It communicates using the human neural network as a stepping stone and even neutralizes the immune system.
Entered 2024.02.03 19:00 Entered 2024.02.03 19:00 Modified 2024.02.04 09:00 Views 284
Cancer cells depend on human nerve cells for everything, from attracting blood vessels to eat and grow, from onset to spread. [사진= 게티이미지뱅크]It has been revealed that cancer cells not only use our body’s nerve cells or neuroblasts, the precursor cells of nerve cells, as hostages or accomplices as a means of communication, but also disrupt our body’s immune system. This is what the scientific journal Nature reported on the 31st (local time) by compiling several papers published between 2001 and 2023.
In 2017, cancer neuroscientist Humsa Venkatesh was shocked while observing on a computer monitor whether blue electrical signals were passing between cancer cells of glioma, a type of brain cancer. He thought that there might be some communication between cancer cells, but then he observed that tremendous electrical signals were generated between glioma cancer cells. “I was shocked that cancer cells, not even nerve cells, could communicate so actively,” said Venkatesh, who was a postdoctoral researcher at Stanford University School of Medicine at the time and is now a professor at Harvard University School of Medicine.
Scientists had no idea that that level of electrical communication could occur between cancer cells, even in cancer cells in the brain. However, research results showing that cancer cells communicate tremendously for survival and growth were published in 《Nature》 in 2019, leading to a boom in a new discipline called ‘cancer neuroscience’, which combines oncology and neuroscience. Cancer cells depend on human nerve cells for everything, from attracting blood vessels to eat and grow, from onset to spread.
Scientists are beginning to understand which signals sent by nerve cells are associated with cancer, but the story becomes much more complicated when the interaction between cancer and the immune system is added. As we dig deeper into the relationship between cancer and the nervous system, treatments that target that connection are emerging. Some of these treatments are becoming possible through existing drugs.
Are neurons victims or accomplices?
Scientists first discovered contact between cancer cells and nerve cells nearly 200 years ago. In the mid-19th century, French anatomist and pathologist Jean Cruveyer described a case of breast cancer invading the cranial nerves responsible for facial movement and sensation. This was the first report of perineural invasion, in which cancer cells spread by squeezing between nerves. This phenomenon is a sign of an aggressive tumor and portends poor health outcomes.
Scientists thought nerves acted as passive highways that carried cancer and its associated pain. Many people thought of the nervous system as a “victim, a structure that is destroyed or damaged by cancer,” said Michel Monger, a neuro-oncologist at Stanford University School of Medicine who was Venkatesh’s advisor.
However, in the late 1990s, Professor Gustavo Ayala, a urological pathologist at the University of Texas at Houston Health Science Center (UTHealth Houston), began to examine the interaction more closely. He placed mouse nerves in a dish stained with human prostate cancer cells. Within 24 hours, the mice’s nerves began growing small branches called neurites, which extended toward the diseased cells. Then, when contact was made, the cancer moved along the nerve and reached the nerve cell body. This was published in the international academic journal “Prostate” in 2001.
Nerves were not just bystanders. Actively pursued a link with cancer. Professor Ayala delved into this field, but was treated like a weirdo by academics, who called him ‘the nerve guy’. In 2008, he published a paper titled “Clinical Cancer Research,” which brought about a change in the atmosphere. He discovered that prostate cancer tumor samples had more nerve fibers called axons than healthy prostates.
In 2013, a paper published in Science by professor Claire Magnon (cancer biology) at the French National Institute for Health and Medical Research (INSERM) brought about a further groundbreaking change. They showed that nerve fibers were sprouting within and around prostate tumors in mice. It was also found that cutting off the connection to the nervous system stopped the spread of prostate cancer.
Nerve cells provide safe harbor for cancer
Over the next few years, a flood of research showed that the same phenomenon occurred not only in the prostate, but also in cancers of the stomach, pancreas, and skin. It has also been found that some of the severed nerves carry pain associated with cancer. Scientists have already discovered that in patients with pancreatic cancer, blocking this pathway can alleviate some of the pain. “The stars are starting to align,” said Brian Davis, professor of neuroscience at the University of Pittsburgh in the U.S. “The role of the nervous system as a component of the tumor microenvironment, which had been ignored, has become clear.”
Predictions are beginning to emerge that cancer cells can transform into nerve cells, or at least acquire nerve cell-like characteristics. Professor Magnon’s research team reported in a paper published in Science in 2019 that they had discovered a new cell that was useful for cancer cells. It was discovered that neuroblasts, which are precursor cells of nerve cells, migrate to mouse prostate cancer cells through the blood, settle there, and transform into nerve cells.
In any case, the cancer was affecting the area of the brain that contains these cells, an area called the subventricular zone. In mice, these cells are known to be helpful in treating certain brain diseases, such as stroke. Although this idea is controversial, some evidence suggests that the same region produces neurons in human adults.
In 2020, it was discovered that cancer can force nerve cells to change their identity. A study of oral cancer in mice found that a group of nerves called sensory neurons, which transmit sensation to the brain, developed a ‘fight or flight’ response, a characteristic of the sympathetic nervous system that is generally rare in the oral cavity. Moran Ammitt, a cancer neuroscience professor at the University of Texas MD Anderson Cancer Center and lead author of the paper, said, “Because sympathetic nerves are helpful for certain cancers, these changes may help cancer cell growth.”
