| Summary: | 博士 === 國立臺灣大學 === 藥學研究所 === 101 === Prostate cancer (PCa) has propensity to metastasize to bone and bone metastasis is the major cause of PCa related mortality. Cell adhesion molecules that mediate the interactions between metastatic PCa cells and osteoblasts, a major cell type in bone, may play a role in the metastasis of PCa cells to bone. Cadherin-11, also known as OB-cadherin, is one such adhesion molecule and highly expressed in a PCa cell line.
Cadherin-11 has been shown to play a role in the metastasis of PCa cells to bone but the mechanism by which cadherin-11 is involved in this process is not known. In this study, we show that expression of cadherin-11 in cadherin-11-negative C4-2B4 cells increases their spreading and intercalation into an osteoblast layer, and stimulates C4-2B4 cell migration and invasiveness. Downregulation of cadherin-11 in cadherin-11-expressing metastatic PC3 cells decreases cell motility and invasiveness. Further, both the juxtamembrane and β-catenin binding domains in the cytoplasmic tail of cadherin-11 are required for cell migration and invasion. These observations suggest that cadherin-11 not only provides a physical link between PCa cells and osteoblasts but also increases PCa cell motility and invasiveness through its cytoplasmic domain that may facilitate the metastatic colonization of PCa cells in bone.
We also identify a novel adhesion motif that mediates cadherin-11 homophilic cell-cell adhesion. We show that interfering cadherin-11-mediated PCa cell and osteoblast adhesion through inhibition of this motif may be developed for preventing or delaying prostate cancer bone metastasis.
The cadherin family of cell adhesion molecules mediates Ca2+-dependent cell-cell adhesion. We identified a novel adhesion motif in the EC3 domain in cadherin-11. We generated 21 monoclonal antibodies against cadherin-11 EC domains. Among them, mAb 2C7 and 1A5 were found to inhibit cadherin-11-mediated cell aggregation. Mutation of the mAb 2C7 epitope in the EC3 domain abolished cadherin-11-mediated adhesion.
In PCa cells, the aberrant expression of cadherin-11 increases their adhesion to osteoblasts in vitro and metastasis to bone in vivo. Whether blocking this adhesion will inhibit PCa metastasis to bone was previously unknown. Using an experimental metastasis model by injecting PCa cells intracardially, we showed that systemic delivery of mAb 2C7 significantly reduced the metastasis of disseminated PC3-mm2 to bone. Our studies suggest that perturbing cadherin-11-mediated adhesion may prevent bone metastasis from prostate or other cancers.
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