Researchers at The University of Texas MD Anderson Cancer Centre found that, in preclinical models of colorectal cancer, tumours can start damaging peripheral nerves before chemotherapy begins.

These findings suggest tumour-related inflammation and changes to fat metabolism could damage the protective coating around nerves, disrupting signals and potentially making them more vulnerable to treatment-induced peripheral neuropathy, or nerve damage.

The study, published in Nature Communications and led by Andrew Shepherd, Ph.D., associate professor of Translational Neuroscience, challenges the conventional thought that peripheral neuropathy in patients with colorectal cancer is due mostly to chemotherapy treatment.

Rather, the findings suggest that much of the nerve damage may already be present because of the cancer itself, even without overt pain symptoms.

“These findings advance our understanding of how colorectal cancer can cause damage to the peripheral nervous system,” Shepherd said.

“This nerve damage, which affects the protective insulation around nerves, is largely latent and could have major implications for quality of life in survivors, even when there are no obvious pain symptoms.”

What is peripheral neuropathy and why is it difficult to recognise?

Peripheral neuropathy occurs when nerves outside of the brain and spinal cord become damaged.

This damage can cause pain, numbness, balance problems, weakness and/or reduced sensitivity to touch and temperature.

Chemotherapy is commonly used to treat colorectal cancers, and some drugs can cause peripheral neuropathy and associated symptoms.

The researchers wanted to understand and identify possible cancer-related nerve changes prior to treatment to reduce the risk of patients developing chronic pain.

Previous research has shown reduced nerve-fibre density and sensory dysfunction in preclinical models prior to receiving chemotherapy, but these changes are usually considered mild and may not be recognised as signs of nerve damage.

Properly identifying this damage could help researchers understand why some patients develop more severe or persistent symptoms after treatment.

Studies such as this are part of UT MD Anderson’s Cancer Neuroscience Programme, a first-of-its-kind initiative that examines the interactions between cancer and the nervous system, taking a multidisciplinary approach to enhance patient quality of life.

What were the signs of nerve injury in preclinical models?

In preclinical models of colorectal cancer, researchers observed a loss of small nerve fibres in the skin and subtle problems with movement and coordination.

However, there was no clear sensitivity to touch or temperature, suggesting that neuropathy could occur without obvious pain symptoms.

Further analyses revealed damage to myelin sheaths, the protective material surrounding nerve fibres, as well as signs of stress in the cells that produce and maintain myelin.

Additionally, the nerve cells showed problems regulating calcium, which helps transmit signals.

These changes were accompanied by weaker electrical signals and reduced nerve-cell activity.

The researchers also found changes in inflammatory proteins and fat molecules associated with inflammation in the blood and nerves.

Macrophages – immune cells that respond to injuries – also accumulated in peripheral sensory nerves.

However, removing these cells exacerbated movement problems in the models, meaning that some macrophages may actually play a protective or reparative role.

Treatment with an anti-inflammatory drug reduced some early abnormalities but did not prevent all signs of nerve injury, implying that inflammation contributes to neuropathy but is not the only factor involved.

What does this mean for patients with colorectal cancer?

Together, the results suggest a model in which tumour-driven inflammation and altered fat metabolism contribute to stress and damage in peripheral nerves.

The findings also raise questions about whether subtle nerve damage before treatment makes patients more vulnerable to later neurological side effects.

While these findings were consistent in preclinical models that developed colorectal cancer naturally and, in turn, suggest that this phenomenon occurs across species, the study did not include human samples or patient outcomes.

Additional research is also needed to examine nerve function in patients before, during and after chemotherapy to determine whether neuropathy occurs similarly across different colorectal cancer subtypes.

Source: University of Texas M. D. Anderson Cancer Center