Cadherin-11-mediated interactions with bone marrow stromal/osteoblastic cells support selective colonization of breast cancer cells in bone.
Cadherin-11-mediated interactions with bone marrow stromal/osteoblastic cells support selective colonization of breast cancer cells in bone.
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DOI：
10.3892/ijo.33.1.17
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发表时间：
2008-07
影响因子：
5.2
通讯作者：
D. Tamura;T. Hiraga;A. Myoui;H. Yoshikawa;T. Yoneda
中科院分区：
文献类型：
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作者：
D. Tamura;T. Hiraga;A. Myoui;H. Yoshikawa;T. Yoneda
细胞粘附分子与癌症在远处器官中的选择性定植有关。乳腺癌很容易扩散到骨骼。钙粘蛋白-11是经典的2型钙粘蛋白家族成员之一，在骨髓基质细胞和成骨细胞中组成性表达，介导嗜同性细胞间的粘附。在侵袭性人类乳腺癌中也发现钙粘蛋白-11表达升高。在这里，我们研究了乳腺癌细胞和骨髓基质/成骨细胞之间的相互作用，通过钙粘蛋白-11在选择性扩散到骨的作用。MDA-MB-231人乳腺癌细胞的骨寻求克隆显示出比亲本和脑寻求克隆更高的钙粘蛋白-11表达。MDA-MB-231细胞中钙粘蛋白-11的过度表达增加了骨转移，促进了骨吸收，而不能建立细胞-细胞粘附的钙粘蛋白-11的天然变体形式则没有。值得注意的是，钙粘蛋白-11的引入对肺转移没有影响。使用荧光染料标记的癌细胞进行的荧光激活细胞分选仪分析表明，钙粘蛋白-11增加了骨髓中的早期定植。与组成型表达钙粘蛋白-11的MC 3 T3-E1成骨细胞共培养导致过表达钙粘蛋白-11的MDA-MB-231细胞中甲状旁腺相关蛋白（PTH-rP）的产生上调。共培养物的条件培养基增加破骨细胞生成，其被PTH-rP的中和抗体阻断。总之，我们的研究结果表明，钙粘蛋白-11促进归巢和迁移到骨和破骨细胞通过介导乳腺癌细胞与骨髓基质/成骨细胞的嗜同性相互作用，从而增强骨转移。
Cell adhesion molecules have been implicated in the selective colonization of cancer in distant organs. Breast cancer has a strong predilection for spreading to bone. Cadherin-11, which is one of the classical type-2 cadherin family members and mediates homophilic cell-cell adhesion, is constitutively expressed in stromal and osteoblastic cells in bone marrow. Elevated cadherin-11 expression is also found in aggressive human breast cancers. Here, we investigated the role of the interactions between breast cancer cells and bone marrow stromal/osteoblastic cells via cadherin-11 in the selective spread to bone. The bone-seeking clone of the MDA-MB-231 human breast cancer cells showed greater cadherin-11 expression than the parental and the brain-seeking clone. Cadherin-11 overexpression in MDA-MB-231 cells increased bone metastases with promoted bone resorption, while the natural variant form of cadherin-11 that is unable to establish cell-cell adhesion did not. Of note, introduction of cadherin-11 showed no effects on lung metastases. Fluorescence-activated cell sorter analysis using the fluorescent dye-labeled cancer cells showed that early colonization in bone marrow was increased by cadherin-11. Co-cultures with the MC3T3-E1 osteoblastic cells that constitutively expressed cadherin-11 caused an up-regulation of parathyroid hormone-related protein (PTH-rP) production in MDA-MB-231 cells overexpressing cadherin-11. The conditioned medium of the co-cultures increased osteoclastogenesis, which was blocked by a neutralizing antibody to PTH-rP. In conclusion, our results suggest that cadherin-11 promotes homing and migration to bone and osteoclastogenesis through mediating the homophilic interactions of breast cancer cells with marrow stromal/osteoblastic cells, thereby enhancing bone metastases.