Abstract
Platelets have been demonstrated to be vital in cancer epithelial-mesenchymal transition (EMT), an important step in metastasis. Markers of EMT are associated with chemotherapy resistance. However, the association between the development of chemoresistance, EMT, and the contribution of platelets to the process, is still unclear. Here we report that platelets regulate the expression of (1) human equilibrative nucleoside transporter 1 (hENT1) and (2) cytidine deaminase (CDD), markers of gemcitabine resistance in pancreatic cancer. Human ENT1 (hENT1) is known to enable cellular uptake of gemcitabine while CDD deactivates gemcitabine. Knockdown experiments demonstrate that Slug, a mesenchymal transcriptional factor known to be upregulated during EMT, regulates the expression of hENT1 and CDD. Furthermore, we demonstrate that platelet-derived ADP and ATP regulate Slug and CDD expression in pancreatic cancer cells. Finally, we demonstrate that pancreatic cancer cells express the purinergic receptor P2Y12, an ADP receptor found mainly on platelets. Thus ticagrelor, a P2Y12 inhibitor, was used to examine the potential therapeutic effect of an ADP receptor antagonist on cancer cells. Our data indicate that ticagrelor negated the survival signals initiated in cancer cells by platelet-derived ADP and ATP. In conclusion, our results demonstrate a novel role of platelets in modulating chemoresistance in pancreatic cancer. Moreover, we propose ADP/ATP receptors as additional potential drug targets for treatment of pancreatic cancer.
Highlights
Despite remarkable advancements in our understanding of cancer development and progression, pancreatic ductal adenocarcinoma (PDAC) continues to be one of the most aggressive types of cancer, with a mortality rate that has not changed for the last 50 years
In order to address if platelets enable PDAC cells to survive the antiproliferative effect of gemcitabine, platelet releasate isolated from collagen-related peptide (CRP)-aggregated platelets was incubated with cancer cells at increasing concentrations of gemcitabine
We examined if platelet releasate can initiate survival signals in cancer cells challenged with gemcitabine
Summary
Despite remarkable advancements in our understanding of cancer development and progression, pancreatic ductal adenocarcinoma (PDAC) continues to be one of the most aggressive types of cancer, with a mortality rate that has not changed for the last 50 years. In addition to relatively late stage symptoms and high metastasis, chemotherapy resistance contributes significantly to increased mortality in PDAC [1]. Hypercoagulable disorders often characterise people living with PDAC, marked with an increased risk of venous thromboembolism (VTE) [2]. The association of PDAC with thrombotic events suggests a close interplay between cancer and platelets, the key player in haemostasis and thrombosis. Tumour cells can form aggregates with platelets to avoid natural killer cell-mediated cytotoxicity [3,4,5]. PDAC cells can induce platelet activation and aggregation [6]
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