A recent study unearthed that tumors possess the capacity to boost their own proliferation by enlisting sensory neurons and subverting them for their purposes. By connecting with the tumor cells, these neurons dispatch a signal to the brain, which consequently curtails the defensive function of immune cells in the afflicted area, thereby permitting the cancerous cells to multiply unchecked. This finding was reported on February 4th in the journal Nature.
Scientists managed to map the entire signaling sequence—spanning from the tumor to the brain and back again. According to Anna-Maria Globig, an immuno-oncologist at the Allen Institute for Immunology in Seattle, the tumor essentially hijacks this communication process and utilizes it to its advantage. Chengcheng Jin, a co-author and immuno-oncologist from the University of Pennsylvania, noted that when the team genetically disabled the sensory neurons, a “very strong, dramatic decrease” in tumor growth—exceeding 50%—was observed.
It has long been established that neural cells are present within tumor masses. Nevertheless, comprehending precisely how they influence tumor survival proved challenging for an extended period. One obstacle was that available genetic instruments previously lacked the precision needed to thoroughly analyze neuronal activity. Furthermore, obtaining genetic data specifically from neurons via biopsy is difficult because they represent the longest cell type in the body.
Jin and her associates, armed with microscopic evidence showing that neurons envelop and infiltrate lung tumors, sought to suppress the activity of specific neurons using pharmacological or genetic interventions to assess the resulting impact on cancer progression. Hao-Han Wei, a co-author, emphasized that the researchers spent nearly a year testing various compounds without yielding any discernible effects.
The breakthrough, reportedly, occurred “almost by chance,” when the group connected with Rui Chang, a neurobiologist from Yale University specializing in genetic “knockout” techniques. Together, the scientists managed to inactivate specific sensory neurons of the vagus nerve—a crucial conduit between the brain and visceral organs such as the heart and lungs. This enabled them to elucidate the signaling pathway operating between the brain and lung tumors in murine models.
The researchers also discovered that once the tumor captures this circuit, other neurons originating from the brainstem and running back toward the tumor release norepinephrine. This chemical marker ultimately serves to inhibit the tumor-destroying immune cells.
As per the publication, the scientists initially did not anticipate that neurons would interfere with the immune system’s anti-cancer efforts. On the contrary, the prevailing assumption was that these nerves would function to “warn” the brain about the presence of the tumor and assist the body in resisting the disease.
The researchers now propose a potential rationale. Isaac Chiu, an immunologist at Harvard Medical School, offered insight that macrophages, immune cells sensitive to nerve signals, are vital for tissue repair. He suggested that the existence of a pathway capable of dampening their responsiveness likely evolved to “switch off detrimental inflammation.”
These findings corroborate the conclusions of scientists who previously faced skepticism when asserting that nerves promote tumor growth.
“I am very pleased that the community is no longer skeptical. We are only at the beginning of truly grasping how these nerves develop,” concluded Claire Mignon, a neuro-oncologist at the French National Institute of Health and Medical Research, who was the first to demonstrate at a molecular level that nerves can accelerate cancer progression.
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