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In a groundbreaking new study, scientists have discovered the mechanism of the blood tumor barrier, which is one of
the most important obstacles to improving treatment effectiveness and preventing cancer cells from returning.
The research team, led by Dr.
Xi Huang, a senior scientist in the Developmental and Stem Cell Biology Program at SickKids, laid the groundwork for
more effective treatment of medulloblastoma, the most common childhood malignant brain tumor.
"Despite decades of research on brain cancer, little is known about the mechanisms that control the formation and function of the blood tumor barrier," said Huang, who is also principal investigator at Arthur and Sonia Labatt Brain Tumor Research Centre and Canadian Research Chair in
Cancer Biophysics.
"Our findings represent a breakthrough
in understanding how the blood tumor barrier forms and works.
"
In a paper published today in the journal Neuron, the research team has identified a way to
reduce the impact of the blood tumor barrier on the treatment of medulloblastoma.
"Our study points the way
to overcoming the blood-oncology barrier and more effectively treating devastating brain tumors in children.
"
The blood-brain barrier controls the extent to which molecules in the blood enter brain tissue, and its biological purpose is to prevent harmful substances from spreading to the brain
.
However, this process also prevents more than 95% of small molecule drugs from entering the brain, making the condition very difficult to treat
.
This barrier is formed
in part by special cell astrocytes embedded in the blood vessels of the central nervous system.
Researchers have long believed that these astrocytes also constitute a blood tumor barrier, which forms a similar barrier around brain tumor cells to prevent the effective delivery of
chemotherapy.
Huang and his team have now identified the blood tumor barrier in medulloblastoma as an entirely new structure
built by the tumor cells themselves.
Huang's team, co-led by Chen Xin, Ali Momin and Siyi Wanggou of SickKids, found that medulloblastoma tumor cells rely on ion channels "pressure sensitive," a protein that plays an important role in cell signaling, to help form a blood-tumor-related barrier
.
By silencing the piezoelectric gene in mice, medulloblastoma tumor cells are unable to form a blood tumor barrier
.
In the absence of this barrier, etoposide, a common chemotherapy drug, is better able to cross the blood tumor barrier to treat medulloblastoma tumor cells
.
In addition to improving the delivery of chemotherapy, the researchers also found that medulloblastoma tumor cells were significantly more sensitive
to etoposide after piezoelectric 2 was suppressed.
"The two major barriers to brain cancer treatment are the blood-tumor-tumor barrier and a unique population of
tumor cells that are insensitive to the nature of chemotherapy.
We found that removing piezoelectricity solves two barriers that can lead to treatment failure in patients," Huang said
.
"This study may not only provide potential new ways to provide an effective treatment for brain cancer in children, but may also inspire new research
into the blood tumor barrier of other primary and metastatic brain tumors.
"
Huang started the project seven years ago in his SickKids lab, and there are other notable discoveries, including how brain tumor cells hijack force-activated ion channels that promote tumor hardening and growth
.
Mechanosensitive brain tumor cells construct blood-tumor barrier to mask chemosensitivity
