Cancers produce painkillers

PD-1 ribbon. Image source: Wikimedia Commons

Cancer is often synonymous with pain and suffering. Abnormal cell growths produce multiple substances which increase the sensitivity and excitability of nociceptors (pain transmitting neurons), inducing hyperalgesia, a general increased sensitivity to pain, as well as allodynia, when a pain response is triggered by stimuli which do not normally provoke pain.

However, not all types of cancers emit pro-nociceptive mediators, and cancers at different growth stages may produce different pain sensations. In fact, early-stage tumours, before metastasis to bone, are often not painful at all. Why is that? A collaboration of scientists from the United States, China and the Republic of Korea may have found the answer.

In an article recently published in Nature, Chen and colleagues describe a phenomenon in which a small protein secreted by a melanoma (skin cancer), called the PD-L1, exhibits painkilling properties. PD-L1 stands for ‘Programmed cell death ligand-1’, and it is known to suppress immunity through binding to its cognate receptor, the PD-1, expressed on T cells (a type of white blood cell). Our bodies normally produce PD-L1 in abundance in the liver, but also in the skin, brain and spinal cord. Interestingly, melanoma generates about 400 times more PD-L1 than healthy skin and about 5 times more than liver. PD-L1 produced at such high levels suppresses normal immune responses to tumours, preventing the healing processes, and it is therefore often targeted and inhibited by certain cancer treatments.

Chen and colleagues demonstrated that inhibiting the PD-L1 protein in healthy mice made the animals more sensitive to pain, and injecting ‘extra’ PD-L1 increased their pain threshold near the injection site. Moreover, mice with melanoma in their hind paws showed reduction in cancer-related discomfort, while blocking PD-L1 instantly generated spontaneous pain, demonstrated by licking or flinching of the tumour-bearing paw. However, the analgesic (pain relieving) properties of the molecule are much broader. In subsequent experiments the researchers have shown that PD-L1 was also able to inhibit acute inflammatory and chronic neuropathic pain after nerve injury.

So, how does PD-L1 provide pain relief? In brief, pain is detected by the sensory receptors, then passed along the afferent nerves to the spinal cord and finally to the brain. Chen and colleagues have shown that PD-L1 strongly suppressed the transmission of pain at the spinal cord level, but the specific mechanisms by which this is achieved still require further investigation.

The most fascinating aspect of this study is that our bodies are perhaps able to produce our own painkillers. Maybe, instead of poisoning our bodies with dangerous chemicals and addictive drugs, we could instead reduce our suffering by exploring and harnessing the potential of molecules we already possess.


This article was written by Marta Mikolajczak and edited by Sam Stanfield.

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