How do brain cancer cells evade destruction, and can their defense mechanism be disrupted?
The National Cancer Institute (NCI) estimate that in 2018, there will be 23,880 new diagnoses of GBM and other cancers of the central nervous system in the United States.
GBM is challenging to treat. This is because the cells that form it are often therapy-resistant, and the damage they do to adjacent healthy tissue is usually permanent, since the brain cannot easily repair itself.
This is why researchers from Virginia Commonwealth University in Richmond have been studying the mechanisms through which cancer cells protect themselves, in the hopes of identifying new ways of disrupting them that might lead to improved treatments in the future.
How cancer stem cells avoid destruction
Study author Paul B. Fisher and team explain that glioma stem cells are able to avoid anoikis, which is a type of cell death (or apoptosis) that occurs when a cell detaches from the extracellular matrix. This is the "scaffolding" that supports cells and helps to regulate stem cell differentiation and homeostasis.
Glioma stem cells resist anoikis through protective autophagy, in which the cells "eat" and "recycle" their own cellular detritus.
What the researchers discovered was that, in the case of glioma stem cells, protective autophagy is regulated by a gene called MDA-9/Syntenin, which was originally identified by Fisher.
This gene, as Fisher and others have previously shown, also happens to be overexpressed in many different types of cancer.
In this study, the team was able to ascertain that inhibiting MDA-9/Syntenin expression seemed to deactivate glioma stem cells' defense mechanism.
"We discovered that when we blocked the expression of MDA-9/Syntenin, glioma stem cells lose their ability to induce protective autophagy and succumb to anoikis, resulting in cancer cell death."
Paul B. Fisher
Specifically, Fisher and research collaborator Webster K. Cavenee — of the University of California, San Diego — alongside their colleagues noticed that MDA-9/Syntenin supports autophagy by activating another gene, BCL2, which is responsible for inducing and inhibiting cell death.
Disrupting the self-protective mechanism
But MDA-9/Syntenin does not just support autophagy; it maintains it at levels that are low enough not to become toxic and destructive to the glioma stem cells. This is done through epidermal growth factor receptor (EGFR) signaling.
EGFR signaling is important in regulating the "growth, survival, proliferation, and differentiation" of cells, and excessive signaling has been proved by several studies to support tumor growth in several types of cancer.
But, Fisher explains, "In the absence of MDA-9/Syntenin, EGFR can no longer maintain protective autophagy."
"Instead," he continues, "highly elevated and sustained levels of toxic autophagy ensue that dramatically reduce cancer cell survival."
According to the scientists, this is the first time that this complex connection between protective autophagy and the evasion of anoikis has been explored in GBM.
"This is the first study to define a direct link between MDA-9/Syntenin, protective autophagy, and anoikis resistance," explains Fisher, noting that the scientists involved in the study "[are] hopeful [that they] can exploit this process to develop new and more effective treatments for GBM and possibly other cancers."
In further experiments, Fisher and team used human GBM cells and glioma stem cell cultures to show that the suppression of MDA-9/Syntenin expression blocked the cancer's self-protective mechanism.
This was again seen in mouse models of human glioma stem cells, in which case the researchers observed an increase in survival following the inhibition of MDA-9/Syntenin expression.
In the future, their goal is to verify whether the protective mechanism that they discovered in this study also occurs in stem cells found in other types of cancer.
And, they will continue to develop novel ways to inhibit MDA-9/Syntenin, which, they hope, may lead to improved cancer treatments.