Mutant cadherin affects epithelial morphogenesis and invasion, but not transformation.
MDCK cells were engineered to reversibly express mutant E-cadherin protein with a large extracellular deletion. Mutant cadherin overexpression reduced the expression of endogenous E- and K-cadherins in MDCK cells to negligible levels, resulting in decreased cell adhesion. Despite severe impairment of the cadherin adhesion system, cells overexpressing mutant E-cadherin formed fluid-filled cysts in collagen gel cultures and responded to hepatocyte growth factor/scatter factor (HGF/SF) that induced cellular extension formation with a frequency similar to that of control cysts. However, cells were shed from cyst walls into the lumen and into the collagen matrix prior to and during HGF/SF induced tubule extension. Despite the propensity for cell dissociation, MDCK cells lacking cadherin adhesion molecules were not capable of anchorage-independent growth in soft agar and cell proliferation rate was not affected. Thus, cadherin loss does not induce transformation, despite inducing an invasive phenotype, a later stage of tumor progression. These experiments are especially relevant to tumor progression in cells with altered E-cadherin expression, particularly tumor samples with identified E-cadherin extracellular domain genomic mutations.
Department of Molecular and Cellular Physiology, Beckman Center B109, Stanford University School of Medicine, Stanford, CA 94305-5426, USA.
M L
ML
Troxell
D J
DJ
Loftus
W J
WJ
Nelson
J A
JA
Marrs
D000362:Agar; D000818:Animals; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D002449:Cell Aggregation; D002455:Cell Division; D002460:Cell Line; D003094:Collagen; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D005782:Gels; D015870:Gene Expression; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D009024:Morphogenesis; D016296:Mutagenesis; D014170:Transformation, Genetic
D015820:Cadherins; D005782:Gels; D017228:Hepatocyte Growth Factor; D000362:Agar; D003094:Collagen