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Blockade of autophagy reduces pancreatic cancer stem cell activity and potentiates the tumoricidal effect of gemcitabine

Overview of attention for article published in Molecular Cancer, October 2015
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Title
Blockade of autophagy reduces pancreatic cancer stem cell activity and potentiates the tumoricidal effect of gemcitabine
Published in
Molecular Cancer, October 2015
DOI 10.1186/s12943-015-0449-3
Pubmed ID
Authors

Ming-Chen Yang, Hao-Chen Wang, Ya-Chin Hou, Hui-Ling Tung, Tai-Jan Chiu, Yan-Shen Shan

Abstract

Cancer stem cells (CSCs) are considered responsible for the recurrence and chemoresistance of cancer. Dysregulated autophagy is highly prevalent in many types of cancer including pancreatic cancer and has been implicated in cytoprotection and tumor promotion. This study aimed to investigate the role of autophagy in regulating cancer stemness and chemoresistance of pancreatic cancer. The correlation between autophagy and CSCs and its clinical significance were analyzed using pancreatic cancer tissue microarrays. Genetic and pharmacological approaches were applied to explore the function of autophagy on CSC activity and gemcitabine resistance of pancreatic cancer cells in vitro and in vivo. LC3 expression positively correlated with the expression of CSC markers aldehyde dehydrogenase 1 (ALDH1), CD44, and CD133 in pancreatic cancer tissues. High coexpression of LC3/ALDH1 was associated with both poor overall survival and progression-free survival. In pancreatic cancer cell lines, higher LC3-II expression was observed in the sphere-forming cells than in the bulk cells. Blockade of autophagy by silencing ATG5, ATG7, and BECN1 or the administration of autophagy inhibitor chloroquine markedly reduced the CSC populations, ALDH1 activity, sphere formation, and resistance to gemcitabine in vitro and in vivo. Furthermore, osteopontin (OPN) was found to stimulate LC3-II, ALDH1, CD44, and CD133 expression in PANC-1 cells, whereas this effect could be prevented by OPN knockdown and autophagy blockade. After treatment with various inhibitors against the major signaling pathways downstream of OPN, only the inhibitor of NF-κB activation, BAY 1170-82, could effectively counteract OPN-induced autophagy and CSC activity. According to the histochemical results, pancreatic cancer patients manifesting high levels of OPN/LC3/ALDH1 and OPN/CD44/CD133 had poor survival. Induction of autophagy mediated by OPN/NF-κB signaling is required for maintenance of pancreatic CSC activity. Combination of gemcitabine with pharmacological autophagy inhibitors is a promising therapeutic strategy for pancreatic cancer.

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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 86 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Spain 1 1%
United States 1 1%
Unknown 84 98%

Demographic breakdown

Readers by professional status Count As %
Researcher 21 24%
Student > Ph. D. Student 14 16%
Student > Bachelor 7 8%
Student > Master 6 7%
Student > Doctoral Student 5 6%
Other 13 15%
Unknown 20 23%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 29 34%
Agricultural and Biological Sciences 15 17%
Medicine and Dentistry 12 14%
Pharmacology, Toxicology and Pharmaceutical Science 2 2%
Mathematics 1 1%
Other 4 5%
Unknown 23 27%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 14 July 2016.
All research outputs
#14,718,998
of 23,577,654 outputs
Outputs from Molecular Cancer
#944
of 1,782 outputs
Outputs of similar age
#146,456
of 280,480 outputs
Outputs of similar age from Molecular Cancer
#12
of 35 outputs
Altmetric has tracked 23,577,654 research outputs across all sources so far. This one is in the 35th percentile – i.e., 35% of other outputs scored the same or lower than it.
So far Altmetric has tracked 1,782 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 6.0. This one is in the 43rd percentile – i.e., 43% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 280,480 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 44th percentile – i.e., 44% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 35 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 60% of its contemporaries.