Metastatic human breast cancer to the spine produces mechanical hyperalgesia and gait deficits in rodents

Rachel Sarabia Estrada, Alejandro Ruiz-Valls, Hugo Guerrero Cazares, Ana M. Ampuero, Ismael Jimenez-Estrada, Samantha De Silva, Lydia J. Bernhardt, Courtney Rory Goodwin, Ali Karim Ahmed, Yuxin Li, Neil A. Phillips, Ziya L. Gokaslan, Alfredo Quinones-Hinojosa, Daniel M. Sciubba

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background Context: Metastases to the spine are a common source of severe pain in cancer patients. The secondary effects of spinal metastases include pain, bone fractures, hypercalcemia, and neurological deficits. As the disease progresses, pain severity can increase until it becomes refractory to medical treatments and leads to a decreased quality of life for patients. A key obstacle in the study of pain-induced spinal cancer is the lack of reliable and reproducible spine cancer animal models. In the present study, we developed a reproducible and reliable rat model of spinal cancer using human-derived tumor tissue to evaluate neurological decline using imaging and behavioral techniques. Purpose: The present study outlines the development and characterization of an orthotopic model of human breast cancer to the spine in immunocompromised rats. Study Design/Setting: This is a basic science study. Methods: Female immunocompromised rats were randomized into three groups: tumor (n=8), RBC3 mammary adenocarcinoma tissue engrafted in the L5 vertebra body; sham (n=6), surgery performed but not tumor engrafted; and control (n=6), naive rats, no surgery performed. To evaluate the neurological impairment due to tumor invasion, functional assessment was done in all rodents at day 40 after tumor engraftment using locomotion gait analysis and pain response to a mechanical stimulus (Randall-Selitto test). Bioluminescence (BLI) was used to evaluate tumor growth in vivo and cone beam computed tomography (CBCT) was performed to evaluate bone changes due to tumor invasion. The animals were euthanized at day 45 and their spines were harvested and processed for hematoxylin and eosin (H&E) staining. Results: Tumor growth in the spine was confirmed by BLI imaging and corroborated by histological analysis. Cone beam computed tomography images were characterized by a decrease in the bone intensity in the lumbar spine consistent with tumor location on BLI. On H&E staining of tumor-engrafted animals, there was a near-complete ablation of the ventral and posterior elements of the L5 vertebra with severe tumor invasion in the bony components displacing the spinal cord. Locomotion gait analysis of tumor-engrafted rats showed a disruption in the normal gait pattern with asignificant reduction in length (p=.02), duration (p=.002), and velocity (p=.002) of right leg strides and only in duration (p=.0006) and velocity (p=.001) of left leg strides, as compared with control and sham rats. Tumor-engrafted animals were hypersensitive to pain stimulus shown as a significantly reduced response in time (p=.02) and pressure (p=.01) applied when compared with control groups. Conclusions: We developed a system for the quantitative analysis of pain and locomotion in an animal model of metastatic human breast cancer of the spine. Tumor-engrafted animals showed locomotor and sensory deficits that are in accordance with clinical manifestation in patients with spine metastasis. Pain response and locomotion gait analysis were performed during follow-up. The Randall-Selitto test was a sensitive method to evaluate pain in the rat's spine. We present a model for the study of bone-associated cancer pain secondary to cancer metastasis to the spine, as well as for the study of new therapies and treatments to lessen pain from metastatic cancer to the neuroaxis.

Original languageEnglish (US)
JournalSpine Journal
DOIs
StateAccepted/In press - Jan 23 2017

Fingerprint

Hyperalgesia
Gait
Rodentia
Spine
Breast Neoplasms
Neoplasms
Pain
Locomotion
Neoplasm Metastasis
Cone-Beam Computed Tomography
Leg
Animal Models
Staining and Labeling
Bone and Bones
Bone Neoplasms
Bone Fractures
Hypercalcemia
Hematoxylin
Eosine Yellowish-(YS)
Growth

Keywords

  • Breast cancer
  • Gait
  • Locomotion
  • Metastasis
  • Pain
  • Spine

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

Cite this

Metastatic human breast cancer to the spine produces mechanical hyperalgesia and gait deficits in rodents. / Sarabia Estrada, Rachel; Ruiz-Valls, Alejandro; Guerrero Cazares, Hugo; Ampuero, Ana M.; Jimenez-Estrada, Ismael; De Silva, Samantha; Bernhardt, Lydia J.; Goodwin, Courtney Rory; Ahmed, Ali Karim; Li, Yuxin; Phillips, Neil A.; Gokaslan, Ziya L.; Quinones-Hinojosa, Alfredo; Sciubba, Daniel M.

