Sensory neuron dysfunction in orthotopic mouse models of colon cancer
Abstract Reports of neurological sequelae related to colon cancer are largely restricted to rare instances of paraneoplastic syndromes, due to autoimmune reactions. Systemic inflammation associated with tumor development influences sensory neuron function in other disease models, though the extent t...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-08-01
|
| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-022-02566-z |
| _version_ | 1818499045298012160 |
|---|---|
| author | Mihály Balogh Jixiang Zhang Caitlyn M. Gaffney Neha Kalakuntla Nicholas T. Nguyen Ronnie T. Trinh Clarissa Aguilar Hoang Vu Pham Bojana Milutinovic James M. Nichols Rajasekaran Mahalingam Andrew J. Shepherd |
| author_facet | Mihály Balogh Jixiang Zhang Caitlyn M. Gaffney Neha Kalakuntla Nicholas T. Nguyen Ronnie T. Trinh Clarissa Aguilar Hoang Vu Pham Bojana Milutinovic James M. Nichols Rajasekaran Mahalingam Andrew J. Shepherd |
| author_sort | Mihály Balogh |
| collection | DOAJ |
| description | Abstract Reports of neurological sequelae related to colon cancer are largely restricted to rare instances of paraneoplastic syndromes, due to autoimmune reactions. Systemic inflammation associated with tumor development influences sensory neuron function in other disease models, though the extent to which this occurs in colorectal cancer is unknown. We induced orthotopic colorectal cancer via orthotopic injection of two colorectal cancer cell lines (MC38 and CT26) in two different mouse strains (C57BL/6 and Balb/c, respectively). Behavioral tests of pain sensitivity and activity did not detect significant alterations in sensory sensitivity or diminished well-being throughout tumor development. However, immunohistochemistry revealed widespread reductions in intraepidermal nerve fiber density in the skin of tumor-bearing mice. Though loss of nerve fiber density was not associated with increased expression of cell injury markers in dorsal root ganglia, lumbar dorsal root ganglia neurons of tumor-bearing animals showed deficits in mitochondrial function. These neurons also had reduced cytosolic calcium levels in live-cell imaging and reduced spontaneous activity in multi-electrode array analysis. Bulk RNA sequencing of DRGs from tumor-bearing mice detected activation of gene expression pathways associated with elevated cytokine and chemokine signaling, including CXCL10. This is consistent with the detection of CXCL10 (and numerous other cytokines, chemokines and growth factors) in MC38 and CT26 cell-conditioned media, and the serum of tumor-bearing mice. Our study demonstrates in a pre-clinical setting that colon cancer is associated with latent sensory neuron dysfunction and implicates cytokine/chemokine signaling in this process. These findings may have implications for determining risk factors and treatment responsiveness related to neuropathy in colorectal cancer. |
| first_indexed | 2024-12-10T20:23:55Z |
| format | Article |
| id | doaj.art-85536c3a22814902b2f5577ec9654d11 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-10T20:23:55Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-85536c3a22814902b2f5577ec9654d112022-12-22T01:34:56ZengBMCJournal of Neuroinflammation1742-20942022-08-0119112110.1186/s12974-022-02566-zSensory neuron dysfunction in orthotopic mouse models of colon cancerMihály Balogh0Jixiang Zhang1Caitlyn M. Gaffney2Neha Kalakuntla3Nicholas T. Nguyen4Ronnie T. Trinh5Clarissa Aguilar6Hoang Vu Pham7Bojana Milutinovic8James M. Nichols9Rajasekaran Mahalingam10Andrew J. Shepherd11The MD Anderson Pain Research Consortium and the Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer CenterThe MD Anderson Pain Research Consortium and the Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer CenterThe MD Anderson Pain Research Consortium and the Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer CenterThe MD Anderson Pain Research Consortium and the Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer CenterThe MD Anderson Pain Research Consortium and the Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer CenterThe MD Anderson Pain Research Consortium and the Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer CenterThe MD Anderson Pain Research Consortium and the Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer CenterThe MD Anderson Pain Research Consortium and the Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer CenterThe MD Anderson Pain Research Consortium