Enhanced Bone Metastases in Skeletally Immature Mice

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.

Targeting disseminated estrogen-receptor-positive breast cancer cells in bone marrow

“…Bioluminescence imaging showed MCF7 cells in both right and left ovaries, distal femur and proximal tibia (knees), and hind paws (locations shown in Fig 4A ) four-weeks post-injection (Fig 4B). Metastases occurred most commonly in bilateral knees, consistent with our previous findings that cancer cells hone to developing growth plates in skeletally immature mice (26) (Fig 4C). Mice presented with metastases on average in 4 out of the six analyzed sites (Fig 4A , C) per animal (SD = 1 site).…”

“…The University of Michigan Institutional Animal Care and Use Committee approved all experimental procedures involving animals, and we housed mice as previously described (63). We used FAI to introduce breast cancer cells into hindlimb bone marrow as detailed previously (26). Briefly, we injected 1 × 10 6 cancer cells into the left femoral artery of 10-12-week old female NSG mice (The Jackson Laboratory, Bar Harbor, ME, USA).…”

Comparison of diagnostic efficacy of MRI and PET/CT in lung cancer of mouse with spinal metastasis

“…What's more, MRI is very sensitive to the detection of bone metastases. This is due to the ability to display a focal aggregation map of radiotracers on bone scans before cortical destruction occurs (14,15).…”

The In Vivo Selection Method in Breast Cancer Metastasis

“…Since this discovery, many metastasis-promoting genes, suppressor genes and molecular mechanisms of metastasis have been identified from the analysis of gene signatures of highly metastatic cell lines [ 48 , 49 ]. Although the highly metastatic cell lines that are frequently used are limited, many metastatic cell lines have been established by various transplantation methods ( Figure 1 and Table 2 ) [ 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. In addition, to promote the exchange of information on these valuable resources, the brain metastasis cell lines panel (BrMPanel) [ 58 ] and the metastasis map (MetMap) of human cancer cell lines [ 59 ] has been published as a useful public dataset.…”