Lethal migration: the bradykinin story.

What makes quiescent glial cells in the CNS convert into the most aggressive of all glial cell-derived tumours? Contrary to assumptions long past, CNS cells are exquisitely responsive to changes in their physiological surroundings during development and disease. Far from being a settled environment, the intricate cerebral landscape continuously bombards cells with signals to run or grow or migrate, significantly altering cellular behaviour. Some signals even accelerate cell migration in ways that prove fatal. Glioblastoma multiforme (GBM), also classified as grade 4 astrocytoma, is a rapidly growing glioma of the CNS that originates predominantly from astrocytes, the most numerous macroglia in the brain. Glioblastoma multiforme is most often found in the cerebral hemispheres, either frontal or temporal lobes. Several tumour characteristics pose exceptional treatment challenges; as a result, patients typically die 15 months or less after diagnosis. Glioblastoma multiforme is by far the most invasive glial cell-derived tumour, being characterized by fast growth and rapid invasion of surrounding brain tissue. Tumour resection is not curative, firstly, because neoplastic cells can migrate quickly into brain regions near the original tumour, forming secondary tumours; secondly, GBMs are not homogeneous (Holland, 2000) but are composed of diverse cell types (mostly derived from astrocytes and oligodendrocytes) with properties differing from the cells of origin. This is particularly true for GBM that evolves from low-grade astrocytomas or oligodendrogliomas. The tumour environment is also not optimal for drug treatment. Blood supply is usually disrupted in GBM, reducing the efficacy of drug delivery, and capillary leakage causes peritumoural fluid accumulation and intracranial hypertension. Additional therapeutic obstacles include the intrinsic resistance of GBM to conventional cancer therapy and the neurotoxic effects of many treatments targeting these tumours. Invasion of the brain tissue and vasculature by GBM is a crucial and early step in tumour metastasis. Thus, defining the cellular and physiological mechanisms involved in metastasis is fundamental for developing therapeutic approaches to prevent GBM cell migration and metastasis. Despite the heterogeneity of GBM, it would be vital to determine whether the tumours display shared properties that could be harnessed to reduce their migration potential. Identifying common cellular signals and elucidating their mechanisms of action in GBM cell migration would enhance the efficacy of therapeutic interventions. The study in this issue of The Journal of Physiology by Seifert & Sontheimer (2014) identifies a cellular signal that promotes glioma migration, illuminates its mechanism of action and defines the process leading to enhanced neoplastic cell migration. The authors combine in vitro and in vivo approaches to demonstrate that the neuropeptide bradykinin guides glioma cell migration and significantly changes the physiological properties of the cells. Bradykinin induces the formation of irregular bulges (called blebs) in the plasma membrane through a B2 receptor-mediated increase in intracellular Ca2+. This triggers cytoskeletal contraction, cytoplasmic flow and activation of specific Ca2+-dependent K+ and Cl− channels, which then participate in regulating bleb formation. Finally, and most importantly, Seifert & Sontheimer (2014) analysed gliomas formed by human cell lines in mouse brain in vivo and demonstrated that bradykinin treatment stimulates growth and significantly expands tumour size by accelerating cell migration at the tumour periphery. In vivo treatment with blebbistatin, which blocks myosin kinase II and bleb retraction, prevents glioma migration. Why are these findings original and important? Firstly, the cellular factors promoting glioma cell migration are largely unknown, but this study identifies bradykinin as one factor (presumably of many). Sontheimer and his team previously demonstrated that this neuropeptide promotes chemotaxis of glioma cells in vitro (Montana & Sontheimer, 2011), but the present study shows that bradykinin also enhances tumour cell migration in situ. Secondly and more importantly, Seifert and Sontheimer's experimental analysis illuminates a long-standing controversy about how tumour cells, including GBM, migrate through the brain's densely packed extracellular environment. Tumour cells were believed to migrate primarily through a mechanism called mesenchymal migration, involving the release of enzymes that enable the tumour cells themselves to degrade the extracellular matrix (Wolf et al. 2003). Yet, more recent studies highlight a different and pervasive mechanism called amoeboid migration that is specifically associated with bleb formation. This mechanism is common to many tumour cell types and involves activating several cytoskeletal proteins. Some have proposed that cytoskeleton-dependent bleb formation could be the cellular mechanism responsible for directed cell migration towards chemoattractants (Montana & Sontheimer, 2011), which would be consistent with the mechanism of action of bradykinin and its effects on glioma migration. Bradykinin is present in brain vasculature and chemotactically attracts glioma cells to blood vessels (Montana & Sontheimer, 2011), which supports the notion that bradykinin might guide the invasion of glioma cells in vivo through blood vessels or white matter tracts. This observation raises a crucial question. Do relatively less invasive GBMs, with longer than average patient survival (3–5% of patients surviving more than 3 years), originate in brain regions where tumour cells are exposed to lower levels of bradykinin or perhaps in regions with defective bradykinin signalling? Comparing tumours from these patients and from the majority of individuals with shorter postdiagnosis survival has the potential to uncover associations between bradykinin signalling and tumour lethality. Another issue worth investigating is whether bradykinin is a crucial cellular signal regulating GBM growth, migration and invasion in the human brain. Seifert and Sontheimer's analysis was performed in human tumour cell lines, but the therapeutic potential of interfering with bradykinin signalling remains largely undefined. Thus, targeting bradykinin signalling through the B2 receptor might be a beneficial therapeutic approach, in conjunction with other treatments (Huse & Holland, 2010), for preventing the growth of GBM and other similarly aggressive brain tumours.