Researchers' discovery that forces enhancing fluid flow within a glioblastoma's interstitial spaces can increase the cancer's invasion of surrounding tissue has critical implications for a new drug delivery technique. However, the investigators have also found a solution to this problem.
The most common form of brain cancer, glioblastoma is also the most malignant. Because it is characterized by invasion into the surrounding brain tissue, it is highly difficult to treat and invariably relapses.
"It [glioblastoma] is so deadly, and there hasn't been a shift in treatment response in decades. Something needs to change," commented the study's senior researcher, Jennifer Munson, PhD, Assistant Professor in the Department of Biomedical Engineering and Mechanics at Virginia Tech.
Glioblastoma and other solid cancers increase interstitial pressure and therefore increase interstitial fluid flow, the flow of fluid from the vasculature through the interstitial tissue. In glioblastoma, studies of cell lines have shown that this increase in interstitial fluid flow also increases the cancer's invasion of surrounding brain tissue as a result of the CXCR4-CXCL12 signaling pathway.
Interstitial fluid flow, remarked Dr. Munson, "is a force that isn't accounted for much in brain tissues. My goal is to have more people thinking about this force and that it can actually have effects on cells that we don't intend."
Dr. Munson and her research teams, first at the University of Virginia and then at Virginia Tech, hypothesized that because convection-enhanced delivery (CED)—an experimental drug delivery technique used to overcome high pressure within a tumor and increase drug distribution—effectively mimics interstitial fluid flow by driving fluids through the interstitial spaces in the tumor, it may stimulate glioblastoma invasion.
In their study, published in Scientific Reports, the researchers found that inducing convective flow using CED within glioblastoma tumors implanted in mice did in fact increase the cancer's spread to surrounding tissue. However, they also found a solution to this dilemma: administering AMD3100, a CXCR4 antagonist which has already been used in clinics, effectively canceled this response, blocking the flow of interstitial fluid and avoiding the spread of glioblastoma cells.
The study's lead author, Chase Cornelison, PhD, a postdoctoral researcher at Virginia Tech, emphasized the practical application of these results: "I am hopeful that since the drug that we used to block flow stimulation is currently used in patients that maybe clinicians, when they do consider using convection-enhanced delivery, will combine that with this drug."
For More Information
Cornelison RC, Brennan CE, Kingsmore KM & Munson JM (2018). Convective forces increase CXCR4-dependent glioblastoma cell invasion in GL261 murine model. Sci Rep, 8:17057. DOI:10.1038/s41598-018-35141-9