Background & Aims
Colorectal cancer (CRC) is the third most common cancer type among men and women in the United States (Kuipers EJ, et al., 2015). Advances in screening and treatment regimens have led to an increase of CRC survivors living longer (Snijders, R. A. H. et al., 2023). However, 45-60% of survivors are affected by widespread pain persistent for months to years after completing treatment (Koskinen, M. J. et al., 2011), but the underlying factors that cause chronic pain in CRC survivors are not fully understood. This epidemiological evidence, coupled with sensory and histological deficits in CRC patients suggestive of neuropathy led us to hypothesize that CRC directly contributes to peripheral neuropathy. Here in this study, we aimed to determine whether neuropathy is due to CRC growth per se, or whether other perturbations secondary to tumor growth represent more proximate causes of CRC-associated neuropathy.
Methods
Orthotopic CRC via injection of the MC38 cancer cell line was induced in C57BL/6 mice. Tumor growth was monitored for 3 weeks by bioluminescent imaging. Behavioral tests were conducted weekly to characterize stimulus-evoked pain sensitivity (von Frey and thermal gradient ring test), spontaneous pain sensitivity (burrowing), motor coordination (beam walk), and gait (Catwalk). Metabolic and hemostatic disturbances were assessed by measuring blood glucose levels, plasma lipid profile and fibrinogen levels, and tail bleeding time. Gut integrity was assessed by the FITC-dextran assay and histological staining of the colon. Levels of oxidative stress and ryanodine receptor (RyR) oxidation in the dorsal root ganglia (DRG) were assessed by Western Blotting, ELISA, and calcium imaging. Spontaneous and evoked activity in DRG neurons was examined using a Multi-Electrode Array. Transmission electron microscopy, IHC of Schwann cells, and lipidomic profile of sciatic nerves were performed as well.
Results
While tactile and thermal sensitivity remained normal, tumor-bearing mice exhibit deficits in motor coordination. MC38 tumor growth was associated with blood hypercoagulability without any evidence to suggest hyperglycemia or dyslipidemia. Importantly, there were no differences observed in dextran absorption from the GI tract into the bloodstream. Mechanistically, MC38 tumor burden increased oxidation of RyR in the DRG of mice, consistent with the systemic elevation in pro-inflammatory cytokines. Overall electrical activity in cultured DRG neurons of tumor-bearing mice was not significantly different, but spontaneous spike amplitudes were significantly reduced in tumor-bearing mice. We also saw macrophage infiltration of the sciatic nerve and DRG of MC38-injected mice, along with increased Schwann cell S100B intensity. Additionally, TEM of the sciatic nerve revealed pronounced myelination deficits and swelling of unmyelinated axons.
Conclusions
Paraneoplastic neuropathy is considered a somewhat rare complication of most cancers and is characterized as a form of autoimmune or chronic inflammatory demyelinating polyneuropathy. Our data suggest that in addition to these overt neurological syndromes that present clinically, other, less severe symptoms of neurological dysfunction may be much more widespread. Prior studies suggested that subtle sensory deficits are common at diagnosis in CRC patients; our results now suggest there is a direct causal link between CRC and the development of this neuropathy. Neuronal dysfunction directly induced by tumor growth is important to understand as pre-existing neuropathy is a risk factor for the subsequent development of neuropathic pain, particularly concerning oxaliplatin-based chemotherapy. Overall, our CRC model replicates key features seen clinically; these mice are overtly normal but exhibit sensory deficits, IENF loss, systemic inflammation, and hypercoagulability.
References
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Presenting Author
Caitlyn Gaffney
Poster Authors
Caitlyn M. Gaffney, M.S.
MSc
The University of Texas MD Anderson Cancer Center
Lead Author
Angela Casaril
PhD
MD Anderson Cancer Center
Lead Author
Karen Valadez
BS
MD Anderson Cancer Center
Lead Author
Elizabeth Kolb
BS
MD Anderson Cancer Center
Lead Author
Fisher R. Cherry
B.S.
The University of Texas MD Anderson Cancer Center
Lead Author
Lei Shi
PhD
MD Anderson Cancer Center
Lead Author
Theresa Guise
PhD
MD Anderson Cancer Center
Lead Author
Andrew Shepherd
The University of Texas MD Anderson Cancer Center
Lead Author
Topics
- Specific Pain Conditions/Pain in Specific Populations: Cancer Pain & Palliative Care