In: Spine Journal, 23.01.2017.

Research output: Contribution to journalArticle

Sarabia Estrada, R, Ruiz-Valls, A, Guerrero Cazares, H, Ampuero, AM, Jimenez-Estrada, I, De Silva, S, Bernhardt, LJ, Goodwin, CR, Ahmed, AK, Li, Y, Phillips, NA, Gokaslan, ZL, Quinones-Hinojosa, A & Sciubba, DM 2017, 'Metastatic human breast cancer to the spine produces mechanical hyperalgesia and gait deficits in rodents', Spine Journal. https://doi.org/10.1016/j.spinee.2017.04.009
Sarabia Estrada, Rachel ; Ruiz-Valls, Alejandro ; Guerrero Cazares, Hugo ; Ampuero, Ana M. ; Jimenez-Estrada, Ismael ; De Silva, Samantha ; Bernhardt, Lydia J. ; Goodwin, Courtney Rory ; Ahmed, Ali Karim ; Li, Yuxin ; Phillips, Neil A. ; Gokaslan, Ziya L. ; Quinones-Hinojosa, Alfredo ; Sciubba, Daniel M. / Metastatic human breast cancer to the spine produces mechanical hyperalgesia and gait deficits in rodents. In: Spine Journal. 2017.
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title = "Metastatic human breast cancer to the spine produces mechanical hyperalgesia and gait deficits in rodents",
abstract = "Background Context: Metastases to the spine are a common source of severe pain in cancer patients. The secondary effects of spinal metastases include pain, bone fractures, hypercalcemia, and neurological deficits. As the disease progresses, pain severity can increase until it becomes refractory to medical treatments and leads to a decreased quality of life for patients. A key obstacle in the study of pain-induced spinal cancer is the lack of reliable and reproducible spine cancer animal models. In the present study, we developed a reproducible and reliable rat model of spinal cancer using human-derived tumor tissue to evaluate neurological decline using imaging and behavioral techniques. Purpose: The present study outlines the development and characterization of an orthotopic model of human breast cancer to the spine in immunocompromised rats. Study Design/Setting: This is a basic science study. Methods: Female immunocompromised rats were randomized into three groups: tumor (n=8), RBC3 mammary adenocarcinoma tissue engrafted in the L5 vertebra body; sham (n=6), surgery performed but not tumor engrafted; and control (n=6), naive rats, no surgery performed. To evaluate the neurological impairment due to tumor invasion, functional assessment was done in all rodents at day 40 after tumor engraftment using locomotion gait analysis and pain response to a mechanical stimulus (Randall-Selitto test). Bioluminescence (BLI) was used to evaluate tumor growth in vivo and cone beam computed tomography (CBCT) was performed to evaluate bone changes due to tumor invasion. The animals were euthanized at day 45 and their spines were harvested and processed for hematoxylin and eosin (H&E) staining. Results: Tumor growth in the spine was confirmed by BLI imaging and corroborated by histological analysis. Cone beam computed tomography images were characterized by a decrease in the bone intensity in the lumbar spine consistent with tumor location on BLI. On H&E staining of tumor-engrafted animals, there was a near-complete ablation of the ventral and posterior elements of the L5 vertebra with severe tumor invasion in the bony components displacing the spinal cord. Locomotion gait analysis of tumor-engrafted rats showed a disruption in the normal gait pattern with asignificant reduction in length (p=.02), duration (p=.002), and velocity (p=.002) of right leg strides and only in duration (p=.0006) and velocity (p=.001) of left leg strides, as compared with control and sham rats. Tumor-engrafted animals were hypersensitive to pain stimulus shown as a significantly reduced response in time (p=.02) and pressure (p=.01) applied when compared with control groups. Conclusions: We developed a system for the quantitative analysis of pain and locomotion in an animal model of metastatic human breast cancer of the spine. Tumor-engrafted animals showed locomotor and sensory deficits that are in accordance with clinical manifestation in patients with spine metastasis. Pain response and locomotion gait analysis were performed during follow-up. The Randall-Selitto test was a sensitive method to evaluate pain in the rat's spine. We present a model for the study of bone-associated cancer pain secondary to cancer metastasis to the spine, as well as for the study of new therapies and treatments to lessen pain from metastatic cancer to the neuroaxis.",
keywords = "Breast cancer, Gait, Locomotion, Metastasis, Pain, Spine",
author = "{Sarabia Estrada}, Rachel and Alejandro Ruiz-Valls and {Guerrero Cazares}, Hugo and Ampuero, {Ana M.} and Ismael Jimenez-Estrada and {De Silva}, Samantha and Bernhardt, {Lydia J.} and Goodwin, {Courtney Rory} and Ahmed, {Ali Karim} and Yuxin Li and Phillips, {Neil A.} and Gokaslan, {Ziya L.} and Alfredo Quinones-Hinojosa and Sciubba, {Daniel M.}",
year = "2017",
month = "1",
day = "23",
doi = "10.1016/j.spinee.2017.04.009",
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journal = "Spine Journal",
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TY - JOUR

