Oncotarget

Research Papers:

Dormant tumor cells expressing LOXL2 acquire a stem-like phenotype mediating their transition to proliferative growth

Keren Weidenfeld, Sagi Schif-Zuck, Hanan Abu-Tayeh, Keunsoo Kang, Ofra Kessler, Marina Weissmann, Gera Neufeld and Dalit Barkan _

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Oncotarget. 2016; 7:71362-71377. https://doi.org/10.18632/oncotarget.12109

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Abstract

Keren Weidenfeld1, Sagi Schif-Zuck1, Hanan Abu-Tayeh1, Keunsoo Kang2, Ofra Kessler3, Marina Weissmann3, Gera Neufeld3, Dalit Barkan1

1Department of Human Biology, University of Haifa, Haifa, Israel

2Department of Microbiology, Dankook University, Cheonan, Republic of Korea

3Cancer Research and Vascular Biology Center, The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel

Correspondence to:

Dalit Barkan, email: dalitbrk@gmail.com

Keywords: dormant tumor cells, breast cancer recurrence, cancer stem cells, epithelial mesenchymal transition, LOXL2

Received: January 24, 2016     Accepted: September 12, 2016     Published: September 19, 2016

ABSTRACT

Recurrence of breast cancer disease years after treatment appears to arise from disseminated dormant tumor cells (DTC). The mechanisms underlying the outgrowth of DTC remain largely unknown. Here we demonstrate that dormant MCF-7 cells expressing LOXL2 acquire a cancer stem cell (CSC)-like phenotype, mediating their outgrowth in the 3D BME system that models tumor dormancy and outgrowth. Similarly, MCF-7-LOXL2 cells colonizing the lung transitioned from dormancy to metastatic outgrowth whereas MCF-7 cells remained dormant. Notably, epithelial to mesenchymal transition (EMT) of MCF-7-LOXL2 cells was required for their CSC-like properties and their transition to metastatic outgrowth. These findings were further supported by clinical data demonstrating that increase in LOXL2 mRNA levels correlates with increase in the mRNA levels of EMT and stem cells markers, and is also associated with decrease in relapse free survival of breast cancer patients. Notably, conditional hypoxia induced expression of endogenous LOXL2 in MCF-7 cells promoted EMT and the acquisition of a CSC-like phenotype, while knockdown of LOXL2 inhibited this transition. Overall, our results demonstrate that expression of LOXL2 endowed DTC with CSC-like phenotype driving their transition to metastatic outgrowth and this stem-like phenotype is dependent on EMT that can be driven by the tumor microenvironment.


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