Pesquisadores descobrem que na síndrome de predisposição ao câncer NF1, os neurônios hiperativos impulsionam o crescimento do tumor
Pacientes com neurofibromatose tipo 1 (NF1) desenvolvem tumores nos nervos em todo o corpo. Esses tumores são tipicamente benignos, o que significa que não se espalham para outras partes do corpo e não são considerados com risco de vida; no entanto, eles ainda podem causar sérios problemas médicos, como cegueira, quando se formam no cérebro e nos nervos.
Pesquisadores da Escola de Medicina da Universidade de Washington em St. Louis descobriram que neurônios com uma mutação no gene Nf1 são hiperexcitáveis e que suprimir essa hiperatividade com lamotrigina, um medicamento aprovado pelo FDA para tratar a epilepsia, interrompe o crescimento do tumor em camundongos.
“Os tumores são muito comuns em pessoas com NF1”, disse o autor sênior David H. Gutmann, MD, Ph.D., Professor da Família Donald O. Schnuck e diretor do Centro de Neurofibromatose (NF) da Universidade de Washington. “Mostramos que podemos bloquear o crescimento de tumores NF1 desligando a hiperexcitabilidade neuronal. Fizemos isso agora de duas maneiras diferentes, e não há dúvida de que o reaproveitamento de antiepilépticos é uma maneira eficaz de inibir o crescimento de tumores, pelo menos em camundongos. Isso ressalta o papel crítico que os neurônios desempenham na biologia do tumor.”
O estudo foi publicado em 19 de maio na
NF1 is a genetic disorder that affects one out of every 3,000 people on the planet. Mutations in the NF1 gene cause the condition. The disorder can affect any part of the body, but the most common symptoms are light brown spots on the skin, benign nerve tumors called neurofibromas, brain and optic nerve tumors, bone deformities, and cognitive differences such as autism, learning disabilities, and attention deficit hyperactivity disorder.
Last year, Gutmann and Michelle Monje, MD, Ph.D., a neurology professor at Stanford University School of Medicine and a Howard Hughes investigator, discovered that light increases neuronal activity in the eyes of Nf1-mutant mice, causing tumors to form on the optic nerve, which connects the eyes and the brain. In the new study, they — along with first author Corina Anastasaki, Ph.D., an assistant professor of neurology at Washington University, and co-author Lu Q. Le, MD, Ph.D., a professor of dermatology at the University of Texas, Southwestern Medical Center — investigated how increased neuronal activity leads to tumors in people with NF1.
The researchers studied neurons from mice with and without Nf1 gene mutations. At baseline, neurons from mice with tumor-causing Nf1 mutations fired electrical impulses more frequently than neurons from normal mice. These hyperexcitable neurons then released molecules that increased the growth of brain and nerve tumors. This hyperexcitability, the researchers discovered, was the result of a dysfunctional ion channel that changed the baseline electrical activity inside the neurons.
They also studied mice with an Nf1 mutation seen in people with NF1 who do not develop brain or nerve tumors. Anastasaki found that neurons from mice with this specific Nf1 mutation are not hyperexcitable and do not develop tumors – providing the first explanation for why this group of patients with NF1 lack optic gliomas or neurofibromas.
Hyperexcitable neurons are also a feature of epilepsy, and the epilepsy medication lamotrigine targets the same ion channel disrupted in hyperexcitable Nf1-mutant neurons. The researchers gave lamotrigine to a group of Nf1-mutant mice that develop optic nerve tumors. Compared to mice receiving a placebo, mice that had received the drug had smaller tumors, which no longer were growing.
Apart from suggesting a new way to treat NF1 tumors, these findings also suggest a new way of thinking about the origins of the disorder’s cognitive symptoms.
“The mutation in the Nf1 gene changes the basic biology of the neuron,” Gutmann said. “During development, neurons form first and tell the rest of the brain how to form. If you have a mutation that affects how neurons behave, that may change everything about how the brain gets set up during development. Nothing we’ve tried so far to prevent learning disabilities has worked. Maybe this discovery could lead to new treatments for the learning and cognitive problems in children with NF1.
“I’m very excited about the scientific and medical implications of these findings. Not hyperexcited,” he added, “but excited.”
Reference: “Neuronal hyperexcitability drives central and peripheral nervous system tumor progression in models of neurofibromatosis-1” by Corina Anastasaki, Juan Mo, Ji-Kang Chen, Jit Chatterjee, Yuan Pan, Suzanne M. Scheaffer, Olivia Cobb, Michelle Monje, Lu Q. Le and David H. Gutmann, 19 May 2022, Nature Communications.