Researchers Reveal How Nerves Drive Small Cell Lung Cancer Growth
The first attempt to describe the relationship between nerves and tumors appeared in The Journal of Experimental Medicine in 1897, authored by H.H. Young, M.D. After more than 120 years of research, numerous discoveries have been made in this field…but still more research is needed.
The study, “Neuronal activity-dependent mechanisms of small cell lung cancer pathogenesis,” published this week, focused on the impact of neuronal activity on tumor growth and spread, particularly small cell lung cancer (SCLC), which is highly aggressive and often metastasizes to the brain. The research was led by Stanford University, together with researchers from Brigham and Women’s Hospital, Harvard Medical School, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Columbia University Irving Medical Center, and the Dana-Farber Cancer Institute.
For clarification, histologically, that is, according to tissue structure, lung cancer is divided into two main types: small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC). SCLC accounts for approximately 15% of lung cancers, while NSCLC accounts for about 85%. As mentioned, this cancer metastasizes rapidly, so understanding what happens to tumor cells, how they spread, and what influences that spread is crucial for the development of effective therapies.
Researchers discovered that SCLC tumor cells can, so to speak, “listen” to nerves and use their signals for faster growth and spread. Humsa Venkatesh, PhD, an assistant professor of neurology at Harvard Medical School, said in a press release, “For the first time, we find that metastatic cancers integrate with neuronal circuitry. This discovery has clear clinical relevance and opens promising new avenues for treatment.”
As explained in the study, the nervous system appears to be a key component of the tumor microenvironment that regulates the pathobiology of cancer. Therefore, they investigated how innervation, that is, the supply of organs with nerve fibers that enable signal transmission between the nervous system and tissues, particularly via the vagus nerve, can affect small cell lung cancer cells.
Increased Investment and Collaboration to Advance Cancer Neuroscience
“Investment in the emerging field of Cancer Neuroscience, including multi-disciplinary training, increased collaboration between neuroscientists and cancer biologists, and funding for basic, translational, and clinical research in Cancer Neuroscience, is needed to advance further down this promising new path towards better cancer outcomes,” said Michelle Monje, the Milan Gambhir Professor in Pediatric Neuro-Oncology and professor of pediatric neurology at Stanford Medicine, who shares senior authorship of the study, for Unknown Focus. In March of this year, Professor Monje was awarded The Brain Prize for her research aimed at finding an effective treatment for diffuse intrinsic pontine glioma, which is an extremely difficult-to-treat pediatric cancer.
The study and the results
The research began in the laboratory using mice with genetically induced SCLC tumors. The mice were divided into two groups: one group had normal vagus nerves (control, 11 mice), while the vagus nerve of the other group (9 mice) was removed. The vagus nerve connects the brain to the lungs, heart, stomach, liver, and other organs; for example, it controls breathing, heartbeats, and transmits signals between organs and the brain. In the context of tumors, the vagus nerve is a source of nerve signals that can stimulate SCLC growth in the lungs, so cutting the vagus nerve (vagotomy) removes these signals, and the tumor grows more slowly or does not form metastases.
The results showed that mice without the vagus nerve almost did not develop tumors, and their liver, the primary site of metastasis, remained completely clear. Control mice developed multiple lung tumors and liver metastases.
“An abundance of nerve fibres was also evident in the vicinity of tumours metastatic to the liver in these mice…” as stated in the study. This demonstrated that nerve signals, particularly from the vagus nerve, support the early stages of tumor growth. When the nerve was cut later, after the tumors had already formed, the effect was smaller, indicating that nerves have the greatest impact at the onset of the disease.
Next, the researchers examined metastatic tumors in nine patients with SCLC. It was observed that cancer cells located near neurons divided faster than those farther away. Since mice do not have a reliable model for spontaneous metastatic growth in the brain, the researchers implanted human or mouse tumor cells directly into the brains of mice. Using this approach, they confirmed that the presence of neurons in the tumor increases the proliferation of SCLC cells, especially in peripheral areas rich in neurons, which corresponds to observations in human samples. According to the study, “it is important to note that this is not a model of metastatic initiation, but rather one of established intracranial tumour growth.” That is, the focus was on how the tumor grows and reacts in the brain, not how metastasis naturally occurs.
Then they also investigated how SCLC cells proliferated when they were in the presence of active neurons. For example, when they added tetrodotoxin (TTX), which blocks neuronal action potentials, it was seen that growth depended on active neurons. Using additional techniques such as optogenetics, a method in which a light pulse activates specific neurons in the mouse brain, it was shown that tumors spread and divide faster.
Given the increased neuronal activity that fuels SCLC growth in the brain, the researchers used levetiracetam, an anti-seizure drug that reduces synaptic signaling, thereby limiting the ability of neurons to transmit electrical signals to cancer cells. After two weeks of treatment, mice with SCLC tumors showed significantly reduced proliferation and tumor size, suggesting that disrupting the interactions between neurons and SCLC may be key to therapy.
What is next?
In a press release, Professor Monje said that, as a clinician, she is humbled by the many ways cancer exploits patients and by how much remains to be understood. At the same time, she emphasized that researchers now have a clearer path toward developing effective therapies for these cancers.
As Professor Monje told Unknown Focus, many questions remain. “We have observed the same membrane depolarization–induced growth effect in primary brain cancers, called gliomas, and now in small cell lung cancer brain metastases,” she explained. Professor Monje highlights a set of pressing questions related to identifying the granular details of the voltage-sensitive signaling pathway(s) triggered by membrane depolarization in cancer cells. “What voltage-gated ion channels are involved? What is the mechanistic cascade triggered by the electrical signal that increases cancer cell proliferation? Do these downstream mechanisms differ between gliomas and lung cancer cells, or are there shared principles of voltage-regulated cancer cell growth? Does this type of voltage-regulated cancer growth happen in cancers outside of the brain? ”
“As we understand these mechanistic details, we hope to be able to develop therapeutic strategies to disrupt cancer’s ability to take advantage of these signals from the nervous system and thereby improve outcomes for these very aggressive cancers,” Professor Monje concluded.
