Abstract
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.
Highlights
Metastatic breast cancer currently affects Ͼ150,000 women in the United States, three-fourths of whom initially presented with local or regional disease [1]
Breast Cancer Cells Injected via the Femoral Artery Distribute Uniformly in Tibia but Produce Only Proximal Osteolytic Metastases As we initially developed our method of femoral artery injection of cancer cells in young (ϳ6- to 8-week-old mice), we observed that mice invariably developed osteolytic bone metastases in the proximal tibia (Figure 1, A and B)
We noted a similar preference for the proximal tibia in multiple publications on bone metastases in mice from both iliac artery and intracardiac injections performed in young animals [16,17,18]
Summary
Metastatic breast cancer currently affects Ͼ150,000 women in the United States, three-fourths of whom initially presented with local or regional disease [1]. Breast cancer most commonly metastasizes to bone, occurring in 80% of patients with metastatic disease in any site. Breast cancer metastases in bone may cause acute life-threatening conditions such as spinal cord compression and malignant hypercalcemia. Patients with local or regional disease have a 5-year survival rate of Ͼ90% or 70%, respectively, while for those with metastatic breast cancer, survival plummets to 20%–30% [2]. These facts underscore the need for mechanistic studies in physiologically relevant model systems to prevent and/or more effectively treat breast cancer metastasis to bone
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