Claudin-2 promotes breast cancer liver metastasis by facilitating tumor cell interactions with hepatocytes |
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Authors: | Tabariès Sébastien Dupuy Fanny Dong Zhifeng Monast Anie Annis Matthew G Spicer Jonathan Ferri Lorenzo E Omeroglu Atilla Basik Mark Amir Eitan Clemons Mark Siegel Peter M |
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Institution: | Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada. |
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Abstract: | We previously identified claudin-2 as a functional mediator of breast cancer liver metastasis. We now confirm that claudin-2 levels are elevated in liver metastases, but not in skin metastases, compared to levels in their matched primary tumors in patients with breast cancer. Moreover, claudin-2 is specifically expressed in liver-metastatic breast cancer cells compared to populations derived from bone or lung metastases. The increased liver tropism exhibited by claudin-2-expressing breast cancer cells requires claudin-2-mediated interactions between breast cancer cells and primary hepatocytes. Furthermore, the reduction of the claudin-2 expression level, either in cancer cells or in primary hepatocytes, diminishes these heterotypic cell-cell interactions. Finally, we demonstrate that the first claudin-2 extracellular loop is essential for mediating tumor cell-hepatocyte interactions and the ability of breast cancer cells to form liver metastases in vivo. Thus, during breast cancer liver metastasis, claudin-2 shifts from acting within tight-junctional complexes to functioning as an adhesion molecule between breast cancer cells and hepatocytes. |
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