Claudin-2 promotes breast cancer liver metastasis by facilitating tumor cell interactions with hepatocytes.
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.
Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.
Sébastien
S
Tabariès
Fanny
F
Dupuy
Zhifeng
Z
Dong
Anie
A
Monast
Matthew G
MG
Annis
Jonathan
J
Spicer
Lorenzo E
LE
Ferri
Atilla
A
Omeroglu
Mark
M
Basik
Eitan
E
Amir
Mark
M
Clemons
Peter M
PM
Siegel
D000818:Animals; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002450:Cell Communication; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology; D057167:Claudins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D034622:RNA Interference; D034741:RNA, Small Interfering; D012878:Skin Neoplasms / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism
C491875:CLDN2 protein, human; D015815:Cell Adhesion Molecules; D057167:Claudins; D016023:Integrins; D034741:RNA, Small Interfering