Drugging the tumour microenvironment? – Human breast cancer metastases to the brain display GABAergic properties in the neural niche.


Original paper Newman et al
http://www.pnas.org/content/early/2014/01/03/1322098111.full.pdf
Metastatic spread from primary tumours is one of the main causes of deaths from cancer, accounting for 90% of all deaths. For example, a large number of breast cancer patients undergo successful treatment for their primary cancer but later die due to metastatic brain tumours. Currently treatment of these metastatic brain tumours is limited to radiotherapy and neurosurgery.

In order for cells from the primary tumour to survive and form a secondary tumour in the brain, the cancer cell must adapt to the microenvironment of the brain. An elegant paper recently published in PNAS demonstrates that breast cancer cells which metastasise to the brain do indeed exhibit neural characteristics enabling then to survive within the brain microenvironment. The authors obtained clinical samples from patients undergoing neurological surgery and demonstrated that breast-to-brain metastatic (BBM) cells overexpressed many proteins related to γ-Aminobutyric acid (GABA) signalling pathways.

GABA is a neurotransmitter that can also act during neuronal development influencing proliferation, migration, differentiation and cell death. A pathway known as the GABA shunt also enables cells to utilise GABA as an energy source. Expression of GABA in adult tissue is highly regulated and abnormal expression has been observed in a number of primary cancers.

Close examination of the BBM cells revealed that the proliferation of these cells was not receptor mediated, although GABAAR was overexpressed. The authors instead revealed that the BBM cells express higher levels of GABA transporter proteins than primary tissues, allowing increased uptake of GABA. The BBM cells also display increased expression of GABA transaminase (ABAT/GABA-T), which is involved in GABA metabolism. These results suggest that an increased level of NADH, via GABA metabolism, is present in the tumour microenvironment. They further showed that increased GABA in cultured BBM cells results in increasing proliferation.

sarah_jan2014
Image from GABA Synthesis, Uptake and Release. Richard W Olsen and Timothy M DeLorey. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.

Additionally, BBM cells exhibited other neuronal properties such as increased Reelin expression. Reelin is an extracellular matrix glycoprotein that is associated with GABAergic neurons and is thought to be connected to migratory capacity of primary cancer cells.

The data presented in the paper provide evidence to support the hypothesis that metastases may result from cells from the primary tumour that have adapted in order to colonise the secondary tumour site. In the future, therapies for brain metastases could focus on drugging the tumour microenvironment to inhibit tumour proliferation, in combination with strategies to kill the tumour mass.

References

Human breast cancer metastases to the brain display GABAergic properties in the neural niche.
Neman J, Termini J, Wilczynski S, Vaidehi N, Choy C, Kowolik CM, Li H, Hambrecht AC, Roberts E, Jandial R.
Proc Natl Acad Sci U S A. 2014 Jan 6. [Epub ahead of print]

GABA Synthesis, Uptake and Release. Richard W Olsen and Timothy M DeLorey.
Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.
Siegel GJ, Agranoff BW, Albers RW, et al., editors.
Philadelphia: Lippincott-Raven; 1999.

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