Pain is often the first sign of oral cancer, as it was for the young woman who came to see Brian Schmidt, a clinician and researcher specializing in head and neck cancer at New York University, US. She complained of persistent severe tongue pain that got worse as the day went on. By the end of the day the woman was unable to eat, drink, or talk. Many treatments failed to ease her pain, and ultimately a biopsy showed an invasive squamous cell carcinoma of the tongue.
Why does this cancer hurt? Schmidt tackled that topic in his plenary talk at the International Association for the Study of Pain’s 15th World Congress in Buenos Aires, Argentina. As Schmidt explained, the pain of oral cancer and some other cancers appears to stem from an intimate association of the tumors with the nervous system. The majority—85 percent—of head and neck cancers show tumor cells invading along nerve pathways. In this woman’s case, Schmidt found the cancer tracking along the branches of the lingual nerve, which supplies sensory innervation to the tongue. All pancreatic cancers and 90 percent of prostate cancers—both very painful malignances—also show a similar pattern of invasion along sensory tracts.
The close contact between cancers and the nervous system sets the stage for pain, Schmidt explained. But cancer pain also signals a more complex interaction between tumor cells and nerves that may warn of disease progression and contribute to tumor survival. “We used to think that cancers were growing along nerves as a path of least resistance, but emerging data suggest a different view,” Schmidt said.
Cancer pain is different from inflammatory pain, and from neuropathic pain, Schmidt said, and is different from pain caused by treatments such as surgery, radiation, or chemotherapy. The current theory holds that cancer pain arises when interactions among tumor cells, immune cells, and the nervous system create a microenvironment full of algogens that activate or sensitize primary afferent nociceptors.
In the same way that tumors are diverse genetically and epigenetically, they are also diverse in the pain mediators they produce, Schmidt explained. (For a recent and comprehensive review on this topic, see Schmidt, 2014). Animal and human studies have identified some mediators such as tumor-derived proteases that enable invasion and also activate the protease-activated receptor-2 (PAR2) in primary afferent neurons to cause pain. The vasoconstrictor peptide endothelin, produced in abundance by certain cancers, acts directly on nociceptors and also sensitizes endothelial cells to produce the algogen ATP. The acidic tumor microenvironment may activate transient receptor potential V (TRPV) and acid-sensing ion channels (ASICs). Neurotrophic factors such as nerve growth factor (NGF) cause neurogenesis and pain. And there are still many mediators yet to be discovered, Schmidt said. “It’s a young field.
“Cancers have a lot of cards in their decks. Different cancers use different mediators,” said Schmidt. Because of this heterogeneity, Schmidt expects no single drug will relieve pain from all types of cancer. Even within a single type of cancer, genetic and epigenetic heterogeneity may result in differences in pain mechanisms.
Schmidt’s lab has used neuronal co-cultures to start to characterize the pain-causing substances secreted by cancer cells. Some cancers activate trigeminal neurons via ATP and purinergic P2X2/3 receptors (Ye et al., 2014), while others do not. Overall, Schmidt has found that 30 to 40 percent of DRG neurons respond to cancer cell-secreted products.
Beyond the peripheral afferents, cancer also causes changes in pain pathways in the central nervous system that are distinct from those seen in inflammatory and neuropathic pain. But he says these changes may not be so clinically relevant, because most patients get pain relief from surgery that removes the tumor. For pain, it appears, the important targets are in the cancer microenvironment.
What can pain tell us about cancer? For one thing, Schmidt’s work suggests pain is a bellwether that signals the transition from precancer to cancer. A few years ago, Schmidt and his colleague David Lam found that patients with oral precancer or precancerous lesions in general do not report pain, but patients with cancerous lesions do (Lam and Schmidt, 2011). That work suggested that pain onset may be an early warning of conversion to malignancy. In practice, Schmidt said he teaches that when a dysplasia becomes painful, the clinician needs to see the patient right away.
That is not to say that all metastatic tumors hurt. Schmidt described a man with oral malignant melanoma where the tumor grew quite large and invaded the nasal cavity but caused no pain. “Despite progression of a deeply invasive cancer and eventually death, he had no pain,” Schmidt said.
Schmidt’s finding of pain in early head and neck cancer went against a common belief that such early-stage cancer is painless. That belief also applies to other types of cancer, including breast cancer. But Schmidt dug up work from more than 50 years ago that clearly described pain as a primary symptom in 10 percent of breast cancers and a secondary symptom in 16 percent (Corry, 1952). Back then, doctors understood that pain in the tumor indicated a carcinoma, and that benign lesions rarely presented with pain as a symptom. A more modern study by Christine Miaskowski and Brad Aouizerat, University of California, San Francisco, US, and colleagues found that 28 percent of a group of nearly 400 women with breast cancer complained of pain before surgery (McCann et al., 2012). So far, the source of the pain is unknown, although studies on the same cohort have linked pain to common variants in genes for inflammatory cytokines, potassium channels, and the TRPV3 channel (McCann et al., 2012; Langford et al., 2014; and new data shown at the meeting). While good animal models exist for studying metastatic breast cancer pain, there are currently no animal models for soft tissue breast cancer pain, Schmidt said.
Cancer takes nerve
Pain comes from tumor cells signaling to the nervous system, but the messaging goes both ways. Tumor cells also seem to use the nervous system to support their growth and invasion. Cancer-induced neurogenesis has become a therapeutic target in prostate cancer, where growth and activity of sympathetic and parasympathetic nerves promote carcinogenesis of prostate cells, invasion, migration, and metastasis (Magnon et al., 2013). Data from both animal models and humans suggest a similar effect of vagal innervation on stomach cancer (Zhao et al., 2014).
“If we continue to look at cancer pain with increasingly sophisticated clinical and experimental tools, and if we continue to ask what cancer pain is telling us, we might be able to save our patients from cancer pain," Schmidt concluded. “Ironically, we might also improve their survival.”