Breast Tumor/Stromal Cell Interactions in Bone

摘要

We are investigating interactions between breast cancer and bone stromal cells and their role in regulating metastasis of breast tumor cells to bone and osteoclast development using an orthotopic mouse model. Results from in vivo experiments indicate that PTHrP is an important factor regulating tumor growth but is not required for specific metastasis of breast tumors to bone. In vitro co-culture of bone stromal and tumor cells leads to up-regulation of RANKL and down-regulation of OPG, a response likely to contribute to the establishment of breast metastases in bone and to increases in bone resorption. The expression of RANKL and OPG in vivo is being investigated using our orthotopic model and immunohistochemistry. The expression of MMP9 significantly increases in these co-cultures and its expression in vivo following tumor cell injection into the mammary gland appears to be most prominent at sites of bone resorption and the bone stroma-breast metastasis interface. Thus, both tumor and stromal-derived MMP9 are likely to contribute to metastatic development and accompanying osteolysis. This is being investigated further using MMP9 null mice and RNAi technology. Work investigating osteoclast requirement in tumor-mediated osteolysis using in vivo administration of OPG, beta 3, integrin peptidomimetics, and/or beta 3 integrin and M-CSF null mice is ongoing.