Nerve cells have become accomplices of oral cancer!

Cancer cells are notoriously greedy and consume more glucose
than normal cells.
This has prompted researchers to look for ways to kill tumors by starving them or disrupting their metabolic pathways, but growing evidence, including research published today (November 16) in the journal Cell Metabolism, suggests that cancers have some tricks that allow them to survive
even in nutrient-poor microenvironments.
The new paper finds that oral cancer cells can use nearby cohorts — in this case, the host's pain-sensing nerves — to produce the peptides
they need to continue growing and resisting treatment.

Jatin Roper, a cancer researcher and clinician at Duke University who was not involved in the study, said, "I think this paper is an exciting and welcome addition to the growing body of literature showing that cancer cells are not isolated
.
" He added that while other studies have looked at the nociceptive nerves (those that detect and transmit pain signals) in the surrounding and tumor-nourishing microenvironment, the study reveals many details
about how they help tumors, particularly oral cancer, survive in the face of nutritional deprivation.

The study focused on oral squamous cell carcinoma (OSCC), a type of cancer that affects cells that line the mouth, tongue, gums and lips and is known to deplete glucose in its microenvironment, but somehow resist treatments
designed to starve them.
The study's co-author Ji Tong, an oncologist and oral disease researcher at Shanghai Jiao Tong University School of Medicine, is that OSCC patients tend to report severe pain and have nerves extending into or around
the tumor.

"As an oncologist specializing in oral and maxillofacial - head and neck oncology, my team and I have noticed high rates of self-reported pain from oral cancer patients," Tong wrote
.
"What's more, uncontrollable cancer pain is clinically associated with worse patient outcomes, which has also been observed
in a variety of cancers, including pancreatic cancer.
" These clinical features inspire us that there may be a vicious cycle between cancer progression and cancer pain, but the underlying biological mechanisms are largely unclear
.
”

Indeed, cohort analysis by Tong and his colleagues of human OSCC patients and mouse models showed a high density of nociceptive nerves around tumors, and in vitro experiments showed that when tumors found themselves in a malnourished environment, tumors promoted peripheral nerve growth by secreting nerve growth factor (NGF), essentially surrounding the tumor
with pain receptors.

To identify the specific signaling pathways and mechanisms by which these nerves contribute to OSCC progression, the researchers transplanted human OSCC onto mouse tongues
.
They found that the area around these xenografts had higher levels of glycolytic enzymes, an enzyme that promotes a low glucose microenvironment
, compared to the tongues of control mice without tumors.
At the same time, human tumors cultured with nerve cells in vitro in a low-sugar environment had increased levels of proliferation biomarkers compared to human tumors cultured in a high-sugar environment, leading to increased nerve growth, suggesting that communication between cancer and nerve cells only occurs in malnourished environments
.

Tong writes: "We found that the direct interaction between cancer cells and the pain nerve is triggered by a malnourished environment, exacerbated
in the treatment of nutritional starvation.
" He also added that the work was the first sign
of a direct interaction between cancer cells and the nociceptive nerve.

The researchers also found that feeding sugar water to mice with OSCC stunted tumor growth, Tong wrote, evidence that
low-sugar-induced nerve growth does support tumor growth.

The next step is to figure out exactly how nerves support tumors
.
The researchers found that tumor-associated neurosecretion of calcitonin gene-associated peptides (CGRPs) in xenograft mice is commonly associated
with pain pathways and wound healing.
An in vitro experiment found that exposure to these peptides induced cytoprotective autophagy, a known cancer survival mechanism that delays cell death, enhances tolerance to starvation conditions, and increases resistance to chemotherapy drugs and radiotherapy
.
As in other experiments, CGRP is secreted
only under low-sugar conditions.

Tong writes, "Our study reveals that the nociceptive nerve is a microenvironment accomplice
in which cancer cells grow in a malnourished environment.
" He also added that this mechanism can occur in
a wide variety of tumors.

By analyzing tissue samples from OSCC patients, the researchers found that neurogenic CGRP levels were significantly higher than healthy controls, and found that CGRP levels correlated with
worsening clinical outcomes.

However, in vitro and mouse experiments found that rimegepant, a CGRP-blocking drug approved by the U.
S.
Food and Drug Administration for the treatment of migraines, blocked tumor-associated nerve-supporting cancer cells, thereby leaving tumors vulnerable to starvation and inhibiting their growth
.
"We think this discovery may provide a new treatment strategy for cancer patients," Tong wrote
.
"This is cancer treatment
for the nociceptive nerves.
"

Roper added that rimegepant has been approved for use in humans, which is a blessing because it could make it easier to justify early-stage clinical trials for oral cancer without the need for additional mouse studies
.
"I think this study has a lot of clinical applications," he said, especially if it turns out that rimegepant is well tolerated in cancer patients, and if it improves the effectiveness of
existing cancer therapies.