In their report, the investigators identify characteristics of tumors most likely to impose solid stress, describe a potential way of distinguishing patients with such tumors, and identify the neuroprotective drug lithium as a promising treatment strategy. While the deformation of normal brain tissue by a growing tumor has been associated with greater disability and increased risk of death, the impact of specific patterns of tumor growth is not fully understood. Evidence has suggested that nodular tumors – those that continue growing as a single, well-defined mass – exert greater solid stress than do infiltrative tumors, which invade surrounding tissues as individual cells. To pursue this observation, the researchers implanted either nodular or infiltrative glioblastoma cells into the brains of mice and measured the stresses that had developed within and around the tumors 20 days later. They found increased compression and deformation of brain tissue around the nodular but not the infiltrative tumors.
Moreover, analysis of MR images from 64 glioblastoma patients taken prior to any treatment was able to distinguish those with more nodular tumors, determined by perfectly defined tumor margins, from those with infiltrative tumors. Patients with nodular tumors had exhibited significantly poorer results than did those with infiltrative tumors on a standard assessment of functional impairment. There was no difference between the two groups in terms of tumor size or of edema caused by accumulation of excess fluids.
To get a better understanding of how solid stress exerts its effects on brain tissue, the investigators used advanced imaging technology to assess blood vessels surrounding the tumors of mice with either glioblastomas or breast cancer brain metastases. They found that nodular but not infiltrative tumors reduced the perfusion of blood vessels around and at the edges of tumors. The stress induced by nodular tumors also deformed the nuclei of neurons in the surrounding tissues, leading to signs of cellular death.
MR imaging also revealed reduced vascular perfusion in healthy tissue surrounding the tumors of about half the 64 pre-treatment glioblastoma patients, an observation confirmed in another group of 14 patients. In both groups, patients with reduced vascular perfusion around their tumors had greater neurologic impairment than did those in whom perfusion was unchanged. Again, tumor size and edema had no impact on vascular perfusion of surrounding tissue, and neither did pre-treatment with steroids. Reduced perfusion was most commonly seen around nodular tumors. Corroborating analyses of data from a group of 34 patients with breast cancer brain metastases, which are typically nodular, also revealed significantly reduced perfusion in surrounding healthy tissues.
To investigate whether neuroprotective drugs could help preserve function in compressed brain tissue, the researchers then treated mice during chronic, gradual compression and for two weeks after decompression with four drugs known to have neuroprotective effects. Only lithium – a drug used to treat bipolar and other psychiatric disorders – appeared to protect against damaging effects, reducing neuronal death, the amount of compressed cortical tissue and other signs of cellular distress. Lithium-treated mice also performed significantly better on tests of movement and motor coordination than did untreated animals.
Nature Biomedical Engineering (2019)
Published: 07 January 2019
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