine

• Type: Article in International Scientific Journal
• Date: 2021

Authors

Xavier, CPR (Author) Other; Castro, I (Author) Other; Caires, HR (Author) Other; Ferreira, D (Author) Other; Cavadas, B (Author) Other; Pereira, L (Author) Other; Santos, LL (Author) Other; Oliveira, MJ (Author) ICBAS; Helena Vasconcelos, MH (Author) FFUP

Journal

Title: Cancer Letters

Vol. 501

Pages: 210-223

ISSN: 0304-3835

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 29 Citations

Scopus - 28 Citations

Other information

Authenticus ID: P-00T-3ZS

DOI: 10.1016/j.canlet.2020.11.013

Abstract (EN): Tumour-associated macrophages have been implicated in pancreatic ductal adenocarcinoma (PDAC) therapy response and Extracellular vesicles (EVs) shed by macrophages might have a role in this process. Here, we demonstrated that large EVs released by anti-inflammatory human macrophages decreased PDAC cellular sensitivity to gemcitabine. Using proteomic analysis, chitinase 3-like-1 (CHI3L1) and fibronectin (FN1) were identified as two of the most abundant proteins in the cargo of macrophages-derived EVs. Overexpression of CHI3L1 and FN1, using recombinant human proteins, induced PDAC cellular resistance to gemcitabine through ERK (extracellular-signal-regulated kinase) activation. Inhibition of CHI3L1 and FN1 by pentoxifylline and pirfenidone, respectively, partially reverted gemcitabine resistance. In PDAC patient samples, CHI3L1 and FN1 were expressed in the stmma, associated with the high presence of macrophages. The Cancer Genome Atlas analysis revealed an association between CHI3L1 and FNI gene expression, overall survival of PDAC patients, gemcitabine response, and macrophage infiltration. Altogether, our data identifies CHI3L1 and FN1 as potential targets for pharmacological inhibition in PDAC. Further pre-clinical in vivo work is warranted to study the possibility of repurposing pentoxifylline and pirfenidone as adjuvant therapies for PDAC treatment.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 14