A Novel Strategy to Inhibit Osteolytic Bone Metastases of Breast Cancer
Abstract
More than 70% of women who die from breast cancer show osteolytic bone metastases which cause significant morbidity. Therefore, inhibition of osteolytic bone metastasis would improve the quality of life of patients with advanced breast cancer. Rational therapies to prevent osteolytic bone metastasis of breast cancer should be based on the unique characteristics of the bone microenvironment. The development and progression of osteolytic bone metastases are dependent on the resorption of bone by osteoclasts, multinucleated giant cells that originate from hematopoietic stem cells of the macrophage/monocyte lineage. Differentiation of osteoclasts is absolutely dependent on cell-to-cell contact between osteoblasts/stromal cells and hematopoietic cells. Of critical importance is a membrane-bound cytokine expressed in osteoblasts/stromal cells: RANKL (receptor activator of NF-kB ligand). RANKL binds to RANK, a cell-associated protein present on hematopoietic cells, thereby controlling the development and activation of osteoclasts. In this Concept Award, we proposed to downregulate the expression of RANKL by osteoblasts. Functional knockout of RANKL was accomplished by the intracellular expression of an anti-RANKL single-chain antibody. We hypothesize that this will inhibit the recruitment and activation of osteoclasts, thereby reducing osteoclastic bone resorotion.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2002
- Accession Number
- ADA405259
Entities
People
- Joanne T. Douglas
Organizations
- University of Alabama