Bone metastasis is an important factor of morbidity in cancer patients: It is commonly seen in advanced cancers of the breast, the prostate, and the lung, and in multiple myeloma. It has been traditional to think of bone metastases as either osteolytic or osteoblastic. In osteolytic metastasis seen in breast cancer, tumor cells produce cytokines such as parathyroid hormone related protein (PTHrP) that stimulate the production of the receptor activator of nuclear factor KB ligand (RANKL) by osteoblasts and bone marrow stromal cells. RANKL then stimulates osteoclast maturation and activation. When activated, osteoclasts form resorption lacunae, and express matrix degrading proteases including matrix metalloproteinase-9 (MMP-9). In our laboratory we have studied bone metastasis in neuroblastoma, the third most common cancer in children and one that frequently metastasizes to the bone. Using an in vivo bone invasion model in nude mice recently developed in the laboratory, we have obtained experimental evidence that neuroblastoma cells when present in the bone marrow cavity recruit osteoclasts to create osteolytic lesions, in a manner similar to breast cancer cells. Using an in vitro model of osteoclast activation and maturation, we have then obtained evidence that the recruitment of osteoclasts by neuroblastoma cells requires the active contribution of bone marrow stromal cells. This research proposal consists of a joint research effort between a cancer biologist, a bone biologist and an imaging chemist. The proposal has two aims.
The first aim i s focused on examining the role of MMPs in bone metastasis and more specifically on testing the hypothesis that MMP-9 produced by osteoclasts contributes to osteoclast recruitment by solubilizing RANKL, thereby increasing its bioavailability.
The second aim i s translational and focused on developing sensitive techniques to quantify the amount of bone destruction that occurs during bone invasion. We will do our experiments with neuroblastoma cells and breast cancer cells, as they both generate osteolytic lesions. These studies will determine whether inhibition of MMP activity could be of therapeutic value in bone metastasis, and will dentify novel and sensitive methods to test agents that inhibit bone invasion in preclinical models.
| Mouchess, Maria L; Sohara, Yasuyoshi; Nelson Jr, Marvin D et al. (2006) Multimodal imaging analysis of tumor progression and bone resorption in a murine cancer model. J Comput Assist Tomogr 30:525-34 |
| Sohara, Yasuyoshi; Shimada, Hiroyuki; Minkin, Cedric et al. (2005) Bone marrow mesenchymal stem cells provide an alternate pathway of osteoclast activation and bone destruction by cancer cells. Cancer Res 65:1129-35 |
| Sohara, Yasuyoshi; Shimada, Hiroyuki; DeClerck, Yves A (2005) Mechanisms of bone invasion and metastasis in human neuroblastoma. Cancer Lett 228:203-9 |
