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Influence of tumor-associated E-cadherin mutations on tumorigenicity and metastasis
Marcus Kremer1, Leticia Quintanilla-Martinez, Margit Fuchs
1Technische Universität München, Klinikum rechts der Isar, Institut für Allgemeine Pathologie und Pathologische Anatomie, München, Germany.
Abstract:
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.
Insights
Tumor-associated E-cadherin mutations can impair its tumor-suppressive function. The specific mutation type, such as exon 9 deletion or exon 8 point mutation, influences tumor growth, but metastasis formation remained unaffected in this mouse model.
Area of Science:
- Oncology
- Molecular Biology
- Cell Adhesion
Background:
- E-cadherin is a crucial cell adhesion molecule with known tumor-suppressive functions.
- Mutations in E-cadherin are frequently observed in various cancers, but their specific impact on tumor suppression and metastasis is not fully understood.
Purpose of the Study:
- To investigate how specific tumor-associated E-cadherin mutations (exon 8 deletion, exon 9 deletion, exon 8 point mutation) affect its tumor-suppressive activity.
- To determine the influence of these E-cadherin mutations on metastasis formation in a preclinical mouse model.
Main Methods:
- Stable transfection of human breast carcinoma cells (MDA-MB-435S) with wild-type (wt) or mutant E-cadherin.
- Injection of transfected cells into the mammary fat pad of immunodeficient mice.
- Tumor growth monitoring and analysis of lung metastasis formation.
- Immunohistochemical analysis of E-cadherin expression in tumors and metastases.
Main Results:
- Wild-type E-cadherin expression significantly reduced tumor size compared to parental cells.
- Exon 9 deletion and exon 8 point mutations impaired E-cadherin's tumor-suppressive function, resulting in medium-sized tumors.
- Exon 8 deletion did not significantly affect tumor size compared to wild-type E-cadherin.
- All cell lines induced lung metastases, with no significant differences observed between groups.
- Tumors showed heterogeneous E-cadherin expression, while metastases were consistently E-cadherin negative.
Conclusions:
- The impact of E-cadherin mutations on tumor suppression is mutation-specific.
- While certain E-cadherin mutations can compromise tumor suppression, they did not significantly alter metastasis formation in this model.
- Loss or down-regulation of E-cadherin is a common feature in both primary tumors and metastases, highlighting its critical role in cell adhesion and tumor progression.