Andrew Shepherd

Abstract

Peripheral Nerve Injury Induced by Colorectal Cancer: Mechanisms and Implications for Chemotherapy-Induced Peripheral Neuropathy

Advances in screening, detection and therapy have significantly increased survivorship of patients with non-metastatic colorectal cancer. However, cancer survivors are at elevated risk of developing chronic neurological issues such as peripheral neuropathy and chronic pain.

Although pre-existing neuropathy is a clinically established risk factor for chronic neuropathic pain, this had yet to be established in a pre-clinical cancer model. In agreement with clinical observations, we show that an orthotopic, immunocompetent mouse model of colorectal cancer develops peripheral neuropathy.

Consistent with the notion that tumor-driven inflammation is the primary driver of this neuropathy, we did not find evidence to support other potential causes (such as cancer-related leaky gut, hematochezia, or metabolic dysfunction). Tumor-related neuropathy was associated with subtle locomotor deficits, without overt hypersensitivity or sensory loss.

We also detected proinflammatory cytokine production, macrophage infiltration and myelin decompaction in peripheral nerves from tumor-bearing mice, along with ryanodine receptor oxidation and impaired calcium homeostasis, along with mitochondrial dysfunction and reduced spike amplitude in dorsal root ganglion neurons. These pathological changes may underlie the non-resolving pain hypersensitivity we see in MC38 tumor-bearing mice after treatment with oxaliplatin chemotherapy.

Collectively these findings suggest that colorectal cancer can be causally linked to a subtle form of chronic inflammatory demyelinating polyneuropathy, which may represent an under-reported, yet important risk factor for subsequent neurological dysfunction in colorectal cancer survivors.