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Cancer - from mechanisms of invasion to targeted therapy

Wicki, Andreas Christian. Cancer - from mechanisms of invasion to targeted therapy. 2007, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_7944

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Abstract

Cancer is one of the big challenges of modern medicine. The manifestations of cancer are manifold, and the knowledge of the etiology of cancer is still fragmentary. In order to understand the disease, the complete molecular apparatus and the whole signal transduction network of the cell must be analysed.
Tumor invasion is one specific topic in the vast field of cancer research. It investigates the intra- and extracellular mechanisms that define the migratory properties of a cancer cell and lead to invasion and destruction of the surrounding tissue. In a healthy human tissue, cells are connected one to another by adhesive molecules. Loss of the adhesion results in the migration of single cells and the infiltration of neighboring tissues. This is part of a larger phenomenon known as epithelial-mesenchymal transition (EMT), during which cells lose their epithelial markers and start to act as if they were mesenchymal cells. The cellular program that determines this transition is similar to that active during developmental processes such as gastrulation or neurulation.
Alternatively, cells can maintain contact with their neighbors and invade as a cell sheet. This so-called collective cell invasion is characterized by a specialization of the cells of the invasive margin. This invasion pattern usuall yis independent from EMT.
In this study, we investigated both EMT-dependent single cell invasion and EMT-independent collective cell invasion. We show that the loss of the adhesion molecule E-cadherin induces single cell invasion, which is accompanied by the upregulation of p120-catenin, an adaptor molecule, and the C-terminal fragment of N-cadherin, another cell adhesion molecule. In contrast, the expression of podoplanin, a small mucin-like transmembrane protein, promotes collective cell invasion. E-cadherin is maintained at the cell membrane, and ezrin, another adaptor protein, is phosphorylated. In addition, members of the small GTPase family, including RhoA, Rac and Cdc42, are downregulated.
A second major topic in cancer research is the herapy of cancer. the aim is to develop drugs that selectively trrget cancer cells. this is either done by targeting drugs to a specific marker that is only expressed on cancer and not on healthy cells, or by developing compounds that selectively inhibit molecular pathways active in cancer cells.
In the second part of this study we show that the glucagon-like-peptide-1 (GLP1) receptor is selectively upregulated by malignant [beta]-cells of tha Langerhans islets. With the help of a specific ligand, radionuclides can be targeted to the transformed [beta]-cells. We labeled the ligand with "111-Indium," a [gamma]- and Auger-emitter. Using the [gamma]-component, we performed single photon emission computed tomography (SPECT), combined with conventional computed tomography (CT) or magnetic resonance (MR) imaging. Through this technique, we could detect tumors of 1mm in diameter. The Auger-component has a therapeutic effect, and after the injection of 29 MBq in a mouse model of human insulinoma, the tumer mass was reduced by more than 94%. The dose-limiting factor of this therapy is nephrotoxicity.
Advisors:Christofori, Gerhard M.
Committee Members:Rüegg, Curzio
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Biochemistry and Genetics > Tumor Biology (Christofori)
UniBasel Contributors:Christofori, Gerhard M.
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:7944
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:110
Language:English
Identification Number:
Last Modified:22 Jan 2018 15:50
Deposited On:13 Feb 2009 16:41

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