Manish Vira, a urologist at Northwell Health in New York performs prostate biopsy procedures three to five times a week. He inserts 12 needles into the prostate gland in specific locations, identified by MRI images that reveal malignant or suspicious lesions. The samples then go to a pathologist who determines whether cancer is present and how aggressive it is. 鈥淚t鈥檚 a standard protocol,鈥� explains Vira, who is also a chief oncologist at Northwell.
For the past few years, however, that standard protocol had a few extra steps. Now, the biopsy 鈥渨ash鈥濃�攁 collection of molecules washed off the sample鈥攇oes to the research lab of Lloyd Trotman, a professor at 黑料吃瓜资源 (CSHL), who studies what makes these tumors aggressive or aids their metastases. Trotman鈥檚 team looks at the tumors鈥� genomic signatures鈥攖heir genetic make-up, which can make them more or less aggressive. They look at the tumors鈥� microenvironments鈥攖he molecules that cancer surrounds itself with. And while researching these factors, they also dig into something that鈥檚 rarely looked at in cancer biology: the nervous system and its role in helping tumors spread.
In the past decade, scientists have realized that cancer isn鈥檛 just a localized disease, but a systemic problem that involves the whole organism. They realized that tumors don鈥檛 exist in a vacuum but require a permissive and supportive environment to take hold and thrive. To do so, tumors create their own ecosystems, in which they recruit and reprogram the body鈥檚 own cells鈥攕ometimes even those that are supposed to destroy cancer鈥攖o help them grow and travel to new locales. What is less understood is the role that nerves play in these complex physiological interactions, says Jeremy Borniger, also an assistant professor at the CSHL Cancer Center, who works with Trotman. In the complicated scenario of how tumors burgeon and metastasize, the nervous system had not received its due attention.
鈥淚f you look at any cancer review paper from until about five or six years ago, you see that the research has been hyper-focused on the oncogenes, the tumor microenvironment鈥攃ancer cells, immune cells, endothelial cells, fibroblasts, maybe a couple of other cell types,鈥� says Borniger. That biological picture is of course important, but not complete. 鈥淭he nerves are almost never mentioned. So what鈥檚 been missing from the equation is how the tumor interacts with the body on the physiological scale, such as with the nervous system.鈥�
Trotman and Borniger try to view cancer as a whole-body disease, in which the brain (the central processing unit) and the nervous system (its communication channels) occupy an important spot in cancer progression鈥攑erhaps even the final frontier in our understanding of this disease. For starters, no single organ can exist without being 鈥渋nnervated鈥濃�攎eaning served and attended by nerves, which deliver signals back and forth from the brain, directly affecting how this body part functions. The brain, for its part, is the master regulator of the body, coordinating all chemical processes that happen inside us. The brain collects the info about the body through the nervous system and via circulating chemical cues in the blood. Then, it interprets the info and sends back chemical messages to neurons that pass them to the organs, muscles, and glands鈥攖o monitor and influence the activity of those tissues.
鈥淭he nervous system controls everything in normal tissues鈥攇rowth or atrophy, or anything else,鈥� says Massimo Loda, a molecular pathologist at the Weill Cornell Medical Center in New York. So there鈥檚 reason to believe that the same is happening with malignancies. 鈥淐ancer tissue grows fast so it needs the support of the nervous system,鈥� Loda says. Moreover, scientists know that certain cancers have a particular predilection for nerves. 鈥淔or example, breast and prostate tumors have a propensity to look for nerves and kind of invade and travel through those nerves,鈥� Loda says. It is as if there are some shadowy dealings happening between the nerve endings and tumors. 鈥淭hat suggests that there is synergy there.鈥�
The observational knowledge suggests that a greater amount of nerves bunching up around a tumor signals a grimmer prognosis. For example, when pathologists assess the severity of prostate cancer, the number of nerves that surround these tissues factors in. 鈥淭he pathologist will score that, and if there鈥檚 a lot of nerves in the area, it usually means a worse, or a more urgent situation,鈥� Borniger explains. 鈥淭o us, that seems like a blind spot or a missing link.鈥�
It鈥檚 not fully clear why the nerves and their involvement in cancer had languished in scientific obscurity for so long, but scientists have a few ideas. As strange as it sounds, the peripheral nervous system was the anatomy textbooks鈥� stepchild. In Gray鈥檚 Anatomy鈥攖he medical bible written by English doctor Henry Gray in 1858, that still educates generations of physicians鈥攖he nerves and their relationships with some organs remain somewhat of an afterthought. 鈥淚 decided to read the current 42nd edition of Gray鈥檚 Anatomy, and it鈥檚 an interesting picture,鈥� Trotman says. 鈥淔or liver, a site of end-stage prostate metastasis, you see descriptions and depictions of all kinds of cells, all kinds of conduits and blood vessels, but to this day, the nerves are usually not depicted. The innervation of some organs is apparently not a major topic in the organ anatomy.鈥�
Modern science, of course, pays far more attention to the nervous system and the brain than the 150-year-old manual. In 2016, the Allen Institute for Brain Science had published a map of the entire human brain鈥攁 digital atlas of our central processing unit. A 2021 effort preserved, sliced, and imaged a human surgical fragment of a cerebral cortex. And yet, the peripheral nervous system, which is the conduit between the brain and the rest of the body is still not fully specced out. 鈥淲e don鈥檛 really have great maps of the peripheral nervous system, and how it connects the brain to these organs,鈥� Borniger says.
