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First published online 16 September 2003
doi: 10.1242/jcs.00760
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Research Article |
6ß4 integrin supports cell motility and liver metastasis formation
1 Department of Tumor Progression and Immune Defense, German Cancer Research Center, Heidelberg, Germany
2 Division of Cell Biology, Kihara Institute for Biological Research, Yokohama City University, Yokahama, Japan
3 Department of Applied Genetics, University of Karlsruhe, Karlsruhe, Germany
Author for correspondence (e-mail: m.zoeller{at}dkfz.de)
Accepted 8 July 2003
The metastatic subline of a rat pancreatic adenocarcinoma differs from the non-metastasizing subline by overexpression of 5 membrane molecules: CD44 variant isoforms, EpCAM, the tetraspanin D6.1A, an uPAR-related molecule and, as described here, the 
6ß4 integrin. An antibody-defined molecule was identified by mass spectrometry and cloning as 6ß4 integrin. Transfection-induced expression of 6ß4 in the non-metastasizing subline did not support migration on laminin 5 or tumor progression. However, when the non-metastasizing subline was doubly transfected to express 6ß4 and the D6.1A tetraspanin, intraperitoneally injected tumor cells frequently formed liver metastasis. For the following reasons we assume that metastasis formation is supported by an interaction between 6ß4 and D6.1A. (i) The 2 molecules can associate and co-localize. (ii) Co-localization is strengthened by PKC stimulation. (iii) PKC stimulation, which induces a migratory phenotype, leads to a redistribution of 6ß4/D6.1A complexes. In resting cells, the molecules co-localize at the trail of the cell; during PKC stimulation they become transiently internalized and are (re-)expressed in the leading lamella. Thus, in the appropriate milieu, i.e. intraperitoneally, 6ß4 changes from an adhesion-supporting towards a migration-supporting molecule by its association with a tetraspanin. The findings provide a convincing experimental explanation for the repeatedly described involvement of 6ß4 in tumor progression.
Key words: 6ß4 integrin, Tetraspanin, Metastasis, Adhesion, Motility
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