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

Rachel Sarabia Estrada, Alejandro Ruiz-Valls, Sagar R. Shah, A. Karim Ahmed, Alvaro A. Ordonez, Fausto J. Rodriguez, Hugo Guerrero Cazares, Ismael Jimenez-Estrada, Esteban Velarde, Betty Tyler, Yuxin Li, Neil A. Phillips, C. Rory Goodwin, Rory J. Petteys, Sanjay K. Jain, Gary L. Gallia, Ziya L. Gokaslan, Alfredo Quinones-Hinojosa, Daniel M. Sciubba

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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, S100b, 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' tuknowledge, 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.

Original languageEnglish (US)
Pages (from-to)215-226
Number of pages12
JournalJournal of Neurosurgery: Spine
Volume27
Issue number2
DOIs
StatePublished - Aug 1 2017

Fingerprint

Chordoma
Hindlimb
Spine
Neoplasms
Locomotion
Gait
Cone-Beam Computed Tomography
Rodentia
Growth
Hot Temperature

Keywords

  • Chordoma
  • Locomotion
  • Model
  • Nociception
  • Oncology
  • Rat
  • Spine
  • Tumor

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Effects of primary and recurrent sacral chordoma on the motor and nociceptive function of hindlimbs in rats : An orthotopic spine model. / Sarabia Estrada, Rachel; Ruiz-Valls, Alejandro; Shah, Sagar R.; Ahmed, A. Karim; Ordonez, Alvaro A.; Rodriguez, Fausto J.; Guerrero Cazares, Hugo; Jimenez-Estrada, Ismael; Velarde, Esteban; Tyler, Betty; Li, Yuxin; Phillips, Neil A.; Goodwin, C. Rory; Petteys, Rory J.; Jain, Sanjay K.; Gallia, Gary L.; Gokaslan, Ziya L.; Quinones-Hinojosa, Alfredo; Sciubba, Daniel M.

In: Journal of Neurosurgery: Spine, Vol. 27, No. 2, 01.08.2017, p. 215-226.

Research output: Contribution to journalArticle

Sarabia Estrada, R, Ruiz-Valls, A, Shah, SR, Ahmed, AK, Ordonez, AA, Rodriguez, FJ, Guerrero Cazares, H, Jimenez-Estrada, I, Velarde, E, Tyler, B, Li, Y, Phillips, NA, Goodwin, CR, Petteys, RJ, Jain, SK, Gallia, GL, Gokaslan, ZL, Quinones-Hinojosa, A & Sciubba, DM 2017, 'Effects of primary and recurrent sacral chordoma on the motor and nociceptive function of hindlimbs in rats: An orthotopic spine model', Journal of Neurosurgery: Spine, vol. 27, no. 2, pp. 215-226. https://doi.org/10.3171/2016.12.SPINE16917
Sarabia Estrada, Rachel ; Ruiz-Valls, Alejandro ; Shah, Sagar R. ; Ahmed, A. Karim ; Ordonez, Alvaro A. ; Rodriguez, Fausto J. ; Guerrero Cazares, Hugo ; Jimenez-Estrada, Ismael ; Velarde, Esteban ; Tyler, Betty ; Li, Yuxin ; Phillips, Neil A. ; Goodwin, C. Rory ; Petteys, Rory J. ; Jain, Sanjay K. ; Gallia, Gary L. ; Gokaslan, Ziya L. ; Quinones-Hinojosa, Alfredo ; Sciubba, Daniel M. / Effects of primary and recurrent sacral chordoma on the motor and nociceptive function of hindlimbs in rats : An orthotopic spine model. In: Journal of Neurosurgery: Spine. 2017 ; Vol. 27, No. 2. pp. 215-226.
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abstract = "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, S100b, 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' tuknowledge, 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.",
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author = "{Sarabia Estrada}, Rachel and Alejandro Ruiz-Valls and Shah, {Sagar R.} and Ahmed, {A. Karim} and Ordonez, {Alvaro A.} and Rodriguez, {Fausto J.} and {Guerrero Cazares}, Hugo and Ismael Jimenez-Estrada and Esteban Velarde and Betty Tyler and Yuxin Li and Phillips, {Neil A.} and Goodwin, {C. Rory} and Petteys, {Rory J.} and Jain, {Sanjay K.} and Gallia, {Gary L.} and Gokaslan, {Ziya L.} and Alfredo Quinones-Hinojosa and Sciubba, {Daniel M.}",
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TY - JOUR

T1 - Effects of primary and recurrent sacral chordoma on the motor and nociceptive function of hindlimbs in rats

T2 - An orthotopic spine model

AU - Sarabia Estrada, Rachel

AU - Ruiz-Valls, Alejandro

AU - Shah, Sagar R.

AU - Ahmed, A. Karim

AU - Ordonez, Alvaro A.

AU - Rodriguez, Fausto J.

AU - Guerrero Cazares, Hugo

AU - Jimenez-Estrada, Ismael

AU - Velarde, Esteban

AU - Tyler, Betty

AU - Li, Yuxin

AU - Phillips, Neil A.

AU - Goodwin, C. Rory

AU - Petteys, Rory J.

AU - Jain, Sanjay K.

AU - Gallia, Gary L.

AU - Gokaslan, Ziya L.

AU - Quinones-Hinojosa, Alfredo

AU - Sciubba, Daniel M.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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, S100b, 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' tuknowledge, 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.

AB - 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, S100b, 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' tuknowledge, 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.

KW - Chordoma

KW - Locomotion

KW - Model

KW - Nociception

KW - Oncology

KW - Rat

KW - Spine

KW - Tumor

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