More than half of all cancer patients experience pain, most often associated with the malignancy type, body location and disease progression. Pain researchers participating in a symposium at the American Pain Society Annual Scientific Meeting reported that the relationship between tumors and nerves drives persistent and breakthrough pain and tumor progression in certain types of cancers.
With patients living longer thanks to some new cancer therapies, many endure pain for extended durations, but the etiology of cancer pain still remains unknown. Preclinical studies, however, have provided ample evidence that mechanisms driving cancer pain are different from those responsible for inflammatory and neuropathic pain.
"Cancer pain is a complex pathologic process. Malignant cells produce mediators that recruit and affect other cells within the cancer microenvironment, including nerves and immune cells," said Brian L. Schmidt, DDS, MD, PhD, symposium speaker and professor, New York University College of Dentistry and School of Medicine. Schmidt explained that cancer pain, compared to inflammatory and neuropathic pain, induces a distinct set of neurochemical changes in the spinal cord and sensory neurons. "We now recognize that cancers and neurons act reciprocally on each other," he said.
Brian M. Davis, symposium chair and professor of neurobiology and medicine, University of Pittsburgh School of Medicine, reported that the ability of cancer cells to invade along nerves (a process called neuroinvasion) is associated with pain, aggressive disease and poor survival rates. "The nerve itself is a key facilitator of adverse cancer cell behavior," said Davis. "Tumors express nerve growth factor receptors and their ligands, both of which can interact with sensory fibers to cause sensitization and pain. Once the tumor cell is in the nerve it can divide and grow, directly causing nerve damage and inciting neuropathic pain." He added that it is difficult for chemotherapy drugs to kill cancer cells once they have taken residency in nerves.
Davis noted that while nerve involvement contributes significantly to cancer pain, many tumors have shown they depend on nerves to grow and spread. "In recent studies, tumors did not grow if they couldn't interact with nerves," he said. "Sensory neurons release molecules that either negatively alter the tumor microenvironment to promote tumorigenesis or directly interact with cancer stem cells to accelerate the disease. "Further, nerves play a role in metastasis by allowing cancer cells to migrate along them to reach other organs. This usually is associated with poor prognosis," Davis explained.
Genomic heterogeneity of certain cancers is one of the most challenging barriers to overcome for improving treatment and pain management, according to Schmidt. "Histologically and clinically, certain cancers may appear to be identical, but at a genomic level they can display significant heterogeneity. So a single analgesic therapy is unlikely to exhibit equal efficacy for different cancers types and for cancers in different people," Schmidt said. Schmidt believes that improved understanding and treatment of cancer pain will emerge from multidisciplinary teams of investigators studying the disease at molecular, preclinical and clinical levels. "Future research might conclude that pharmacologic and non-pharmacologic antagonism of mechanisms in the neurosensory system and mechanisms integral to cancer proliferation are required to achieve improved relief of cancer pain," he said.
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