Effects of primary and recurrent sacral chordoma on the motor and nociceptive function of hindlimbs in rats: an orthotopic spine model

Rachel Sarabia-Estrada Department of Neurologic Surgery, Mayo Clinic, Jacksonville, Florida;

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Alejandro Ruiz-Valls Departments of Neurosurgery and

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Sagar R. Shah Department of Neurologic Surgery, Mayo Clinic, Jacksonville, Florida;
Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland;

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A. Karim Ahmed Departments of Neurosurgery and

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Alvaro A. Ordonez Pediatrics, Center for Infection and Inflammation Imaging Research,

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Fausto J. Rodriguez Departments of Pathology-Neuropathology,

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Hugo Guerrero-Cazares Department of Neurologic Surgery, Mayo Clinic, Jacksonville, Florida;

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Ismael Jimenez-Estrada Department of Physiology, Biophysics, and Neurosciences, Research Center for Advanced Studies IPN, Mexico City, Mexico;

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Esteban Velarde Radiation Oncology and Molecular Radiation Sciences, and

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Betty Tyler Departments of Neurosurgery and

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Yuxin Li Department of Neurosurgery, Jinan General Hospital of PLA, Jinan, China

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Neil A. Phillips Departments of Neurosurgery and

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C. Rory Goodwin Departments of Neurosurgery and

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Rory J. Petteys Departments of Neurosurgery and

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Sanjay K. Jain Pediatrics, Center for Infection and Inflammation Imaging Research,

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Gary L. Gallia Departments of Neurosurgery and

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Ziya L. Gokaslan Department of Neurosurgery, The Warren Alpert Medical School of Brown University, Providence, Rhode Island; and

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Alfredo Quinones-Hinojosa Department of Neurologic Surgery, Mayo Clinic, Jacksonville, Florida;

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Daniel M. Sciubba Departments of Neurosurgery and

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OBJECTIVE

Chordoma is a slow-growing, locally aggressive cancer that is minimally responsive to conventional chemotherapy and radiotherapy and has high local recurrence rates after resection. Currently, there are no rodent models of spinal chordoma. In the present study, the authors sought to develop and characterize an orthotopic model of human chordoma in an immunocompromised rat.

METHODS

Thirty-four immunocompromised rats were randomly allocated to 4 study groups; 22 of the 34 rats were engrafted in the lumbar spine with human chordoma. The groups were as follows: UCH1 tumor–engrafted (n = 11), JHC7 tumor–engrafted (n = 11), sham surgery (n = 6), and intact control (n = 6) rats. Neurological impairment of rats due to tumor growth was evaluated using open field and locomotion gait analysis; pain response was evaluated using mechanical or thermal paw stimulation. Cone beam CT (CBCT), MRI, and nanoScan PET/CT were performed to evaluate bony changes due to tumor growth. On Day 550, rats were killed and spines were processed for H & E–based histological examination and immunohistochemistry for brachyury, S100β, and cytokeratin.

RESULTS

The spine tumors displayed typical chordoma morphology, that is, physaliferous cells filled with vacuolated cytoplasm of mucoid matrix. Brachyury immunoreactivity was confirmed by immunostaining, in which samples from tumor-engrafted rats showed a strong nuclear signal. Sclerotic lesions in the vertebral body of rats in the UCH1 and JHC7 groups were observed on CBCT. Tumor growth was confirmed using contrast-enhanced MRI. In UCH1 rats, large tumors were observed growing from the vertebral body. JHC7 chordoma–engrafted rats showed smaller tumors confined to the bone periphery compared with UCH1 chordoma–engrafted rats. Locomotion analysis showed a disruption in the normal gait pattern, with an increase in the step length and duration of the gait in tumor-engrafted rats. The distance traveled and the speed of rats in the open field test was significantly reduced in the UCH1 and JHC7 tumor–engrafted rats compared with controls. Nociceptive response to a mechanical stimulus showed a significant (p < 0.001) increase in the paw withdrawal threshold (mechanical hypalgesia). In contrast, the paw withdrawal response to a thermal stimulus decreased significantly (p < 0.05) in tumor-engrafted rats.

CONCLUSIONS

The authors developed an orthotopic human chordoma model in rats. Rats were followed for 550 days using imaging techniques, including MRI, CBCT, and nanoScan PET/CT, to evaluate lesion progression and bony integrity. Nociceptive evaluations and locomotion analysis were performed during follow-up. This model reproduces cardinal signs, such as locomotor and sensory deficits, similar to those observed clinically in human patients. To the authors’ knowledge, this is the first spine rodent model of human chordoma. Its use and further study will be essential for pathophysiology research and the development of new therapeutic strategies.

ABBREVIATIONS

CBCT = cone beam computed tomography.
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