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The role of NCAM signaling and its effector protein, [beta]1-integrin, in tumor progression

Kren, Angelika. The role of NCAM signaling and its effector protein, [beta]1-integrin, in tumor progression. 2007, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_8065

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Abstract

Neural Cell Adhesion Molecule (NCAM) is a member of the large family of Ca2+independent, immunoglobulin (Ig)-like cell adhesion molecules. So far, its function in homophilic and heterophilic interactions has been mainly studied in neuronal cells, where it is implicated in processes such as neurite outgrowth, axon guidance and pathfinding. Apart form its action as a cell adhesion molecule, NCAM contributes to these processes by acting as a modulator of fibroblast growth factor receptor (FGFR) signaling. NCAM is also expressed in a number of non-neuronal tissues and changes in NCAM expression levels have been correlated with increased malignancy in various tumors. In the Rip1Tag2 mouse model of multistage tumorigenesis, deletion of NCAM expression results in the induction of tissue disaggregation, increased lymphangiogenesis and the formation of metastases. Comparison of cell lines derived from NCAM-expressing and NCAM-deficient tumors showed that NCAM binds to FGFR and thereby activates it, triggering signaling cascades that eventually lead to the activation of β 1-integrin, resulting in the promotion of cell-matrix adhesion. However, it has remained elusive how NCAM loss leads to the induction of lymphangiogenesis and whether the impaired cell matrix adhesion of NCAM-deficient cell lines accounted for the tissue disaggregation and metastasis formation observed in vivo. This study investigates NCAM function on several cellular levels. In in vitro coexpression studies NCAM complex formation properties on the cell surface were investigated, showing that NCAM can bind to several growth factor receptors containing Ig domains in their extracellular parts. Studies focusing on the cytoplasmic events and molecular players downstream of the NCAM/FGFR complex formation, revealed a novel, inhibiting function of NCAM in modulating RTK signaling. Finally, in an in vivo approach, the role of β1-integrin, a target protein of NCAM signaling, in tumor progression was analyzed by interfering with β1-integrin expression in the Rip1Tag2 tumor model. These studies demonstrated that the induction of lymphangiogenesis in NCAM-deficient tumors was not due to the loss of β1-integrin function and therefore employed an alternative pathway. Yet, loss of β1-integrin induced tumor cell dissemination but not metastasis formation. Instead, a novel function of β1-integrin in tumor progression was identified. Upon deletion of β1-integrin, tumor size was decreased, potentially through the induction of senescence in β1-integrin-deficient cells. Taken together, this study has identified novel NCAM-binding proteins and provides insights into NCAM signaling on the molecular level as well as in an in vivo context. Furthermore, a so far unrecognized role of β1-integrin in preventing senescence has been revealed.
Advisors:Christofori, Gerhard M.
Committee Members:Rolink, Antonius G. and Keller, Walter
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Biochemistry and Genetics > Tumor Biology (Christofori)
UniBasel Contributors:Christofori, Gerhard M. and Rolink, Antonius G. and Keller, Walter
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:8065
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:95
Language:German
Identification Number:
Last Modified:22 Jan 2018 15:50
Deposited On:13 Feb 2009 16:17

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