ABOVE: Cancerous oral squamous cells © ISTOCK.COM, MD ARIFUL ISLAM

Cancer cells are notoriously ravenous, consuming far more glucose than normal cells do. This has led researchers to search for ways to kill tumors by starving them or disrupting their metabolic pathways, but an increasing pile of evidence, including research published today (November 16) in Cell Metabolism, indicates that cancers have several tricks that allow them to survive even in nutrient-depleted microenvironments. The new paper finds that oral cancer cells can tap nearby accomplices—in this case, the host’s pain-sensing nerves—to produce the peptides they need to continue growing and resist treatments.

“I think the paper is both an exciting and welcome addition to a growing body of literature that shows that cancer cells don’t act in isolation,” says Duke University cancer researcher and clinician Jatin Roper, who didn’t work on the study. He adds that while other research had implicated nearby nociceptive nerves—those that detect and transmit pain signals—in the microenvironments that surround and nurture tumors, this study revealed many details about how they help tumors, especially oral cancers, survive nutrient depletion.

The study focused on oral squamous cell carcinoma (OSCC), a type of cancer in which affected cells that line the mouth, tongue, gums, and lips are known to deplete their microenvironment of glucose, yet somehow resist therapies intended to starve them out. The study was prompted by the fact that OSCC patients tend to report severe pain and to have nerves extending into or around their tumors, study coauthor Ji Tong, an oncologist and oral disease researcher at Shanghai Jiao Tong University School of Medicine, tells The Scientist over email.

“As an oncologist focusing on oral and maxillofacial-head neck oncology, I, as well as my team noticed the high rate of patient-reported pain of patients with oral cancers,” Tong writes. “More importantly, uncontrolled cancer pain clinically correlated with worse patient outcomes, which has also been observed in multiple cancers including pancreatic cancer. These clinical features enlightened us that there might exist a vicious cycle between cancer progression and cancer pain, but the underlying biological mechanisms were largely unknown.”

See “Immune Cells Imitating Neurons Cause Pain in Mice with Tumors

Indeed, Tong and colleagues’ analysis of a cohort of human OSCC patients and mouse models showed a high density of nociceptive nerves surrounding the tumors, and an in vitro experiment showed that tumors prompt neural growth around themselves by secreting neural growth factor (NGF) when they find themselves in a nutrient-poor environment, essentially surrounding the tumors with pain receptors.

To determine the specific signaling pathways and mechanisms that allowed these nerves to promote OSCC progression, the researchers grafted human OSCC onto the tongues of mice. They found that the area surrounding these xenografts had higher levels of glycolytic enzymes, which promote a low-glucose microenvironment, than did the tongues of control mice without tumors. Meanwhile, human carcinomas cultured alongside nerve cells in low-glucose environments in vitro had increased levels of proliferation biomarkers, resulting in increased nerve growth, compared with those cultured in higher-glucose environments, indicating that communication between the cancer and nerve cells only occurred in the nutrient-poor environment.

“We find that [these] direct interactions between cancer cells and nociceptive nerve[s] are initiated by the nutrient-poor environments and aggravated upon nutrient-starvation therapies,” writes Tong, adding that the work is the first indication of a direct interaction between cancer cells and nociceptive nerves.

The researchers also found that feeding sugar water to mice with OSCC impeded tumor growth, which Tong writes is evidence that the nerve growth triggered by low sugar availability is indeed supporting the tumors.

The next step was figuring out how, exactly, the nerves support tumors. The researchers found that the tumor-associated nerves of xenograft-bearing mice were secreting calcitonin gene-related peptides (CGRP), which are typically associated with pain pathways and wound healing. An in vitro experiment found that exposure to these peptides induces cytoprotective autophagy, a known cancer survival mechanism that staves off cell death, boosts tolerance to starvation conditions, and increases resistance to both chemotherapy drugs and radiotherapy. As with the other experiments, CGRP secretion only occurred in a low-glucose condition.

“Our study reveals [the] nociceptive nerve as a microenvironmental accomplice employed by cancer cells to thrive in nutrient-poor environments,” writes Tong, adding that this mechanism likely occurs in a wide variety of tumors.

Analyzing tissue samples from people with OSCC, the researchers found significantly higher levels of neurogenic CGRP than they did in healthy controls, and also found that CGRP levels were correlated with worsened clinical outcomes.

However, in vitro and mouse experiments found that the CGRP-blocking drug rimegepant, which is approved by the US Food and Drug Administration to treat migraines, prevents the tumor-associated nerves from supporting the cancer cells, thereby rendering the tumors vulnerable to starvation and inhibiting their growth. “We think [this] finding may inform a kind of new treatment strategy for cancer patients,” writes Tong. “That is—targeting nociceptive nerve for cancer treatment.”

It’s a stroke of luck that rimegepant is already approved for human use, Roper adds, as that could make it far easier to justify an early-stage clinical trial testing the drug for oral cancer without the need for additional mouse studies.

“I think there’s a lot of clinical applications to this study,” he says, especially if it turns out that rimegepant is well-tolerated by cancer patients and if it boosts the effectiveness of existing cancer therapies.