Abstract 5149: An orthotopic model of human chordoma in rats

Abstract

Introduction. Chordoma (CHO) is a relatively rare, slow-growing, malignant, locally aggressive cancer that constitutes 1% to 4% of all primary bone tumors. It arises from notochordal remnants along the neuraxis at developmentally active sites. CHO causes significant damage through local bone destruction and compromise of surrounding neurologic and neurovascular structures. CHO in the lumbar spine results in devastating effects that include pain, paralysis, bowel/bladder dysfunction, and decreased ambulation. These effects are minimally responsive to conventional chemotherapy and radiotherapy and as such, surgical resection is the mainstay of treatment. Pre-clinical models that better recapitulate the clinical symptoms observed in patients diagnosed with CHO are needed to increase the understanding of this disease and to develop strategies to develop new therapeutic strategies. Here we developed the first orthotopic animal model of human CHO in the lumbar spine of immunocompromised rats.

Methods. 11 immunocompromised rats were implanted in the lumbar spine with human CHO tumor tissue. A group of 6 sham rats (surgical approach without tumor implantation) and another with 6 intact rats were used as control groups. This tumor was obtained from a donor rat that was previously injected with UCH1CHO cells in the flank. Nociceptive response was conducted every week after the first neurological deficits were present using Randal-Sellito. Locomotion gait analysis was used to evaluate gait impairment. Rats were clinically observed for neurological impairment in the lumbar spine and/or hind limbs. Spines were collected after euthanasia, and inspected for signs of spinal cord compression followed by H&E staining to evaluate the histology.

Results. In CHO-implanted rats, the threshold for a mechanic nociceptive response was significantly reduced in time and pressure applied. Locomotion gait analysis showed a disruption in the normal pattern of the rats’ gait. At D25-35 after tumor implantation rats showed impairment in the flexion and extension of the knees, ankles, and toes. At the gross morphology level, the spinal cord showed signs of compression at upper and lower levels related with the implanted CHO tumor. Histology revealed tumor invasion in the spinal canal that was related with deficit in the flexion and extension of the toes. The tumor showed typical CHO morphology: physaliferous cells filled with vacuolated cytoplasm of mucoid matrix.

Conclusions. We have developed a novel orthotopic human CHO model in rats. This model reproduces cardinal clinical signs such as locomotor and sensory deficits present in human patients. To our knowledge, this is the first orthotopic animal model of human CHO. Its use and further study will be essential for pathophysiology research and the development of new therapeutic strategies.

Citation Format: Rachel Sarabia-Estrada, Alejandro Ruiz-Valls, Courtney R. Goodwin, Sagar Sha, Alfredo Quiñones-Hinojosa, Ziya L. Gokaslan, Daniel M. Sciubba. An orthotopic model of human chordoma in rats. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5149. doi:10.1158/1538-7445.AM2015-5149