Primary brain tumors, gliomas, have thus far evaded effective treatment making them a tremendous challenge clinically. This is in part due to the unusual ability of gliomas to infiltrate surrounding brain making surgical resection difficult. Tumr cells can move through the brain parenchyma, following white matter tracts or along blood vessels. Ultimately many glioma cells associate with blood vessels, presumably to gain enhanced access to nutrients. In a recent study, we show that glioma cells are attracted to cerebral vessels by responding to bradykinin which is produced by vascular endothelial cells. Once associated with blood vessels, glioma cells co-opt the vasculature and eventually induce vessel sprouting and angiogenesis. Understanding how gliomas alter the physiology of the existing cerebral vasculature is the primary objective of this grant. We hypothesize that the vascular association provides an intrinsic advantage and that gliomas actively regulate the behavior of the associated blood vessel. More specifically we hypothesize that (1) vessel associated glioma cells displace astrocytic endfeet from the blood vessels;(2) this disrupts normal astrocyte-vascular coupling as astrocyte-derived vasoactive molecules fail to reach vascular smooth muscle cells;(3) displacement of astrocytic endfeet leads to a breakdown of the blood-brain barrier;and (4) once attached to vessels, glioma cells actively regulate vascular tone through the release of vasoactive compounds. These hypotheses will be tested using a clinically relevant animal model of glioma employing a combination of single- and multi-photon imaging studies in situ and in vivo. These studies have the potential to elucidate novel ways to interfere with the destructive biology of these deadly tumors in the future.

Public Health Relevance

We are investigating whether primary brain tumors that associate with blood vessels disrupt the normal interactions between astrocytes, vascular endothelial and smooth muscle cells and how this may disrupt normal blood flow and breach the blood brain barrier.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS082851-02
Application #
8742016
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Fountain, Jane W
Project Start
2013-09-30
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
2
Fiscal Year
2014
Total Cost
$318,346
Indirect Cost
$101,784
Name
University of Alabama Birmingham
Department
Neurosciences
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Cuddapah, Vishnu Anand; Robel, Stefanie; Watkins, Stacey et al. (2014) A neurocentric perspective on glioma invasion. Nat Rev Neurosci 15:455-65
Watkins, Stacey; Robel, Stefanie; Kimbrough, Ian F et al. (2014) Disruption of astrocyte-vascular coupling and the blood-brain barrier by invading glioma cells. Nat Commun 5:4196