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 Quiñones-Hinojosa, Daniel M. Sciubba

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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)
Pages (from-to)1325-1334
Number of pages10
JournalSpine Journal
Volume17
Issue number9
DOIs
StatePublished - Sep 2017

Keywords

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

ASJC Scopus subject areas

  • Surgery
  • Orthopedics and Sports Medicine
  • Clinical Neurology

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