Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2024; 15:504-506.

Aspirin counteracts cancer stem cell features, desmoplasia and gemcitabine resistance in pancreatic cancer

Yiyao Zhang, Li Liu, Pei Fan, Nathalie Bauer, Jury Gladkich, Eduard Ryschich, Alexandr V. Bazhin, Nathalia A. Giese, Oliver Strobel, Thilo Hackert, Ulf Hinz, Wolfgang Gross, Franco Fortunato and Ingrid Herr _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2015; 6:9999-10015. https://doi.org/10.18632/oncotarget.3171

Metrics: PDF 3366 views  |   HTML 3712 views  |   ?  


Abstract

Yiyao Zhang1,2,3,4, Li Liu1,2,3, Pei Fan1,2,3, Nathalie Bauer1,2,3, Jury Gladkich1,2,3, Eduard Ryschich2,3, Alexandr V. Bazhin3, Nathalia A. Giese3, Oliver Strobel3, Thilo Hackert3, Ulf Hinz3, Wolfgang Gross1,2,3, Franco Fortunato2,3, Ingrid Herr1,2,3

1Molecular OncoSurgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany

2Section Surgical Research, University of Heidelberg, Heidelberg, Germany

3Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany

4Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, China

Correspondence to:

Ingrid Herr, e-mail: [email protected]

Keywords: Pancreatic cancer, Cancer stem cells, Novel therapeutics

Received: January 14, 2015     Accepted: January 18, 2015     Published: February 05, 2015

ABSTRACT

Pancreatic ductal adenocarcinoma (PDA) is characterized by an extremely poor prognosis. An inflammatory microenvironment triggers the pronounced desmoplasia, the selection of cancer stem-like cells (CSCs) and therapy resistance. The anti-inflammatory drug aspirin is suggested to lower the risk for PDA and to improve the treatment, although available results are conflicting and the effect of aspirin to CSC characteristics and desmoplasia in PDA has not yet been investigated. We characterized the influence of aspirin on CSC features, stromal reactions and gemcitabine resistance. Four established and 3 primary PDA cell lines, non-malignant cells, 3 patient tumor-derived CSC-enriched spheroidal cultures and tissues from patients who did or did not receive aspirin before surgery were analyzed using MTT assays, flow cytometry, colony and spheroid formation assays, Western blot analysis, antibody protein arrays, electrophoretic mobility shift assays (EMSAs), immunohistochemistry and in vivo xenotransplantation. Aspirin significantly induced apoptosis and reduced the viability, self-renewal potential, and expression of proteins involved in inflammation and stem cell signaling. Aspirin also reduced the growth and invasion of tumors in vivo, and it significantly prolonged the survival of mice with orthotopic pancreatic xenografts in combination with gemcitabine. This was associated with a decreased expression of markers for progression, inflammation and desmoplasia. These findings were confirmed in tissue samples obtained from patients who had or had not taken aspirin before surgery. Importantly, aspirin sensitized cells that were resistant to gemcitabine and thereby enhanced the therapeutic efficacy. Aspirin showed no obvious toxic effects on normal cells, chick embryos or mice. These results highlight aspirin as an effective, inexpensive and well-tolerated co-treatment to target inflammation, desmoplasia and CSC features PDA.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 3171