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.
Highlights
Pancreatic ductal adenocarcinoma (PDA) is one of the most aggressive malignancies and is typically diagnosed at an advanced state, with extensive local invasion, early systemic dissemination and marked resistance to chemo- and radiotherapy [1]
This desmoplasia is derived from pancreatic stellate cells that are activated by inflammation and in turn proliferate and produce collagens, fibronectin and other extracellular matrix (ECM) components, which participate in cancer initiation, progression and metastasis [3,4,5,6]
In PDA, a decreased cancer risk associated with aspirin was observed in a prospective study conducted from 1992 through 1999 in the US among 28,283 post-menopausal women; among 80 incident cases of pancreatic cancer, the authors stated that 43% of pancreatic cancer cases among non-users of aspirin might have been prevented by the daily intake of aspirin [18]
Summary
Pancreatic ductal adenocarcinoma (PDA) is one of the most aggressive malignancies and is typically diagnosed at an advanced state, with extensive local invasion, early systemic dissemination and marked resistance to chemo- and radiotherapy [1]. The poor response to chemotherapy is thought to be due in part to the fibrotic nature of PDA that prevents even small therapeutic molecules from entering and perfusing the extremely dense extracellular matrix (ECM) [2] This desmoplasia is derived from pancreatic stellate cells that are activated by inflammation and in turn proliferate and produce collagens, fibronectin and other ECM components, which participate in cancer initiation, progression and metastasis [3,4,5,6]. An analysis of individual patient data from 8 randomized clinical trials reported that long-term daily aspirin use significantly reduced deaths due to PDA, with the greatest benefit obtained after 5 years of aspirin use [17] These results were confirmed with transgenic mice, where aspirin significantly inhibited the progression of pancreatic intraepithelial neoplasia (PanIN) and tumor formation [19], and together with gemcitabine, extended survival [20]. Data gathered as part of the Nurses Health Study involving almost 90,000 women in the US indicated that women who took 2 or more standard aspirin tablets per week for more than 20 years had a 59% increased risk of PDA compared with women who rarely, or never, used the medication [21]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
