Abstract 558: Constitutive activation of p38 MAPK signaling in tumor cells induces osteolytic bone lesions via regulating bone marrow microenvironment

Abstract

Abstract Bone residing tumor cells cause osteolysis, characterized with severe bone pain, multiple fractures and hypercalcemia in patients. While it has been proposed that tumor cells activate osteoclasts and/or inhibit osteoblasts, leading to bone resorption, the mechanism underlying tumor-induced osteoclastogenesis activation in bone marrow microenvironment, which causes osteolytic bone lesions, is yet to be elucidated. P38 mitogen-activated protein kinase (MAPK) is commonly constitutively activated in malignant osteolytic tumors. We hypothesize that constitutive activity of p38 MAPK in tumor cells might contribute to osteolytic bone lesions via regulating bone marrow microenvironment. For this purpose, we applied of small hairpin RNAs (shRNAs) to disrupt p38 MAPK activity in myeloma ARP-1 and bone metastatic breast cancer MDA-MB-231 cells. To evaluate the role of tumor p38 MAPK in bone lesions, tumor cells with p38 MAPK-shRNAs or control vectors were intravenously injected to SCID mice. Lytic lesions in tibial bones were measured by radiograph and μ-CT, and further confirmed by histological examination. The results showed that lytic bone lesions were found in mice bearing of tumor cells with control vectors. In contrast, no or less bone lesions were found in mice with shRNA-expressing tumor cells. Moreover, decrease of osteoclast amounts covered bone surface, as well as circulating levels of collagen type I (bone resorption marker) and TRAP5b (active osteoclast marker), but increase of osteoblast amounts, and osteocalcin (bone formation marker) and ALP (active osteoblast marker), were found in those mice injected with shRNA-tumor cells. Noticeably, tumor p38 MAPK enhanced osteoclast differentiation and activity, as well as inhibited osteoblast maturation and function in vitro. However, disruption of p38 MAPK activity in tumor cells did not affect tumor growth and tumor cell homing to bone. We further identified that tumor p38 MAPK-derived monocyte chemotactic protein-1 (MCP-1) and dickkopf-1 (DKK-1) induced bone lesions via activation of RANK/RANKL-mediated NFκB, p38 MAPK and ERK1/2 signaling pathways. In conclusion, our results elucidate a novel mechanism that tumor p38 MAPK activity regulates bone marrow microenvironment and contributes to tumor-induced osteolytic bone lesions. Thus, inhibition of p38 MAPK signaling in tumor cells may have an important implication to treat bone lesions in patients with osteolytic tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 558.