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Effects Of PAR-1 On The Growth,Angiogenesis And Osteoclastogenesis Of Giant Cell Tumor Of Bone

Posted on:2018-03-25Degree:MasterType:Thesis
Country:ChinaCandidate:H ZhangFull Text:PDF
GTID:2334330518454069Subject:Surgery
Abstract/Summary:PDF Full Text Request
Giant cell tumor(GCT)of bone accounts for approximately 6% of all primary bone tumors.It is characterized by rapid growth,severe destruction of bone,and extension into the surrounding soft tissues.Although GCT is considered a histologically benign tumor,its local recurrence rate is as high as 8-62% after primary surgical resection,and more than 5% GCT patients develop pulmonary metastasis.GCT consists of three major cell types: multinucleated osteoclast-like giant cells,monocytic round-shaped macrophage-like cells,and spindle-shaped fibroblast-like stromal cells,also known as giant-cell tumor stromal cells(GCTSCs).GCTSCs are the only proliferating population and represent the neoplastic component of GCT.Growing evidence exists that GCTSCs develop from mesenchymal stem cells(MSCs),which are also considered the progenitor of osteoblasts.By secreting a series of cytokines including RANKL and M-CSF,GCTSCs stimulate giant cell formation and osteoclast differentiation,which further induces bone resorption.Protease activated receptor-1(PAR-1),also known as coagulation factor II receptor(F2R),is recognized as a main receptor for thrombin and a member of the 7 trans-membrane domain G-coupled receptor family.The PAR family consists of four members,PAR-1,2,3 and 4,of which PAR-1 is the prototype that is expressed in numerous tissues and exerts multiple biological functions,including blood coagulation,vascular remodeling,inflammation and cell proliferation.In addition,the increased expression of PAR-1 has been reported to be correlated with disease progression and overall survival in breast,lung,prostate,and gastric cancers.Activation of PAR-1 could promote cancer cell proliferation,motility and invasion by regulating NF-kappaB and ERK1/2.Yang et al and Foley et al also demonstrated that PAR-1 promoted cancer progression by promoting epithelial-tomesenchymal transition(EMT)and angiogenesis.Besides thrombin,several other cytokines have also been reported to be involved in tumorigenesis by binding to PAR-1,including matrix metalloproteinase 1(MMP1),MMP2,transforming growth factor-beta(TGF-?),Kallikrein-related peptidase 6(KLK6),tissue factor(F3)and coagulation factor VII(F7).Although confirmed as an oncogene in many human cancers,PAR-1 in GCT has rarely been reported before.Recent studies also showed that PAR-1 played a critical role in bone remodeling,as represented by increased bone mass and trabecular thickness and decreased bone resorption marker protein in PAR-1 knockout mice.In vitro experiments [8] showed that activation of PAR-1 stimulated RANKL expression and secretion from osteoblasts,which is known to be critical to osteoclast differentiation and bone destruction.In addition,PAR-1 was shown to be overexpressed in prostate cancer bone metastasis compared with primary cancer.Wilson et al further showed that activation of PAR-1 promoted chemotaxis of osteoclast precursors in vitro and increased both osteoclast precursors and osteoclasts at the tumor-bone interface of breast cancer in vivo.However,the role and mechanism of PAR-1 in tumor-induced osteoclastogenesis and osteolysis remain unclear.In the present study,we detected the expression of PAR-1 and its activators in GCT of bone and further explored the role of PAR-1 in GCTSC proliferation,osteoclast differentiation and angiogenesis induced by GCTSCs both in vitro and in vivo.Interestingly,we found that microvesicles(MVs)might be involved in PAR-1 induced osteoclastogenesis by participating in PAR-1 transportation.Furthermore,microarray assay was performed to predict downstreams of PAR-1 in GCT.
Keywords/Search Tags:giant cell tumor of bone, PAR-1, proliferation, angiogenesis, osteoclastogenesis
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