Bone destruction is a hallmark of multiple myeloma (MM), a largely incurable B-cell malignancy that affects more than 14,400 Americans annually. Over 80% myeloma patients develop osteolytic bone lesions that can cause pathological fractures and severe bone pain. Our previous study showed that C-reactive protein (CRP), the first acute-phase protein described and a prognostic indicator for MM and other cancers, enhances myeloma cell proliferation under stressed conditions and protects myeloma cells from chemotherapy drug-induced apoptosis in vitro and in vivo. CRP binds activating Fc? receptors, activates PI3K/Akt, ERK, and NF-?B pathways and inhibits caspase cascade activation induced by chemotherapy drugs. CRP also enhanced myeloma cell secretion of IL-6 and synergized with IL-6 to protect myeloma cells from chemotherapy drug-induced apoptosis (Yang et al., Cancer Cell 2007;12:252). Our recent studies have further suggested that CRP may also be involved in myeloma bone disease. We have shown that CRP-producing, but not the unmanipulated or control vector-transduced myeloma cell lines produce osteolytic lesions in both murine and human bones in SCID and SCID-hu mice. Our in vitro studies further showed that, compared with the wild-type or control vector-transduced cells, these two cell lines produced significantly higher levels of receptor activator of nuclear factor ?B ligand (RANKL), TNF-a, and dickkopf-1 (DKK1). Addition of CRP also stimulated myeloma cells (cell lines and primary myeloma cells from patients) to secrete these cytokines. As RANKL and TNF-a are required for osteoclast (OC) differentiation and activity, and DKK1 is an osteoblast (OB) differentiation inhibitor, the central hypothesis of this project is that CRP may play an active role in osteolytic bone destruction in MM via affecting OC and OB differentiation and activity. In this project, we will examine the role of CRP on OC and OB differentiation and activity in vitro (aim 1), examine the mechanism of CRP-mediated bone destruction and develop strategies to counteract the effects of CRP on bones in vivo (aim 2), and examine and validate the role of CRP in bone destruction in patients with MM (aim 3). These novel studies are scientifically innovative and important, and highly significant for the treatment of MM and its associated bone disease.

Public Health Relevance

Multiple myeloma (MM) is a cancer of the bone marrow. We recently found that C-reactive protein (CRP), a serum protein that is highly elevated in myeloma and other cancers, can protect myeloma tumor cells from antimyeloma drug-induced apoptosis, and may also be involved in myeloma cell-mediated bone destruction in this disease. In this research project, we will focus on the ability of CRP to promote the generation of OCs and inhibit the generation of OBs in vitro;our studies will uncover a new mechanism by which bone destruction is caused by myeloma cells, and provide a new method to prevent the development of bone disease in patients with MM.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA138398-06
Application #
8595291
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Woodhouse, Elizabeth
Project Start
2010-07-01
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
6
Fiscal Year
2014
Total Cost
$323,010
Indirect Cost
$119,218
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Li, Yi; Zheng, Yuhuan; Li, Tianshu et al. (2015) Chemokines CCL2, 3, 14 stimulate macrophage bone marrow homing, proliferation, and polarization in multiple myeloma. Oncotarget 6:24218-29
Zhang, Liang; Bi, Enguang; Hong, Sungyoul et al. (2015) CD4⁺ T cells play a crucial role for lenalidomide in vivo anti-tumor activity in murine multiple myeloma. Oncotarget 6:36032-40
Zhang, Mingjun; He, Jin; Liu, Zhiqiang et al. (2015) Anti-β₂-microglobulin monoclonal antibodies overcome bortezomib resistance in multiple myeloma by inhibiting autophagy. Oncotarget 6:8567-78
Hong, Bangxing; Li, Haiyan; Zhang, Mingjun et al. (2015) p38 MAPK inhibits breast cancer metastasis through regulation of stromal expansion. Int J Cancer 136:34-43
Lu, Yong; Hong, Bangxing; Li, Haiyan et al. (2014) Tumor-specific IL-9-producing CD8+ Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers. Proc Natl Acad Sci U S A 111:2265-70
Liu, Zhiqiang; Xu, Jingda; He, Jin et al. (2014) A critical role of autocrine sonic hedgehog signaling in human CD138+ myeloma cell survival and drug resistance. Blood 124:2061-71
Park, Jungsun; Li, Haiyan; Zhang, Mingjun et al. (2014) Murine Th9 cells promote the survival of myeloid dendritic cells in cancer immunotherapy. Cancer Immunol Immunother 63:835-45
Lu, Yong; Zhang, Mingjun; Wang, Siqing et al. (2014) p38 MAPK-inhibited dendritic cells induce superior antitumour immune responses and overcome regulatory T-cell-mediated immunosuppression. Nat Commun 5:4229
Li, Haiyan; Lu, Yong; Qian, Jianfei et al. (2014) Human osteoclasts are inducible immunosuppressive cells in response to T cell-derived IFN-γ and CD40 ligand in vitro. J Bone Miner Res 29:2666-75
Zhang, Mingjun; Qian, Jianfei; Lan, Yongsheng et al. (2014) Anti-β₂M monoclonal antibodies kill myeloma cells via cell- and complement-mediated cytotoxicity. Int J Cancer 135:1132-41

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