Trafficking of Metastatic Breast Cancer Cells in Bone
Annual rept. 1 Aug 2004-31 Jul 2005
PENNSYLVANIA STATE UNIV UNIVERSITY PARK
Pagination or Media Count:
Breast cancer metastases are usually found at the ends metasphyses of long bones where they cause osteolysis. The objective was to determine the trafficking of cancer cells in the marrow cavity and to identify factors that attract them. Human breast cancer cells that GFP express green fluorescent protein MDA-MB 231GFP were inoculated intracardiacly into athymic mice. femurs harvested from 1 hr to 6 wk later and analyzed by fluorescence microscopy, immunohistochemistry, histomorphometry, flow cytometry and PCR. Single cells were detected within 1 hr in the distal metasphyses. Most cleared the marrow by 72 hi but at 1 wk small foci formed in the ends near osteoblasts. At 2 wk the foci grew and coalesced. By 4 wk, the tumor masses were large and extended into the diaphysis. The osteoblasts were dramatically reduced 8 of control, while osteoclasts were reduced modestly -6O of control. Ours is the first in vivo evidence that tumor cells influence not only osteoclasts, as widely believed, but also eliminate functional osteoblasts, thereby restructuring the bone microenvironment to strongly favor osteolysis. Using an ELISA array we also found that the metasphyseal bone was rich in several cyokines and factors that were only weakly detected in the shaft of the bone. Strategies that restore osteoblast function, perhaps by modifying the bone microenvironment, are needed to improve treatment of osteolytic bone metastases.
- Anatomy and Physiology
- Medicine and Medical Research