For years, American neurologist Michelle Monje observed a surprising pattern in some of her patients with glioblastoma, the deadliest type of brain tumor. After the primary tumor has been removed, the cancer will recur after some time; However, this does not happen in any part of the brain, but in the area that patients used most for their work. In a classical dancer, it reappeared in the area of the cerebellum that controls balance. In one author, it grew back several times in the area of the cerebral cortex where language resides.
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“It’s a pattern recognized by many neuropsychiatrists,” says Monje. “I wonder if the fact that these people have greater development and plasticity in these areas of the brain makes them more at risk of having this type of tumor,” said the Stanford University researcher (UNITED STATES). The scientist is one of the promoters of cancer neuroscience, a new discipline trying to elucidate the connection between brain activity and cancer.
In a recent study, Monje and other neurologists looked at which areas of the brain are activated when people with glioblastoma perform simple cognitive activities, such as looking at a picture of an umbrella and saying the word “umbrella.”
When the patients responded, not only was Broca’s area, which controls language, activated, but also other brain areas affected by the tumor. The cancer had reorganized the brain’s language circuits based on the synapses between neurons to connect to them. These cognitive tasks generate electrical currents that reach the tumor and promote its growth. The more the affected areas lit up, the worse the prognosis for the patients, who gradually lost their ability to speak. It is likely that the neuronal overstimulation caused by the tumors explains why many patients suffer from epileptic seizures and cognitive problems.
Brain tumors, gliomas and glioblastomas account for about 2% of all tumors diagnosed annually. Despite their low incidence, they pose a major medical challenge because they respond poorly to treatment. Gliomas account for 15% of all childhood tumors and are the leading cause of cancer death.
The interaction between the nervous system and cancer extends to other organs through the nerve branches that reach from the brain to the rest of the body and reach a length of 150,000 kilometers.
Malignant cells migrate along the nerves and receive key molecules from them for their growth. According to animal studies and analysis of patient samples, tumors with more nerve branches in the prostate, stomach or pancreas have a poorer prognosis. In some cases, malignant cells from a primary breast tumor can travel to the brain, lodge there, attach to neurons, and metastasize much more deadly than the primary tumor.
The interaction between the nervous system and cancer is complex and different in each organ. In the stomach, acetylcholine, a neurotransmitter, promotes the spread of tumor cells, but in the pancreas it has exactly the opposite effect and slows the progression of the tumour.
This role of the nervous system in cancer has long been ignored. In 1899, Spanish physician and Nobel Prize winner in medicine Santiago Ramón y Cajal was the first to describe a growth pattern of neural tissue in which glia, a type of nerve cell, grew around neurons as if they were their scaffolding.
At the beginning of the last century, the German pathologist Hans-Joachim Scherer observed the same structures in samples from patients with brain tumors: tumor cells grew around neurons and it was very difficult to determine where the tumor ended and healthy brain tissue began.
This research was practically at an impasse until 10 years ago, physician and researcher Paul Frenette of the Albert Einstein School of Medicine (USA) presented the first tests on animals and patient samples examining the nerve endings of prostate tumors , the more aggressive they are and the worse they respond to treatment.
Since then, similar connections have also been observed in other organs and this new research area has grown explosively, sums up Frank Winkler, neuro-oncologist at the University Hospital Heidelberg (Germany) and research leader in this field in Europe. “Now we know that tumor cells form connected networks and how neurons communicate with each other,” he explains. “Many of the biochemical processes that we observe are the same that occur in an embryo to form all the organs of the body. The tumor behaves like any other organ. It does not invent new growth mechanisms, but adopts those that have already been invented,” adds Winkler. His team has perfected a new microscopy technique to study the formation of tumors, their communication with other brain cells, their progression and recurrence in live animals and in real time. This data will be compared to that of patients with brain tumors to better understand this new dimension of cancer.
Neurologist Michelle Monje in her lab at Stanford University in Palo Alto, California. LIPO CHING (MediaNews Group via Getty Images)
Neuroscientist Manuel Valiente of the National Cancer Research Center believes that cancer neuroscience can elucidate not only the role of the nervous system in the development of primary tumors, but also brain metastases, which are 10 times more common than glioblastomas. In addition, “examining these associations could shed light on why brain tumors cause cognitive impairment in 44% of patients and potentially help avoid them so their minds aren’t as badly affected during treatment,” he explains.
One of the explanations for why this field is still thriving is that cancer research teams have traditionally not known how to analyze neural tissue or neural activity, which rely on a complicated interaction between small electrical currents and the production of biochemical compounds. Physicist and neuroscientist Liset Menéndez de la Prida, head of the Neural Circuits Laboratory at the Cajal Institute, is a specialist in this type of analysis. Together with Valiente, he is involved in a 3.5 million euro European project to develop new photonic tools to measure the electrical and biochemical activity of cancer cells in the brain. “We are experiencing a complete paradigm shift and the birth of a new field,” emphasizes the scientist.
Manuel Sepúlveda, an oncologist at the Hospital 12 de Octubre in Madrid, explains that brain tumors, both the most aggressive glioblastomas and the low-grade gliomas, arise from mutations in glial cells, another type of nerve cell. “The nervous system alone wouldn’t initiate it, but it encourages it and encourages its growth,” he points out. “We see that there is a new way to study these types of tumors, although the importance of this interaction with the nervous system remains to be elucidated and whether it can be stopped with drugs,” he says. Sepúlveda recently participated in a clinical trial that showed how a drug that targets certain mutations in gliomas can significantly delay cancer recurrence after surgery. There are patients who have not had any relapses or epileptic seizures for six years.
There are already approved drugs for the treatment of mental, circulatory and neurological disorders that affect some of the mechanisms observed and could impair the development of tumors in both the brain and other organs. Trials are already underway in patients with perampanel, an anti-seizure drug that blocks glutamate-mediated communication between tumors and neurons. Another study in patients is examining the effect of meclofenamate, a pain reliever, on blocking communication between tumor cells in patients with glioblastoma.
“A whole new field of therapeutic interventions in tumors with a very poor prognosis is opening up,” emphasizes Michelle Monje, who believes that interventions in the nervous system could become a new pillar of oncology, similar to immunotherapy – it affects the immune system and has made tumors curable , which used to be a death sentence. “Blocking the communication between the tumor and the nervous system may not be enough to eliminate it, but I think it will be absolutely necessary to achieve this,” he concludes.
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