However, the relationship between the effect on cancer cells and the type of nerve is complex. In the pancreas, for example, there is a push and pull between two types of nerves that have opposite effects on the tumor. The sympathetic nervous system is involved in a vicious cycle that helps develop cancer. They send out signals that instruct diseased cells to secrete a protein called nerve growth factor, which attracts more nerve fibers. On the other hand, the parasympathetic nervous system sends chemical messages responsible for the ‘rest and digest’ response, interfering with the progression of the disease.
In stomach cancer, parasympathetic signals act in the opposite direction and promote tumor growth. In prostate cancer, two types of nerves support the tumor. In the early stages of cancer development, the sympathetic nerves help, and in the later stages, the parasympathetic nerves are activated and metastasis occurs.
“Every cancer is slightly different in how it interacts with the nervous system,” said Timothy Wang, a professor of gastroenterology at Columbia University in the United States. This means that the treatment target must be specific about the type of cancer and how the cancer is or is connected to the nervous system.
Nerve cells can have a direct effect on cancer, but they can also act indirectly by weakening the immune system so that it cannot fight cancer cells effectively. A paper by Canadian and American researchers published in Nature in 2022 suggests one such mechanism. A chemical called calcitonin gene-related peptide (CGRP), released by sensory nerves, silences the activity of certain immune cells, preventing them from fighting off cancer.
Nerve cells can suppress the activity of immune cells to keep themselves safe. This is because if too much inflammation occurs due to the activity of immune cells, it can also harm nerve cells. Jamie Saloman, a professor of cancer neurology at the University of Pittsburgh, explained that for this very reason, nerve cells appear to provide a safe harbor as well as a path and platform for the spread of cancer.
It is difficult for drugs to penetrate nerves. This may allow cancer cells to attach to nerves because they are protected from both the immune system and drugs. “Cancer cells can cling to life waiting for the storm of biology and chemotherapy to pass and then reemerge,” he said.
Beyond the nerves to the central nervous system
Some of the most aggressive cancers affect the brain. As Professor Venkatesh and others have discovered, cancer cells even form direct synapses with nerves whose signals help them grow.
There are still more ways in which cancer cells in the brain appear to behave like brain cells. A paper by Professor Mongé’s research team published in Nature last November reported that gliomas use typical brain signal transmission methods to enhance nerve cell infiltration. When glioma cancer cells are exposed to a protein called ‘neurotrophic factor’ that helps nerve cells grow, they respond by producing more receptors that can receive signals from nerve cells. “This is exactly the same mechanism that healthy neurons use for learning and memory,” said Professor Monger. “Cancer is not actually creating something new; it is just hijacking a process that already exists.”
In addition, some glioma cells can generate their own rhythmic waves of electrical activity, like neural networks. “They are no different from the beating of a small heart,” said Dr. Frank Winkler, a neuro-oncologist at the German Cancer Research Center.
These electrical impulses spread throughout the cancer cells using thin, stringy networks called ‘tumor microtubes’. This activity coordinates the proliferation and survival of cancer cells, just as pacemaker neurons coordinate their activity during the formation of neural circuits. “Once again, cancer hijacks important neural mechanisms for neural development,” said Dr. Winkler.
Brain cancer can even affect entire neural networks. A paper by Professor Mongé’s research team, published in Nature in May last year, discovered that gliomas can reorganize the entire functional circuit of the brain. When people with cancer cells in the brain area involved in speech production were asked questions to activate the speech area, it was observed that activity not only in the speech area but also in all areas of the brain where the cancer cells had infiltrated increased rapidly. Professor Mongé said, “Cancer cells remodeled functional language circuits to feed themselves,” and said, “I was horrified” when he first saw the data.
Searching for cancer treatment using existing drugs
These findings suggest a potential cancer treatment. It also explains why existing cancer treatments damage the brain. Professor Venkatesh said many people who receive chemotherapy for cancer develop cognitive decline, a deterioration of nerve fibers in the ‘chemical brain’ and elsewhere in the body. Attacking cancer cells also results in the destruction of nerve cells.
One strategy is to target specific parts of the nervous system. And existing treatments may help. “We have drugs that target almost every area of the nervous system, and most of them have very well-established safety profiles,” Professor Ammitt said.
For example, beta blockers can disrupt sympathetic nerve signals that lead to cancer progression in breast, pancreatic, and prostate cancers. Since the 1960s, these drugs have been used to treat heart conditions such as high blood pressure and sometimes anxiety.
Professor Erica Sloan’s research team (cancer biology) at Mona University in Australia announced the results of a phase 2 clinical trial testing the beta blocker propranolol in breast cancer patients in 2020. Just one week of this medication reduced signs of the cancer spreading. Another phase 2 clinical trial demonstrated that combining chemotherapy and propranolol is safe for people being treated for breast cancer. Professor Sloan’s team also reported last year that the drug improves standard chemotherapy treatments.
Other researchers are applying drugs that disrupt neural communication in cancer treatments, including drugs developed for seizures and migraines. Clinical trials are also underway to block the synapse formed between nerve cells and cancer cells in glioma using an anti-extrusion drug that calms hyperexcitable cells.
A clinical trial is also being planned to see whether people receiving immunotherapy for skin or head and neck cancer might benefit from migraine medication. Migraines can be triggered by high levels of CGRP, a molecule that can slow down the activity of some cancer-fighting immune cells. Therefore, drugs that block the CGRP receptor can help immune cells fight cancer again.
Professor Venkatesh envisions that controlling cancer will require a cocktail of drugs with complementary effects. “There is really no panacea,” he said, adding that there is a long way to go as the insidious tactics of cancer are only just beginning to be understood.
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2024-02-04 22:08:17
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