Dormant tumor cells expressing LOXL2 acquire a stem-like phenotype mediating their transition to proliferative growth
| Autor: | Sagi Schif-Zuck, Dalit Barkan, Gera Neufeld, Hanan Abu-Tayeh, Keunsoo Kang, Ofra Kessler, Marina Weissmann, Keren Weidenfeld |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
cancer stem cells Epithelial-Mesenchymal Transition epithelial mesenchymal transition Breast Neoplasms 03 medical and health sciences 0302 clinical medicine Breast cancer Cancer stem cell dormant tumor cells Tumor Microenvironment Medicine Humans Epithelial–mesenchymal transition Neoplasm Metastasis Cell Proliferation Gene knockdown Tumor microenvironment LOXL2 business.industry medicine.disease Phenotype Cell Hypoxia 030104 developmental biology breast cancer recurrence Oncology 030220 oncology & carcinogenesis Immunology Cancer research MCF-7 Cells Neoplastic Stem Cells Female Amino Acid Oxidoreductases Stem cell Neoplasm Recurrence Local business Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Keren Weidenfeld 1 , Sagi Schif-Zuck 1 , Hanan Abu-Tayeh 1 , Keunsoo Kang 2 , Ofra Kessler 3 , Marina Weissmann 3 , Gera Neufeld 3 , Dalit Barkan 1 1 Department of Human Biology, University of Haifa, Haifa, Israel 2 Department of Microbiology, Dankook University, Cheonan, Republic of Korea 3 Cancer 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. |
| Databáze: | OpenAIRE |
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