Malignant gliomas are the most common primary brain tumor. They are high invasive and complete surgical resection is typically impossible. We and others have demonstrated that glioma cells often migrate along the brain's vasculature, possibly using blood vessels as guides or conduits for invasion. Alternatively, they may associate with blood vessels to be in an oxygen and nutrient-rich environment. In the normal brain, the surface of most arterial blood vessels is covered with astrocytic endfeet. These have been shown to release vasoactive molecules including arachidonic acid metabolites and potassium to control vessel tone and thereby blood flow. This proposal seeks to study the interactions of invading glioma cells with vascular cells and the astrocytic endfeet normally covering them. We will specifically question whether the degree of vascular invasion correlates with the invasiveness of the tumors;whether invading tumor cells prefer arteries over veins;whether they transiently or permanently displace the astrocytic endfeet, and finally whether the actively regulate vessel tone as they are invading. We hypothesize that invading glioma cells may benefit from transient constriction of the blood vessel as this would enlarge the space through which tumor cells invade. On the other hand, as cells form satellite tumor at vessel branch point, these would benefit form maximal vessel dilation to shunt nutrients and oxygen to the growing tumor mass. These studies make extensive use of single and multiphoton laser scanning microcopy and some studies will image tumor invasion in vivo through a cranial window placed on the skull of tumor-bearing animals. Tumor dispersal will be evaluated by unbiased stereology and vascular response to glioma-releases vasoactive compounds will be studied through IR-DIC video microcopy. Data obtained from this proposal will aid in the understanding of an aspect glioma biology that may provide specific molecular targets for future anti-invasive therapy.
Due to the high prevalence and limited success in treatment, malignant gliomas, specifically glioblastoma multiforme (GBM), are of major clinical concern. Attempts to understand the regulation of the vasculature by invading glioma cells seek to identify novel pathways for future therapies needed to combat this destructive cancer.
|Kimbrough, Ian F; Robel, Stefanie; Roberson, Erik D et al. (2015) Vascular amyloidosis impairs the gliovascular unit in a mouse model of Alzheimer's disease. Brain 138:3716-33|
|Robert, Stephanie M; Buckingham, Susan C; Campbell, Susan L et al. (2015) SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma. Sci Transl Med 7:289ra86|
|Robel, Stefanie; Buckingham, Susan C; Boni, Jessica L et al. (2015) Reactive astrogliosis causes the development of spontaneous seizures. J Neurosci 35:3330-45|
|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|
|Cuddapah, Vishnu Anand; Robel, Stefanie; Watkins, Stacey et al. (2014) A neurocentric perspective on glioma invasion. Nat Rev Neurosci 15:455-65|
|Watkins, Stacey; Sontheimer, Harald (2012) Unique biology of gliomas: challenges and opportunities. Trends Neurosci 35:546-56|