Cancer 'Pain Signal' Sparks Research Into Pain Rx
Living with cancer presents many challenges, one of which is fear of pain.1 Although great strides have been made in the treatment of pain over the last 20 years, cancer pain remains difficult to treat.
As doctors investigate the mechanisms that drive cancer pain, new burgeoning research is starting to unravel its complexities. And one gene in particular could be the key that leads to new therapies and better pain relief for patients with cancer.
Transmembrane protease, serine 2, or TMPRSS2 for short, is an androgen-responsive gene highly expressed in prostate cancers and a key role-player in carcinogenesis.2-5 It encodes a serine protease, an enzyme, which doctors believe could be a kind of “pain signal.”
Traveling out into the extracellular space, this serine protease could be activating receptors, sparking the spontaneous and exacerbated pain that cancer patients often report. And now, researchers say TMPRSS2 is prevalent in the most painful of cancers and could be the target of choice for future drugs to curb cancer pain.
A Common Trait in Painful Cancers
Head and neck Squamous Cell Carcinoma (SCC) has been said to be the most painful out of all the cancers, which worsens as the disease progresses.6,7 To find out if SCC patients have a high percentage of cells positive for TMPRSS2, researchers evaluated 10 patients, all diagnosed with SCC.8 All of the patients were assessed with Visual Analog Scale questions (VAS) to record their pain symptoms, while biopsy specimens were collected to conduct immunocytochemistry for TMPRSS2.
“Pain scores and TMPRSS2 immunoreactivity were highly correlated for SCC patients, suggesting that the proportion of TMPRSS2-positive cells predicted the severity of cancer pain. Noncancer patients demonstrated neither pain nor significant TMPRSS2 immunoreactivity,” the researchers reported.
Next, they compared head and neck cancer cells (SCC-9 and HSC-3) to other cancer cells, such as human melanoma (WM164) and breast cancer (MCF-7). In theory, less painful cancers, like WM164 and MCF-7, should have less TMPRSS2 frequency. Their theory was correct. HSC-3, SCC-9, and prostate cancer cell lines (as positive control) all had far greater TMPRSS2 immunoreactivity than WM164 and MCF-7.
TMPRSS2 Needs Specific Receptor
Researchers believe TMPRSS2 and other serine proteases excite nociceptive reactions through a very specific pathway: protease-activated receptor-2 (PAR2). When up-regulated on peripheral nerves, PAR2 could be altering pain processing, causing hyperalgesia, neuronal excitability, and even the progression to chronic pain.9-11
They found TMPRSS2 was so potent at activating peripheral neurons, it outperformed a PAR2 agonist (63.8% vs. 24.4%, respectively).12 Indeed, when wild-type mice were administered TMPRSS2, their injected hind paws showed spontaneous nocifensive behaviors, followed by significant allodynia.
However, TMPRSS2 seems to be dependent on this receptor. PAR2-deficient mice didn’t show any reaction when administered TMPRSS2. According to researchers, these may be clues to developing future therapies.
Potential for New therapies
Could PAR2 antagonists and serine protease inhibitors become tools for blocking this pain pathway?
PAR2 is an emerging target for treating all kinds of conditions, like arthritis, cardiovascular diseases, and neurodegenerative conditions,13 and various PAR2 antagonists have yet to reach human clinical trials, but PAR2 doesn’t seem to function in a vacuum.
Being a G-protein coupled receptor, it sensitizes other nociceptive receptors, like TRPV1 and TRPV4.14-15It has a broad involvement in tissue function, appearing in dorsal root, TG neurons16,17 and central nervous system neurons and astrocytes in the brain,18,19 which make it a hard target to isolate.
Other pain pathways in the body could be potential targets for new therapies, as well, like adenosine receptors, specifically ADORA3. Practical Pain Management reported on a recent study that found promising results using adenosine, a purine nucleoside, to quell symptoms of chemotherapy-induced neuropathy, cancer-induced bone pain, and other cancer pain etiologies.20
There is also adiponectin, a protein in the body that regulates glucose levels and fatty acid breakdown, and according to Alvin Beitz, PhD, a professor of veterinary and biomedical science as the University of Minnesota, it could play a crucial role in the ceramidase pathway in cancer and other types of pain.
“Ceramidase is an enzyme which cleaves fatty acids from ceramide, producing sphingosine (SPH), which in turn is phosphorylated by sphingosine kinase to form sphingosine-1-phosphate (S1P),” Dr. Beitz told Practical Pain Management in an email interview.
“While we are just getting into this area, we find that systemic or intrathecal administration of a ceramidase inhibitor or an S1P inhibitor produces a profound analgesic effect in animals with tumors and in animals with paw inflammation.
“Conversely, injection of the S1P antagonist directly into the hind paw produces pain and if injected into a hind paw tumor, it increases tumor pain. So we are currently trying to figure out differential mechanisms behind these contradictory effects.”
The study in PAIN was supported by a grant from the National Institutes of Health and the National Institute of Dental and Craniofacial Research. The authors declared no conflicts of interest.
Photo courtesy of National Cancer Institute and Kelly Nelson (Photographer).