Differential contributions of host-derived matrix metalloproteinases in mammary tumor growth in the bone microenvironment

Abstract

Breast to bone metastasis is a common event during breast cancer progression. The resultant lesions often cause extensive bone destruction that results in a number of complications including intense pain that dramatically affects the patients quality of life and leads to increased morbidity. Understanding the mechanisms through which breast cancer cells destroy bone can ultimately lead to the generation of new therapies that will successfully battle the disease. In the osteolytic tumor bone environment, activation of osteoclasts, the cells responsible for bone resorption, is critically dependent on proper signals derived from osteoblasts, the cells responsible for bone synthesis. Matrix metalloproteinases (MMPs) are a family of proteinases that have been implicated in mediating cell-cell communication in the tumor bone environment. Interestingly, in human breast-to-bone metastases samples, MMP-2 has been shown to be expressed by osteoblasts and osteocytes and MMP-7 and MMP-9 were found be localized to bone resorbing osteoclasts. In a bid to define the roles of host derived MMP-2, MMP-7 and MMP-9 in the tumor-bone microenvironment, the tibia of MMP-2, MMP-7 and MMP-9 null mice were injected with osteolytic luciferase tagged mammary tumor cell lines. Our studies demonstrated that osteoblast-derived MMP-2 impacts mammary tumor survival in the bone microenvironment by mediating the release of active TGF-β via the processing of a novel MMP-2 substrate, LTBP-3. Furthermore, our results showed that osteoclast-derived MMP-7 but not MMP-9 affect mammary tumor growth in the bone via the solubilization of RANKL that in turn induces osteoclastic resorption of the bone. Thus, this dissertation demonstrated that MMP-2 and MMP-7 support the vicious cycle of bone metastasis via two distinct mechanisms affecting two of the key components of the process, osteoblasts and osteoclasts. Therefore, these two MMPs and their substrates would be attractive targets for future drug therapies to treat patients suffering from breast cancer-induced lytic bone lesions.