Metastasis to the bone represents a significant clinical problem for patients with advanced stage breast cancer. The development of targeted therapies for the treatment and control of bone metastasis is hindered by the paucity of preclinical models that would allow the identification of the molecular mechanisms by which tumor cells are attracted and thrive in the bone microenvironment. The goal of this proposal is to develop a novel animal model to study the processes of extravasation and progression of metastatic bone disease using an in vivo generated 'vitalized' bone matrix. These studies represent a collaboration between cancer biologists with expertise in metastasis from a cellular and molecular perspective, and orthopedic surgeons with expertise in a novel tissue engineered model of skeletogenesis. Bone is generated in vivo by ligating a hydroxyapatite-substituted marine coral scaffold to a vascular leash or pedicle. The graft becomes populated with circulating bone progenitor cells, and bone osteoid can develop within 5 weeks. We propose to use this 'vitalized' bone to assess homing and progression of murine tumor cells following injection into the pedicle. The tumor cells will be tagged with the luciferase gene to allow visualization and monitoring with time using bioluminescent imaging techniques. This approach provides several advantages over existing methodology, including the limited dissemination of the tumor cells, the quantitative assessment of metastatic cell burden, and the ability to manipulate individual components of the bone microenvironment. In proof of principle experiments, we will use this methodology to address the hypothesis that production of the matrix metalloproteinases MMP-2 and MMP-9 by resident bone cells contributes to the ability of malignant breast cells to colonize and grow in the bone microenvironment. These studies will lay the foundation for further studies to identify novel targets for the treatment and control of breast-to-bone metastasis.
| Halpern, Jennifer; Lynch, Conor C; Fleming, Jonathan et al. (2006) The application of a murine bone bioreactor as a model of tumor: bone interaction. Clin Exp Metastasis 23:345-56 |
