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Paclitaxel Resistance and Multicellular Spheroid Formation Are Induced by Kallikrein-Related Peptidase 4 in Serous Ovarian Cancer Cells in an Ascites Mimicking Microenvironment

Overview of attention for article published in PLOS ONE, February 2013
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Title
Paclitaxel Resistance and Multicellular Spheroid Formation Are Induced by Kallikrein-Related Peptidase 4 in Serous Ovarian Cancer Cells in an Ascites Mimicking Microenvironment
Published in
PLOS ONE, February 2013
DOI 10.1371/journal.pone.0057056
Pubmed ID
Authors

Ying Dong, Carson Stephens, Carina Walpole, Joakim E. Swedberg, Glen M. Boyle, Peter G. Parsons, Michael A. McGuckin, Jonathan M. Harris, Judith A. Clements

Abstract

High tumor kallikrein-related-peptidase 4 (KLK4) levels are associated with a poor outcome for women with serous epithelial ovarian cancer (EOC), for which peritoneal dissemination and chemoresistance are key events. To determine the role of KLK4 in these events, we examined KLK4-transfected SKOV-3 and endogenous KLK4 expressing OVCA432 cells in 3-dimensional (3D) suspension culture to mimic the ascites microenvironment. KLK4-SKOV-3 cells formed multicellular aggregates (MCAs) as seen in ascites, as did SKOV-3 cells treated with active KLK4. MCA formation was reduced by treatment with a KLK4 blocking antibody or the selective active site KLK4 sunflower trypsin inhibitor (SFTI-FCQR). KLK4-MCAs formed larger cancer cell foci in mesothelial cell monolayers than those formed by vector and native SKOV-3 cells, suggesting KLK4-MCAs are highly invasive in the peritoneal microenvironment. A high level of KLK4 is expressed by ascitic EOC cells compared to matched primary tumor cells, further supporting its role in the ascitic microenvironment. Interestingly, KLK4 transfected SKOV-3 cells expressed high levels of the KLK4 substrate, urokinase plasminogen activator (uPA), particularly in 3D-suspension, and high levels of both KLK4 and uPA were observed in patient cells taken from ascites. Importantly, the KLK4-MCAs were paclitaxel resistant which was reversed by SFTI-FCQR and to a lesser degree by the general serine protease inhibitor, Aprotinin, suggesting that in addition to uPA, other as yet unidentified substrates of KLK4 must be involved. Nonetheless, these data suggest that KLK4 inhibition, in conjunction with paclitaxel, may improve the outcome for women with serous epithelial ovarian cancer and high KLK4 levels in their tumors.

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The data shown below were compiled from readership statistics for 53 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 53 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 19 36%
Researcher 7 13%
Student > Doctoral Student 4 8%
Student > Bachelor 4 8%
Other 3 6%
Other 6 11%
Unknown 10 19%
Readers by discipline Count As %
Agricultural and Biological Sciences 16 30%
Biochemistry, Genetics and Molecular Biology 9 17%
Medicine and Dentistry 6 11%
Chemistry 3 6%
Nursing and Health Professions 2 4%
Other 5 9%
Unknown 12 23%