Another reason for this strange disconnect is that, traditionally, neuroscientists rarely talked to cancer biologists. 鈥淣euroscientists don鈥檛 typically work on cancer and cancer biologists typically don鈥檛 work with neuroscience questions,鈥� Borniger says. Historically, the two disciplines remained too distant from each other and too siloed inside their own respective dominions.
鈥淭hat鈥檚 what we are trying to change,鈥� Trotman says鈥攅ssentially merging the two fields to study the neuroscience of cancer. In that realm, the prostate makes a particularly good research subject, he explains. 鈥淧rostate is a gland, which means that it already has a lot of nerves surrounding it,鈥� he says. 鈥淭he nervous system controls how the gland functions, such as squeezing out liquids. So it鈥檚 already organized in a way that鈥檚 amenable to our research.鈥� And, with the new tools that became available to scientists in the past decade or two, they are now able to peek at those shadowy nerve鈥搕umor dealings in real time.
Several major technology breakthroughs are making visualizing nerve and tumor interaction possible. One of them was the usage of fluorescent technologies that allowed scientists to engineer tissues to glow a certain color鈥攔ed, green, blue. Another major advancement at peeking into the tangled webs of nerves, neurons, and axons were the optogenetic tools that let researchers manipulate the activity of neurons with light.
With these technologies, mice can be engineered in such a way that whenever a tumor naturally grows in them, it fluoresces in, for instance, the color red. 鈥淭hat means that any descendants of those cancerous cells will also glow red wherever they go,鈥� Trotman explains, which gives researchers a way to see how metastases spread and take hold. Similarly, mice can be engineered to have organs innervated by nerves of shimmering green or some other hue. That gives researchers an unprecedented opportunity to see how nerves and tumors play together. 鈥淲ith these tools we can label all the nerves that are innervating a particular organ,鈥� Trotman says. 鈥淎nd then we can see the green nerves and the red tumor cells, and how they interact.鈥�
Perhaps more importantly, these visualization techniques can help reveal the shortcomings of existing treatments and aid in the development of better ones. For example, the current standard-of-care drugs for prostate cancer鈥攕o-called chemical castration medications that stop sex hormone production鈥攎akes tumors shrink, but only for a while. 鈥淚t鈥檚 a temporary regression, after which the relapse is guaranteed,鈥� Trotman says鈥攁nd medics don鈥檛 know why. The glowing mice can help shed some light on that. 鈥淲e want to know what happens to the peripheral nerves that are near the tumor,鈥� Trotman says. How does the shrinking tumor rebound? Does it stimulate nerve growth? Is it able to get more nutrients as a result? 鈥淭hose are the questions we鈥檇 like to find answers for.鈥�
If we can prevent or reduce the occurrences of the metastatic disease, we really can save a lot of people.”
Lloyd Trotman, Ph.D.
This work may ultimately help answer other puzzling questions about cancer causes. 鈥淔or example, prostate cancer is much more prevalent in tall men,鈥� Massimo shares鈥攍ikely because it has something to do with the growth hormones that come from the brain. Does the tumor somehow hijack the growth hormones for its own benefit? Are the nerves involved? If so, can scientists devise drugs that interfere with that process? Perhaps some of these questions can be answered, too.
When it comes to severity and prognosis, prostate cancer risks can be deceptive. Compared to many other aggressive malignancies like brain or pancreatic tumors, prostate cancer usually doesn鈥檛 spread or kill quickly鈥攎any men live 10 years and even longer after their diagnosis. But because it is so common鈥攁bout 12.5% of men get it, according to the National Institutes of Health鈥攐verall, it takes a lot of lives. In 2019, 224,733 cases were reported, and 31,636 men succumbed to it. 鈥淭he problem is that it鈥檚 so widespread,鈥� Trotman says. 鈥淪ince only 5 to 10% of people who have it will develop metastatic prostate cancer, an average patient has a 90% chance of being fine. But because so many men develop it, it is still the second cause of cancer death in men, after lung cancer. So, if we can prevent or reduce the occurrences of the metastatic disease, we really can save a lot of people.鈥�
Written by: Lina Zeldovich, Science Writer | [email protected] | 516-367-8455