Influence of tumor-associated E-cadherin mutations on tumorigenicity and metastasis.
In this study, we investigated whether tumor-associated E-cadherin mutations impair the tumor-suppressive function of the cell adhesion molecule and influence metastasis formation in a severe combined immunodeficiency mouse model. The investigated E-cadherin mutations were in frame deletions of exons 8 (del 8) or 9 (del 9) and a point mutation in exon 8 (p8). Transfected human MDA-MB-435S carcinoma cells stably expressing wild-type (wt) or mutant E-cadherin were injected into the mouse mammary fat pad. Mice transplanted with wt E-cadherin transfectants developed significantly smaller tumors than animals transplanted with the E-cadherin-negative parental cell line. Animals transplanted with del 9 or p8 E-cadherin transfectants produced medium size tumors, indicating that these mutations impair the tumor-suppressive function of E-cadherin. In contrast, mice transplanted with del 8 E-cadherin transfectants developed tumors of approximately the same sizes as animals transplanted with wt E-cadherin expressing cells. Lung metastases were induced by all cell lines without significant differences. Immunohistochemical analysis of E-cadherin expression in the tumors revealed a heterogeneous staining pattern, indicating loss or down-regulation of E-cadherin in some tumor cells. Metastases were completely negative for E-cadherin. Our data suggest that the type of mutation determines whether the tumor-suppressive function of E-cadherin is impaired.
Kremer
Marcus
M
Technische Universität München, Klinikum rechts der Isar, Institut für Allgemeine Pathologie und Pathologische Anatomie, München, Germany.
Quintanilla-Martinez
Leticia
L
Fuchs
Margit
M
Gamboa-Dominguez
Armando
A
Haye
Sieglinde
S
Kalthoff
Holger
H
Rosivatz
Erika
E
Hermannstädter
Christine
C
Busch
Raymonde
R
Höfler
Heinz
H
Luber
Birgit
B
D000818:Animals; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005091:Exons; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D014162:Transfection
D015820:Cadherins