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Gemcitabine‐Induced Exosome Hypersecretion Increases the Chemoresistance and Migration of Pancreatic Cancer Cells
Author(s) -
Sweeney Ryan,
Richards Katherine E.,
Hill Reginald
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.775.20
Subject(s) - pancreatic cancer , gemcitabine , microvesicles , cancer research , exosome , cancer , metastasis , cancer cell , epithelial–mesenchymal transition , medicine , biology , oncology , microrna , biochemistry , gene
Pancreatic ductal adenocarcinoma (PDAC) is the 3 rd most common cause of cancer‐related deaths, due to its highly metastatic nature, delayed detection and robust chemoresistance. Our previous study implicated the role of cancer associated fibroblast (CAF)‐derived exosomes in the promotion of pancreatic cancer proliferation and chemoresistance. However, no studies have been conducted on the influence of cancer cell‐derived exosomes on the migration and chemoresistance of other cancer cells. This study examines the ability of exosomes secreted by pancreatic cancer cells upon treatment with gemcitabine, the current standard‐of‐care chemotherapy, to affect chemoresistance and migration. We have previously shown that upon gemcitabine treatment, pancreatic cancer cells hypersecrete exosomes, and that these exosomes exhibit increased expression of Snail and mir‐146a. Snail is a transcription factor known to promote epithelial‐to‐mesenchymal transition (EMT), chemoresistance, and metastasis, and miR‐146a is one of its known downstream targets. We hypothesized that the uptake of cancer cell‐derived exosomes would lead to increased resistance to gemcitabine and increased migration of the cancer cells as a whole. Upon knocking down exosome secretion with the drug GW4869, we found that AsPC1, MiaPaca, and Panc1 cancer cell lines were less resistant to gemcitabine. Moreover, treatment with GW4869 markedly reduced AsPC1 and Panc1 migration measured via a wound‐healing assay. Taken together, we have shown that pancreatic cancer cell‐derived exosomes promote the chemoresistance and migration of surrounding cancer cells. These findings suggest that exosomes play an important role in the communication between cancer cells within the tumor that is induced by gemcitabine treatment. Therapeutic strategies aimed at blocking chemotherapy‐induced hypersecretion of exosomes should be considered in order to develop more effective treatments for PDAC patients.