The chronic sensory neuropathy seen in cancer patients receiving chemotherapy is not just a side effect of drug-induced neuronal damage but is a complex interaction between cancer and gene regulation of ion channels, new research shows.
Writing in Cancer Research, neuroscientists from the Georgia Institute of Technology say that about 40% of patients receiving platinum chemotherapy experience peripheral neuropathy, often developing chronic symptoms such as pain, fatigue, or loss of muscle coordination.
But contrary to traditional thinking, chemotherapy-induced structural damage is not the main mechanism for this peripheral neuropathy they say. In their study they show that mechanosensory neurons remain physically intact but have impaired excitability due to downregulation of genes responsible for potassium ion channel function.
In animal models they found that there was some neuronal impairment from chemotherapy and some from cancer, but the combination of the two showed a major potentiation effect
“The idea of damage has been the standard explanation – that these neurones are dying back and that they are retracting. And we have found time and time again zero evidence of this in the neurones we studied here,” said study lead author Dr Stephen Housley, a neuroscience researcher at the Institute’s Biologic Sciences department.
The researchers also found major changes in gene expression in neurones, protein expression, and neurone signalling with chemotherapy and cancer, with significant effects on body movements.
Gene dysregulation went into overdrive in reaction to chemo and cancer, including boosting inflammatory responses while suppressing some of neurones’ protective mechanisms. But despite the plethora of gene regulation red flags, there were also surprising signs of intact neuronal health.
“Many things the neuron relies on to live and function were unscathed on the gene expression level. That’s potentially good news for patients and for fixing neuropathy because it means there may be just one thing or a few things to fix to restore normal functioning,” said co-author Dr Tim Cope.
“The downregulation of just a few genes may be responsible for the problems we’ve seen.”
One downregulated gene is responsible for creating ion channels that appear in a neurone’s cell wall and shuttle potassium ions (K+) in and out of cells, to create action potentials.
The potassium ion channel Kv3.3 was not previously known to exist in muscle spindles, but the researchers found the channel to be prolific there.
“That was a discovery in its own right in basic neuroscience. Finding its involvement in this sensory-motor problem was also profound,” Dr Housley said.
They also found that most Kv3.3 expression disappeared under the combination of chemo and cancer, and the lack of Kv3.3 strongly correlated with observed neural pathology.
“Despite the neurones still having the ability to fire action potentials, the process of neurones encoding information was really corrupted,”Dr Housley observed.
“These original findings identify novel contributors to peripheral neuropathy and emphasise the fundamental dependence of neuropathy on the systemic interaction between chemotherapy and cancer,” the researcher concluded