T1 - Metastatic human breast cancer to the spine produces mechanical hyperalgesia and gait deficits in rodents

AU - Sarabia Estrada, Rachel

AU - Ruiz-Valls, Alejandro

AU - Guerrero Cazares, Hugo

AU - Ampuero, Ana M.

AU - Jimenez-Estrada, Ismael

AU - De Silva, Samantha

AU - Bernhardt, Lydia J.

AU - Goodwin, Courtney Rory

AU - Ahmed, Ali Karim

AU - Li, Yuxin

AU - Phillips, Neil A.

AU - Gokaslan, Ziya L.

AU - Quinones-Hinojosa, Alfredo

AU - Sciubba, Daniel M.

PY - 2017/1/23

Y1 - 2017/1/23

N2 - Background Context: Metastases to the spine are a common source of severe pain in cancer patients. The secondary effects of spinal metastases include pain, bone fractures, hypercalcemia, and neurological deficits. As the disease progresses, pain severity can increase until it becomes refractory to medical treatments and leads to a decreased quality of life for patients. A key obstacle in the study of pain-induced spinal cancer is the lack of reliable and reproducible spine cancer animal models. In the present study, we developed a reproducible and reliable rat model of spinal cancer using human-derived tumor tissue to evaluate neurological decline using imaging and behavioral techniques. Purpose: The present study outlines the development and characterization of an orthotopic model of human breast cancer to the spine in immunocompromised rats. Study Design/Setting: This is a basic science study. Methods: Female immunocompromised rats were randomized into three groups: tumor (n=8), RBC3 mammary adenocarcinoma tissue engrafted in the L5 vertebra body; sham (n=6), surgery performed but not tumor engrafted; and control (n=6), naive rats, no surgery performed. To evaluate the neurological impairment due to tumor invasion, functional assessment was done in all rodents at day 40 after tumor engraftment using locomotion gait analysis and pain response to a mechanical stimulus (Randall-Selitto test). Bioluminescence (BLI) was used to evaluate tumor growth in vivo and cone beam computed tomography (CBCT) was performed to evaluate bone changes due to tumor invasion. The animals were euthanized at day 45 and their spines were harvested and processed for hematoxylin and eosin (H&E) staining. Results: Tumor growth in the spine was confirmed by BLI imaging and corroborated by histological analysis. Cone beam computed tomography images were characterized by a decrease in the bone intensity in the lumbar spine consistent with tumor location on BLI. On H&E staining of tumor-engrafted animals, there was a near-complete ablation of the ventral and posterior elements of the L5 vertebra with severe tumor invasion in the bony components displacing the spinal cord. Locomotion gait analysis of tumor-engrafted rats showed a disruption in the normal gait pattern with asignificant reduction in length (p=.02), duration (p=.002), and velocity (p=.002) of right leg strides and only in duration (p=.0006) and velocity (p=.001) of left leg strides, as compared with control and sham rats. Tumor-engrafted animals were hypersensitive to pain stimulus shown as a significantly reduced response in time (p=.02) and pressure (p=.01) applied when compared with control groups. Conclusions: We developed a system for the quantitative analysis of pain and locomotion in an animal model of metastatic human breast cancer of the spine. Tumor-engrafted animals showed locomotor and sensory deficits that are in accordance with clinical manifestation in patients with spine metastasis. Pain response and locomotion gait analysis were performed during follow-up. The Randall-Selitto test was a sensitive method to evaluate pain in the rat's spine. We present a model for the study of bone-associated cancer pain secondary to cancer metastasis to the spine, as well as for the study of new therapies and treatments to lessen pain from metastatic cancer to the neuroaxis.

