January 9, 2019, New York—A team led by Ludwig Harvard investigator Rakesh Jain has demonstrated for the first time how the physical forces exerted by a tumor can cause life-threatening symptoms in brain cancer patients. The researchers show in the current issue of Nature Biomedical Engineering that a type of tumor growth—bulky and defined, or nodular, rather than diffuse and infiltrating—exerts solid stress on surrounding brain tissue, disrupting blood supply and causing neuronal dysfunction and death. Jain and his colleagues also identify the psychiatric drug lithium, which protects neurons, as a promising treatment to help alleviate these symptoms.
“The mechanical abnormalities of cancer affect tissue and biology through multiple mechanisms,” says Jain, who is also director of the Steele Laboratories of Tumor Biology at Massachusetts General Hospital. “Over the last decade, our team has identified and characterized solid stress as a new biomechanical abnormality in tumors, but little has been known about how these forces affect tissues surrounding a brain tumor, potentially impairing neurological function.”
Jain and his colleagues experimentally confirm in their study that nodular but not the infiltrative tumors cause increased compression and deformation of surrounding brain tissue in mice. Their analysis of pretreatment magnetic resonance imagery of 64 glioblastoma patients also confirms that nodular tumors are associated with greater functional impairment in patients.
Using advanced imaging technology to assess blood vessels around the tumors of mice with either glioblastomas or breast cancer brain metastases, the researchers showed that nodular but not infiltrative tumors reduced the perfusion of blood vessels around tumors. The stress exerted by these tumors also deformed the nuclei of neurons in the surrounding tissues, leading to signs of cellular death.
MRI analysis 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. Analyses of data from 34 patients with breast cancer brain metastases, which are typically nodular, also revealed significantly reduced perfusion in surrounding healthy tissues.
The researchers used a specially designed compression apparatus to apply gradual pressure to the brains of living tumor-free mice and found that 14 days of compression had similar effects on surrounding tissues as did nodular tumors. It also caused dysfunction in movement and coordination.
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 appeared to protect against the damaging effects of compression, 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.
About Ludwig Cancer Research
Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for more than 40 years. Ludwig combines basic science with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested $2.7 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit www.ludwigcancerresearch.org.
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