and the Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer CenterThe MD Anderson Pain Research Consortium and the Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer CenterThe MD Anderson Pain Research Consortium and the Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer CenterThe MD Anderson Pain Research Consortium and the Laboratories of Neuroimmunology, Department of Symptom Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer CenterAbstract Reports of neurological sequelae related to colon cancer are largely restricted to rare instances of paraneoplastic syndromes, due to autoimmune reactions. Systemic inflammation associated with tumor development influences sensory neuron function in other disease models, though the extent to which this occurs in colorectal cancer is unknown. We induced orthotopic colorectal cancer via orthotopic injection of two colorectal cancer cell lines (MC38 and CT26) in two different mouse strains (C57BL/6 and Balb/c, respectively). Behavioral tests of pain sensitivity and activity did not detect significant alterations in sensory sensitivity or diminished well-being throughout tumor development. However, immunohistochemistry revealed widespread reductions in intraepidermal nerve fiber density in the skin of tumor-bearing mice. Though loss of nerve fiber density was not associated with increased expression of cell injury markers in dorsal root ganglia, lumbar dorsal root ganglia neurons of tumor-bearing animals showed deficits in mitochondrial function. These neurons also had reduced cytosolic calcium levels in live-cell imaging and reduced spontaneous activity in multi-electrode array analysis. Bulk RNA sequencing of DRGs from tumor-bearing mice detected activation of gene expression pathways associated with elevated cytokine and chemokine signaling, including CXCL10. This is consistent with the detection of CXCL10 (and numerous other cytokines, chemokines and growth factors) in MC38 and CT26 cell-conditioned media, and the serum of tumor-bearing mice. Our study demonstrates in a pre-clinical setting that colon cancer is associated with latent sensory neuron dysfunction and implicates cytokine/chemokine signaling in this process. These findings may have implications for determining risk factors and treatment responsiveness related to neuropathy in colorectal cancer.https://doi.org/10.1186/s12974-022-02566-zColon cancerNeuropathyParaneoplastic neuropathyDRG neuronNeuropathic pain |
| spellingShingle | Mihály Balogh Jixiang Zhang Caitlyn M. Gaffney Neha Kalakuntla Nicholas T. Nguyen Ronnie T. Trinh Clarissa Aguilar Hoang Vu Pham Bojana Milutinovic James M. Nichols Rajasekaran Mahalingam Andrew J. Shepherd Sensory neuron dysfunction in orthotopic mouse models of colon cancer Journal of Neuroinflammation Colon cancer Neuropathy Paraneoplastic neuropathy DRG neuron Neuropathic pain |
| title | Sensory neuron dysfunction in orthotopic mouse models of colon cancer |
| title_full | Sensory neuron dysfunction in orthotopic mouse models of colon cancer |
| title_fullStr | Sensory neuron dysfunction in orthotopic mouse models of colon cancer |
| title_full_unstemmed | Sensory neuron dysfunction in orthotopic mouse models of colon cancer |
| title_short | Sensory neuron dysfunction in orthotopic mouse models of colon cancer |
| title_sort | sensory neuron dysfunction in orthotopic mouse models of colon cancer |
| topic | Colon cancer Neuropathy Paraneoplastic neuropathy DRG neuron Neuropathic pain |
| url | https://doi.org/10.1186/s12974-022-02566-z |
| work_keys_str_mv | AT mihalybalogh sensoryneurondysfunctioninorthotopicmousemodelsofcoloncancer AT jixiangzhang sensoryneurondysfunctioninorthotopicmousemodelsofcoloncancer AT caitlynmgaffney sensoryneurondysfunctioninorthotopicmousemodelsofcoloncancer AT nehakalakuntla sensoryneurondysfunctioninorthotopicmousemodelsofcoloncancer AT nicholastnguyen sensoryneurondysfunctioninorthotopicmousemodelsofcoloncancer AT ronniettrinh sensoryneurondysfunctioninorthotopicmousemodelsofcoloncancer AT clarissaaguilar sensoryneurondysfunctioninorthotopicmousemodelsofcoloncancer AT hoangvupham sensoryneurondysfunctioninorthotopicmousemodelsofcoloncancer AT bojanamilutinovic sensoryneurondysfunctioninorthotopicmousemodelsofcoloncancer AT jamesmnichols sensoryneurondysfunctioninorthotopicmousemodelsofcoloncancer AT rajasekaranmahalingam sensoryneurondysfunctioninorthotopicmousemodelsofcoloncancer AT andrewjshepherd sensoryneurondysfunctioninorthotopicmousemodelsofcoloncancer |