Characterising the role of substance P in human and experimental brain tumours.

Abstract

Currently within Australia, brain tumours account for one death every eight hours. They are inherently difficult to treat, and even with the best current treatments, prognosis for these patients remains extremely poor. At present, treatment options for patients with either primary or secondary brain tumours are limited. Indeed most brain metastasis patients have a short survival time, despite the fact that initial treatment is often effective in reducing neurological deficits and tumour size. One of the most serious complications of brain tumours is cerebral oedema, which is typically vasogenic in nature due to disruption of normal blood brain barrier function. Cerebral oedema is associated with many life-threatening complications such as raised intracranial pressure, reduction in cerebral perfusion pressure and in severe cases can result in brain herniation and death. Although treatments for cerebral oedema currently exist, they are associated with many deleterious side effects, prompting the search for alternative treatments. The neuropeptide substance P and its NK1 receptor are reported to be upregulated in a number of different cancer types. This increase is thought to correspond with SP mediated increases in cellular proliferation, impairment of apoptosis and increased angiogenesis. Furthermore, SP has recently been implicated in the development of neurogenic inflammation in the brain, where it is associated with vasodilation, plasma extravasation and genesis of oedema. Accordingly, the current thesis sought to determine whether SP may provide a novel treatment target in both tumour associated oedema and tumour growth. Immunohistochemical assessment of human primary and secondary brain tumour tissue demonstrated a marked increase in SP and the NK1 receptor in all tumour types investigated, confirming what has been previously observed in the literature. Of the mestastatic tumours, melanoma demonstrated particularly elevated levels of SP and its receptor. Correspondingly, a human melanoma cell line, A-375, was examined in vitro and found to express both SP and the NK1 receptor. Furthermore, treatment with NK1 antagonists resulted in decreased cell viability of A-375 melanoma cells and an increase in cell death in this cell line in vitro, implicating SP in the facilitation of tumour growth. An in vivo model of brain tumours using the same cell line, demonstrated increased SP and the NK1 receptor not only within the tumour, but also in peritumoural vessels. This increase corresponded with a significant increase in brain water content and BBB permeability, implicating SP in the genesis of tumour associated oedema. Subsequent administration of the NK1 antagonist, Emend decreased BBB dysfunction and oedema formation and was more efficacious than the current clinical treatment choice, dexamethasone. Furthermore, treatment with Emend resulted in a decrease in tumour volume and in the number of proliferating cells, as well as an increase in apoptotic cells, an effect that was not seen with dexamethasone treatment. This indicates that SP may play multiple roles in tumour pathogenesis within the brain. In conclusion, the present studies have identified a role for SP in tumour-associated oedema as well as in tumour growth and progression. Moreover, treatment with the NK1 antagonist Emend was more effective than the currently available clinical treatment, dexamethasone. Treatment with an NK1 antagonist may thus provide a novel therapeutic option, able to treat these two very different aspects of brain tumour pathogenesis.