Animal Cancer Models of Skeletal Metastasis

Hibberd, Catherine; Cossigny, D. A.; Quan, Gerald M. Y.

doi:10.4137/cgm.s11284

Cited by 21 publications

(14 citation statements)

References 44 publications

(164 reference statements)

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“…Direct intraosseous injection of cancer cells eliminates problems of widespread metastasis, allowing studies to focus on the bone environment in metastasis. However, this experimental method introduces cancer cells into nonphysiological niches that may not be relevant to hematogenous spread of metastasis in breast cancer and other solid tumors ( 7 , 8 ).…”

Section: Introductionmentioning

confidence: 99%

Enhanced Bone Metastases in Skeletally Immature Mice

et al. 2018

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Bone constitutes the most common site of breast cancer metastases either at time of presentation or recurrent disease years after seemingly successful therapy. Bone metastases cause substantial morbidity, including life-threatening spinal cord compression and hypercalcemia. Given the high prevalence of patients with breast cancer, health-care costs of bone metastases (>$20,000 per episode) impose a tremendous economic burden on society. To investigate mechanisms of bone metastasis, we developed femoral artery injection of cancer cells as a physiologically relevant model of bone metastasis. Comparing young (~6 weeks), skeletally immature mice to old (~6 months) female mice with closed physes (growth plates), we showed significantly greater progression of osteolytic metastases in young animals. Bone destruction increased in the old mice following ovariectomy, emphasizing the pathologic consequences of greater bone turnover and net loss. Despite uniform initial distribution of breast cancer cells throughout the hind limb after femoral artery injection, we observed preferential formation of osteolytic bone metastases in the proximal tibia. Tropism for the proximal tibia arises in part because of TGF-β, a cytokine abundant in both physes of skeletally immature mice and matrix of bone in mice of all ages. We also showed that age-dependent effects on osteolytic bone metastases did not occur in male mice with disseminated breast cancer cells in bone. These studies establish a model system to specifically focus on pathophysiology and treatment of bone metastases and underscore the need to match biologic variables in the model to relevant subsets of patients with breast cancer.

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Section: Introductionmentioning

confidence: 99%

Enhanced Bone Metastases in Skeletally Immature Mice

et al. 2018

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“…In current models the clinical evaluation is done by observational findings or by semi-quantitative rating scales (BBB modified scale) after tumor engraftment, progression of paraparesis until paraplegia [30, 40, 41, 56–58]. In our model we implemented a quantitative methodology to evaluate gait impairment in tumor implanted rats and demonstrated that stride length, velocity and time in the left hind limbs was affected; in some rats the right hind limb had a compensatory role by supporting more weight during locomotion.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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 orthototopic model of human breast cancer to the spine in immonocompromised 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 no tumor engrafted, and Control (n=6, naive rats, no surgery performed) groups. 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 (Randal-Sellitto 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 H&E staining. RESULTS Tumor growth in the spine was confirmed by bioluminescence imaging and corroborated by histological analysis. CBCT 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 a significant 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 to 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. CONCLUSION 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 Randal-Sellitto test was a sen...

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“…Both techniques involved animal anaesthesia and surgery using an operating microscope, a dorsal skin incision, dissection of the paraspinal miscles For these reasons, immunodeficient mice are currently the commonest host animals used in in vivo cancer models. Indeed, in a recent review of animal models of skeletal metastasis, nude or severe combined immunodeficiency (SCID) mice were utilized in 75% of established models [32].…”

Section: Radiological and Histological Analysismentioning

confidence: 99%

An in vivo mouse model of intraosseous spinal cancer causing evolving paraplegia

et al. 2013

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The spine is the commonest site of skeletal metastatic disease and uncontrolled growth of cancer in the spine will inevitably cause pain and neurologic compromise. Improved understanding of the pathobiology behind this devastating condition is urgently needed. For this reason, the aim of this study was to establish a clinically relevant, animal model of spinal cancer. A percutaneous orthotopic injection of human breast (MDA-MB-231) or human prostate (PC-3) cancer cells was administered into the upper lumbar spine of nude mice (n = 6). Animals were monitored twice daily for general welfare, gait asymmetry or disturbance, and hindlimb weakness. After sacrifice, plain radiographs, micro-CT imaging and histological analysis of the spines were performed on each mouse. All mice recovered fully from the inoculation procedure and displayed normal gait and behaviour patterns for at least 3 weeks post-inoculation. Subsequently, between 3 and 5 weeks post-inoculation, each mouse developed evolving paralysis in their hindlimbs over 48-72 h. All followed the same pattern of decline following onset of neurological dysfunction; from gait asymmetry and unilateral hindlimb weakness, to complete unilateral hindlimb paralysis and finally to complete bilateral hindlimb paralysis. Plain radiographs, micro-CT scanning and histological analysis confirmed local tumour growth and destruction of the spine in all six mice. An in vivo mouse model of human intraosseous spinal cancer has been established forming cancers that grow within the spine and cause epidural spinal cord compression, resulting in a reproducible, evolving neurological deficit and paralysis that closely resembles the human condition.

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Animal Cancer Models of Skeletal Metastasis

Cited by 21 publications

References 44 publications

Enhanced Bone Metastases in Skeletally Immature Mice

Enhanced Bone Metastases in Skeletally Immature Mice

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

An in vivo mouse model of intraosseous spinal cancer causing evolving paraplegia

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