AB - Background Context: Metastases to the spine are a common source of severe pain in cancer patients. The secondary effects of spinal metastases include pain, bone fractures, hypercalcemia, and neurological deficits. As the disease progresses, pain severity can increase until it becomes refractory to medical treatments and leads to a decreased quality of life for patients. A key obstacle in the study of pain-induced spinal cancer is the lack of reliable and reproducible spine cancer animal models. In the present study, we developed a reproducible and reliable rat model of spinal cancer using human-derived tumor tissue to evaluate neurological decline using imaging and behavioral techniques. Purpose: The present study outlines the development and characterization of an orthotopic model of human breast cancer to the spine in immunocompromised rats. Study Design/Setting: This is a basic science study. Methods: Female immunocompromised rats were randomized into three groups: tumor (n=8), RBC3 mammary adenocarcinoma tissue engrafted in the L5 vertebra body; sham (n=6), surgery performed but not tumor engrafted; and control (n=6), naive rats, no surgery performed. To evaluate the neurological impairment due to tumor invasion, functional assessment was done in all rodents at day 40 after tumor engraftment using locomotion gait analysis and pain response to a mechanical stimulus (Randall-Selitto test). Bioluminescence (BLI) was used to evaluate tumor growth in vivo and cone beam computed tomography (CBCT) was performed to evaluate bone changes due to tumor invasion. The animals were euthanized at day 45 and their spines were harvested and processed for hematoxylin and eosin (H&E) staining. Results: Tumor growth in the spine was confirmed by BLI imaging and corroborated by histological analysis. Cone beam computed tomography images were characterized by a decrease in the bone intensity in the lumbar spine consistent with tumor location on BLI. On H&E staining of tumor-engrafted animals, there was a near-complete ablation of the ventral and posterior elements of the L5 vertebra with severe tumor invasion in the bony components displacing the spinal cord. Locomotion gait analysis of tumor-engrafted rats showed a disruption in the normal gait pattern with asignificant reduction in length (p=.02), duration (p=.002), and velocity (p=.002) of right leg strides and only in duration (p=.0006) and velocity (p=.001) of left leg strides, as compared with control and sham rats. Tumor-engrafted animals were hypersensitive to pain stimulus shown as a significantly reduced response in time (p=.02) and pressure (p=.01) applied when compared with control groups. Conclusions: We developed a system for the quantitative analysis of pain and locomotion in an animal model of metastatic human breast cancer of the spine. Tumor-engrafted animals showed locomotor and sensory deficits that are in accordance with clinical manifestation in patients with spine metastasis. Pain response and locomotion gait analysis were performed during follow-up. The Randall-Selitto test was a sensitive method to evaluate pain in the rat's spine. We present a model for the study of bone-associated cancer pain secondary to cancer metastasis to the spine, as well as for the study of new therapies and treatments to lessen pain from metastatic cancer to the neuroaxis.

KW - Breast cancer

KW - Gait

KW - Locomotion

KW - Metastasis

KW - Pain

KW - Spine

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