Bone metastasis in breast cancer causes profound morbidity. This complication is driven by tumor-bone microenvironment interactions where the details remain sketchy. Nevertheless, compelling evidence suggests the osteoclast (OC) is the cell ultimately responsible for bone metastasis. A symbiotic relationship is established between tumor and OC where the tumor cell first secretes osteoclastogenic factors which stimulate OC-mediated osteolysis releasing mitogenic factors which favor additional tumor growth. We suggest that breaking the interdependency between tumor and OC may provide an effective strategy to halt bone metastases. Therefore, understanding how breast cancer cells create such a highly osteoclastogenic microenvironment will be crucial to develop effective therapeutics. We have found that tumor cells directly support OC formation independently of PTH-rP, RANKL, and TNF-alpha secretion. Perhaps more interesting, we have also identified a correlation between a tumor cell phenotype that resists apoptotic stimuli and displays enhanced osteoclastogenic potential suggesting a mechanistic link between susceptibility to apoptosis and capacity to induce OC formation. In this regard, our data suggest NF-kappaB is a key transcription factor regulating both resistance to apoptosis and production of osteoclastogenic factors. We postulate that breast cancer cells, via a NF-(B dependent process, develop an enhanced survival to apoptotic stimuli and express factors which act directly on OC precursors. Without these attributes, cancer cells will be unable to invade bone and thus be more susceptible to clearance by the immune system or chemotherapy. We will test this hypothesis by pursuing the following specific aims. 1. Assess the mechanism of action of tumor cells on OC formation and/or activation in vitro. 2. Decipher intracellular signaling pathways controlling expression and/or secretion of osteoclastogenic factors. 3. Evaluate the role of NF-kappaB activity on osteolysis and bone metastasis in vivo. 4. Characterize a new osteoclastogenic factor produced by breast cancer cells.
| Metkar, Sunil S; Menaa, Cheikh; Pardo, Julian et al. (2008) Human and mouse granzyme A induce a proinflammatory cytokine response. Immunity 29:720-33 |
