Tu Qisheng, Zhang Jin, Fix Amanda, Brewer Erika, Li Yi-Ping, Zhang Zhi-Yuan, Chen Jake
Division of Oral Biology, Tufts University School of Dental Medicine, Boston, Massachusetts, USA.
J Cell Physiol. 2009 Jan;218(1):135-45. doi: 10.1002/jcp.21576.
Bone is one of the most common sites of breast cancer metastasis while bone sialoprotein (BSP) is thought to play an important role in bone metastasis of malignant tumors. The objective of this study is to determine the role of BSP overexpression in osteolytic metastasis using two homozygous transgenic mouse lines in which BSP expression is elevated either in all the tissues (CMV-BSP mice) or only in the osteoclasts (CtpsK-BSP mice). The results showed that skeletal as well as systemic metastases of 4T1 murine breast cancer cells were dramatically increased in CMV-BSP mice. In CtpsK-BSP mice, it was found that targeted BSP overexpression in osteoclasts promoted in vitro osteoclastogenesis and activated osteoclastic differentiation markers such as Cathepsin K, TRAP and NFAT2. MicroCT scan demonstrated that CtpsK/BSP mice had reduced trabecular bone volume and bone mineral density (BMD). The real-time IVIS Imaging System showed that targeted BSP overexpression in osteoclasts promoted bone metastasis of breast cancer cells. The osteolytic lesion area was significantly larger in CtpsK/BSP mice than in the controls as demonstrated by both radiographic and histomorphometric analyses. TRAP staining demonstrated a twofold increase in the number of osteoclasts in the bone lesion area from CtpsK/BSP mice compared with that from wild type mice. We conclude that host tissue-derived BSP also plays important roles in breast cancer metastasis through inducing tumor cell seeding into the remote host tissues. Furthermore, osteoclast-derived BSP promotes osteoclast differentiation in an autocrine manner and consequently promotes osteolytic bone metastasis of breast cancer.
骨是乳腺癌转移最常见的部位之一，而骨唾液酸蛋白（BSP）被认为在恶性肿瘤的骨转移中起重要作用。本研究的目的是利用两种纯合转基因小鼠品系来确定BSP过表达在溶骨性转移中的作用，在这两种品系中，BSP在所有组织中（CMV-BSP小鼠）或仅在破骨细胞中（CtpsK-BSP小鼠）表达升高。结果显示，CMV-BSP小鼠中4T1鼠乳腺癌细胞的骨骼及全身转移显著增加。在CtpsK-BSP小鼠中，发现破骨细胞中靶向性BSP过表达促进了体外破骨细胞生成，并激活了诸如组织蛋白酶K、抗酒石酸酸性磷酸酶（TRAP）和活化T细胞核因子2（NFAT2）等破骨细胞分化标志物。显微CT扫描显示，CtpsK/BSP小鼠的骨小梁体积和骨密度（BMD）降低。实时IVIS成像系统显示，破骨细胞中靶向性BSP过表达促进了乳腺癌细胞的骨转移。影像学和组织形态计量学分析均表明，CtpsK/BSP小鼠的溶骨性病变面积显著大于对照组。TRAP染色显示，与野生型小鼠相比，CtpsK/BSP小鼠骨病变区域的破骨细胞数量增加了两倍。我们得出结论，宿主组织来源的BSP通过诱导肿瘤细胞植入远处宿主组织，在乳腺癌转移中也起重要作用。此外，破骨细胞来源的BSP以自分泌方式促进破骨细胞分化，从而促进乳腺癌的溶骨性骨转移。
