Cancer Exacerbates Chemotherapy-Induced Sensory Neuropathy
Open Access
- 27 April 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 80 (13), 2940-2955
- https://doi.org/10.1158/0008-5472.CAN-19-2331
Abstract
For the constellation of neurologic disorders known as chemotherapy-induced peripheral neuropathy, mechanistic understanding and treatment remain deficient. Here, we present the first evidence that chronic sensory neuropathy depends on nonlinear interactions between cancer and chemotherapy. Global transcriptional profiling of dorsal root ganglia revealed differential expression, notably in regulators of neuronal excitability, metabolism, and inflammatory responses, all of which were unpredictable from effects observed with either chemotherapy or cancer alone. Systemic interactions between cancer and chemotherapy also determined the extent of deficits in sensory encoding and ion channel protein expression by single mechanosensory neurons, with the potassium ion channel Kv3.3 emerging as one potential contributor to sensory neuron dysfunction. Validated measures of sensorimotor behavior in awake, behaving animals revealed dysfunction after chronic chemotherapy treatment was exacerbated by cancer. Notably, errors in precise forelimb placement emerged as a novel behavioral deficit unpredicted by our previous study of chemotherapy alone. These original findings identify novel contributors to peripheral neuropathy and emphasize the fundamental dependence of neuropathy on the systemic interaction between chemotherapy and cancer. Significance: These findings highlight the need to account for pathobiological interactions between cancer and chemotherapy as a major contributor to neuropathy and will have significant and immediate impact on future investigations in this field.Other Versions
Funding Information
- NIH (R01CA221363, R01HD090642)
This publication has 58 references indexed in Scilit:
- Molecular Profiling Predicts the Existence of Two Functionally Distinct Classes of Ovarian Cancer StromaBioMed Research International, 2013
- Subclinical Peripheral Neuropathy Is a Common Finding in Colorectal Cancer Patients Prior to ChemotherapyClinical Cancer Research, 2012
- Anticancer drug oxaliplatin induces acute cooling-aggravated neuropathy via sodium channel subtype Na V 1.6-resurgent and persistent currentProceedings of the National Academy of Sciences of the United States of America, 2012
- Oxidative stress, inflammation, and cancer: How are they linked?Free Radical Biology & Medicine, 2010
- Amiloride‐sensitive channels are a major contributor to mechanotransduction in mammalian muscle spindlesJournal Of Physiology-London, 2010
- KCNC3: phenotype, mutations, channel biophysics-a study of 260 familial ataxia patientsHuman Mutation, 2009
- The kinaesthetic sensesJournal Of Physiology-London, 2009
- Systematic and integrative analysis of large gene lists using DAVID bioinformatics resourcesNature Protocols, 2008
- A target-selected Apc -mutant rat kindred enhances the modeling of familial human colon cancerProceedings of the National Academy of Sciences of the United States of America, 2007
- Candidate mechanisms for chemotherapy-induced cognitive changesNature Reviews Cancer, 2007