The MT1-MMP/RANKL/RANK Axis in Prostate Cancer Bone Metastasis

前列腺癌骨转移中的 MT1-MMP/RANKL/RANK 轴

• 批准号: 7740033
• 负责人: MICHAEL L CHER
• 金额: $ 44.82万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7740033
• 关键词: Address; Animal Model; Binding; Biochemical; Biological; Blood; Bone Growth; Bone remodeling; Cancer Patient; Cell Proliferation; Cell surface; Cells; Cleaved cell; Complex; Data; Deposition; Diagnostic radiologic examination; Event; Growth; Hematogenous; Homeostasis; Human; Laboratories; Lead; Malignant neoplasm of prostate; Marrow; Matrix Metalloproteinases; Membrane; Metastatic Neoplasm to the Bone; Modeling; Molecular; Morbidity - disease rate; Neoplasm Metastasis; Osteolysis; Osteolytic; Pathway interactions; Peptide Hydrolases; Process; Relative (related person); Role; Side; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Stream; Surface of the Prostate; TNFSF11 gene; TRANCE protein; Testing; Tumor Suppressor Proteins; Tumor-Derived; autocrine; base; bone; bone cell; cancer cell; cell associated matrix; defined contribution; human MMP14 protein; inhibitor/antagonist; maspin; mortality; neoplastic cell; response; skeletal; therapeutic development; tumor; tumor growth; tumor progression

Bone metastasis is the leading cause of morbidity and mortality in prostate cancer (pc) patients. MT1-MMP (membrane type 1-MMP, also known as MMP-14) is highly expressed in tumor cells in human pc bone metastases. MT1-MMP has been shown to promote expansion of the metastatic deposit and the osteolytic side of the bone response. MT1-MMP is also responsible for the release (shedding) of RANKL (receptor activator of nuclear factor-kappa B ligand), an osteoclastogenic factor which is crucial for the initiation of the osteoclastic response. However, the biochemical mechanisms by which MT1-MMP releases RANKL and the extent to which RANK signaling in tumor cells promotes progression of the metastatic deposit have not been characterized. Also, the relative effects of RANKL derived from tumor cells vs. bone cells is unknown. Herein, we hypothesize that tumor-derived MT1-MMP cleaves membrane-bound RANKL (mRANKL) on tumor cells. This shedding event yields a soluble form of RANKL (sRANKL) that contributes to the progression of the metastatic deposit by activating specific RANK-associated cell signaling pathways in cancer cells and bone cells. To further understand this process, we propose to (1) investigate the structural basis of MT1-MMP shedding of mRANKL and identify MT1-MMP/mRANKL complexes at the surface of pc cells; (2) investigate the MT1-MMP – RANKL – RANK signaling axis in prostate cancer cells; and (3) define the contributions of tumor-derived RANKL and RANK to intraosseous tumor growth and bone remodeling in MT1-MMP-driven tumors. This proposal will use a variety of biochemical and cellular approaches as well as animal models of bone metastasis.

骨转移是前列腺癌患者发病率和死亡率的主要原因。MT 1-MMP（membrane type 1-MMP，也称为MMP-14）在人pc骨转移瘤的肿瘤细胞中高度表达。MT 1-MMP已显示促进转移性存款的扩张和骨反应的溶骨性侧。MT 1-MMP还负责RANKL（核因子-κ B配体的受体激活剂）的释放（脱落），RANKL是一种破骨细胞生成因子，对骨细胞反应的启动至关重要。然而，MT 1-MMP释放RANKL的生化机制和肿瘤细胞中RANK信号传导促进转移性存款进展的程度尚未得到表征。此外，来源于肿瘤细胞与骨细胞的RANKL的相对效应尚不清楚。在此，我们假设肿瘤来源的MT 1-MMP切割肿瘤细胞上的膜结合RANKL（mRANKL）。该脱落事件产生可溶性形式的RANKL（sRANKL），其通过激活癌细胞和骨细胞中的特定RANK相关细胞信号传导途径促进转移性存款的进展。为了进一步了解这一过程，我们建议（1）研究mRANKL的MT 1-MMP脱落的结构基础，并鉴定pc细胞表面的MT 1-MMP/mRANKL复合物;（2）研究前列腺癌细胞中的MT 1-MMP-RANKL- RANK信号传导轴;（3）确定肿瘤源性RANKL和RANK对MT 1-MMP驱动的肿瘤中骨内肿瘤生长和骨重建的贡献。该建议将使用各种生化和细胞方法以及骨转移的动物模型。