Tumor-promoting function of apoptotic caspases by an amplification loop involving ROS, macrophages and JNK in Drosophila
- University of Massachusetts Medical School, United States
Abstract
Apoptosis and its molecular mediators, the caspases, have long been regarded as tumor suppressors and one hallmark of cancer is “Evading Apoptosis”. However, recent work has suggested that apoptotic caspases can also promote proliferation and tumor growth under certain conditions. How caspases promote proliferation and how cells are protected from the potentially harmful action of apoptotic caspases is largely unknown. Here, we show that although caspases are activated in a well-studied neoplastic tumor model in Drosophila, oncogenic mutations of the proto-oncogene Ras (RasV12) maintain tumorous cells in an “undead”-like condition and transform caspases from tumor suppressors into tumor promotors. Instead of killing cells, caspases now promote the generation of intra- and extracellular reactive oxygen species (ROS). One function of the ROS is the recruitment and activation of macrophage-like immune cells which in turn signal back to tumorous epithelial cells to activate oncogenic JNK signaling. JNK further promotes and amplifies caspase activity, thereby constituting a feedback amplification loop. Interfering with the amplification loop strongly reduces the neoplastic behavior of these cells and significantly improves organismal survival. In conclusion, RasV12-modified caspases initiate a feedback amplification loop involving tumorous epithelial cells and macrophage-like immune cells that is necessary for uncontrolled tumor growth and invasive behavior.
Article and author information
Author details
Funding
National Institute of General Medical Sciences (R35GM118330)
- Andreas Bergmann
National Institute of General Medical Sciences (R01GM107789)
- Andreas Bergmann
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Helen McNeill, University of Toronto, Canada
Version history
- Received: March 13, 2017
- Accepted: August 28, 2017
- Accepted Manuscript published: August 30, 2017 (version 1)
- Version of Record published: September 21, 2017 (version 2)
Copyright
© 2017, Bergmann et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Tumor-promoting function of apoptotic caspases by an amplification loop involving ROS, macrophages and JNK in Drosophila
eLife 6:e26747.
https://doi.org/10.7554/eLife.26747
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