Influence of Neuronal Activity on Tumor Colonization of the Brain

Rat glioma cells growing in the
brain of an immunocompromised mouse.

Many cancer patients develop neurological side effects such as depression, chemobrain, or epilepsy. To manage these side effects, many neurological agents are currently prescribed to breast cancer patients either prophylactically or in response to symptoms without a clear understanding of how these may affect metastasis. Additionally, many neuroactive substances such as caffeine are ubiquitous in the human diet. We believe that many of these substances which affect brain function also alter the brain microenvironment which in turn can affect the colonization of the brain by tumors.

The developing brain has the capacity to undergo rapid changes in response to neuronal activity. A large body of literature suggests that these changes involve the action of proteases which degrade the extracellular matrix allowing physical changes in the structure of neurons. These mechanisms are remarkably similar to those used by tumors to migrate through tissue. For instance it is known that in the visual system, brief periods of monocular lid suture can lead to profound changes in the physiology of neurons in visual cortex, whereby neurons learn to ignore the closed eye while strengthening their responses to the open eye. This change in cortical neurons is critically dependent on the action of tissue plasminogen activator (tPA), a protease which can cleave components of the extracellular matrix and break down the blood brain barrier. Mice which are null for the tPA gene do not show this form of neuronal plasticity.

We are currently using histological, molecular and imaging methods to gain insight into the mechanisms controlling tumor entry through the blood brain barrier as well as the modes of tumor growth within the brain. We believe that investigation into the effects of neuroactive substances on breast tumor metastasis to the brain and the growth of gliomas within the brain will allow informed decisions on treating depression and other ailments in cancer patients. Furthermore we believe this work will establish a new paradigm whereby reagents already used in the clinic for the treatment of neurological disorders are evaluated for their ability to alter the brain microenvironment and hence reduce tumor growth.

This project has been funded, in part, by the

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