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Brain tumour invasion along blood vessels may lead to new cancer treatments.

Invading glioblastoma cells may hijack cerebral blood vessels during early stages of disease progression and damage the blood-brain barrier, a study in mice indicates. This finding could ultimately lead to new ways to bring about the death of the tumour, as therapies may be able to reach these deadly cells at an earlier time point than was previously thought possible.

Glioblastoma, a type of aggressive brain tumour, is one of the most devastating forms of cancer. These tumours spread quickly and are difficult to treat because the brain protects itself from foreign substances.  The blood-brain barrier (BBB) is designed to stand in the way of harmful materials leaking into the brain and to regulate the transport of important molecules back and forth between the brain and the blood. One component of the BBB is close-fitting connections (called tight junctions) that form seals between the blood vessel’s endothelial cells. There are several other types of cells that cover the blood vessel, including specialized brain cells known as astrocytes, which have extensive projections, called endfeet, that cover 90 percent of the blood vessel surface. The astrocytic endfeet release molecules that regulate the tight junctions between the endothelial cells. They also release specific chemicals that cause blood vessels to expand or contract, thereby regulating blood flow in the brain. As a whole, the BBB can be viewed as a smart protective wrapping that separates the blood from the brain.

The team from the University of Alabama investigated the interactions between glioblastoma cells, astrocytes and cerebral blood vessels. They used mouse models of glioblastoma, fluorescent dyes and a variety of imaging techniques to see how tumour cells migrate through the brain and interact with other cells and blood vessels.

The current study showed that almost all of the glioblastoma cells outside the main tumour mass were located in the space between the astrocytic endfeet and the blood vessel outer surface. By using the meshwork of small blood vessels as a scaffold, glioblastoma cells were able to migrate along the vessels and extract nutrients from the blood for themselves.  The vast majority of tumour cells are associated with blood vessels. These cells appear to be using the vessels as highways to travel great distances within the brain.

In addition, the findings revealed the glioblastoma cells hijacked control over the blood flow by taking it away from the astrocytes. As a result, tight junctions became loose, which led to a breakdown in the BBB.  The group were surprised that very small groups of tumour cells, even individual cells, were sufficient to weaken the BBB early in the disease process.

Evidence from these models suggests that early in the disease, invading tumour cells are not completely protected by the blood-brain barrier and may be more vulnerable to drugs delivered to the brain via the blood. If these findings hold true in humans, treatment with anti-invasive agents might be beneficial in newly diagnosed glioblastoma patients.  Localized breaches in the BBB may allow regionally precise delivery of drugs to attack tumour cells even in the earliest stage.

The  findings provide the medical community with new perspectives on how glioblastoma cells successfully invade within the brain and control blood flow to their advantage. These findings have the potential to change current approaches to treating glioblastoma.

Further research is needed to learn more about how the BBB is regulated and how brain tumour cells take over existing vessels to grow and spread. A better understanding of how tumour cells interact with the BBB may increase the ability to treat glioblastoma patients.

Source: National Institutes of Health (NIH)

Perivascular glioma cells disrupt astrocyte-mediated vascular coupling. The perivascular glioma cell (green) inserts itself between the VSMCs (blue) surrounding the vascular endothelial cells (red), displacing the astrocytic endfeet (purple). Bath application of NE and t-ACPD activates astrocytic G-protein-coupled receptors causing an increase in astrocytic [Ca2+]i. Due to perivascular glioma cell displacement of the astrocytic endfeet, astrocyte-released vasoactive molecules (AA, PGE2 and K+) can no longer reach the VSMCs to cause alterations in the vessel diameter. Glioma cell PAR1 activation by the artificial ligand, TFLLR, causes increases in glioma cell [Ca2+]i, which activates Ca2+-activated K+ channels. Glioma efflux of K+ onto VSMCs causes vasoconstriction of the arterioles.  Sontheimer et al 2014.
Perivascular glioma cells disrupt astrocyte-mediated vascular coupling. The perivascular glioma cell (green) inserts itself between the VSMCs (blue) surrounding the vascular endothelial cells (red), displacing the astrocytic endfeet (purple). Bath application of NE and t-ACPD activates astrocytic G-protein-coupled receptors causing an increase in astrocytic [Ca2+]i. Due to perivascular glioma cell displacement of the astrocytic endfeet, astrocyte-released vasoactive molecules (AA, PGE2 and K+) can no longer reach the VSMCs to cause alterations in the vessel diameter. Glioma cell PAR1 activation by the artificial ligand, TFLLR, causes increases in glioma cell [Ca2+]i, which activates Ca2+-activated K+ channels. Glioma efflux of K+ onto VSMCs causes vasoconstriction of the arterioles. Sontheimer et al 2014.

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