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Modulatory effects of T-cadherin on cell behavior and growth factor receptor activity in carcinoma cells

Maslova, Kseniya. Modulatory effects of T-cadherin on cell behavior and growth factor receptor activity in carcinoma cells. 2014, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_10853

Abstract

Cancer is a major health problem. Epidermal growth factor receptor (EGFR) pathway plays an important role in cancer progression. EGFR-targeted anti-cancer drugs are being developed to improve anti-cancer therapy. These drugs can give good results especially when a disease is driven by a dominant oncogene. However, the malignant process is generally supported by multiple genetic alterations and a complex signaling network that can compensate for deactivation of signaling targets by increasing activity of other pathways. Deeper understanding of molecular mechanisms of growth factor signaling regulation in cancer will improve anti-cancer therapy and increase clinical benefits.
Classical cadherins are well recognized to be involved in cancer progression and regulation of receptor tyrosine kinase (RTK) signaling. Implication of T-cadherin, an atypical member of cadherin superfamily, in cancer progression has been documented in many cancers but mostly on genetic and epigenetic levels. Few studies have examined functional effects of T-cadherin in cancer, the molecular mechanisms of its effects are poorly understood, and whether T-cadherin regulates RTK signaling in tumor cells is unknown.
This thesis aimed at delineation of the functions of T-cadherin and molecular mechanisms of action in cutaneous squamous cell carcinoma (SCC). We found that T-cadherin loss promotes cell elongation, cell cluster disorganization, cell motility and invasive potential, while T-cadherin upregulation reduces malignant behavior of cells. T-cadherin loss increases, while T-cadherin upregulation blunts sensitivity to stimulation by EGF, manifest at the levels of ligand-induced EGFR phosphorylation/internalization, signal transduction, cell retraction and motility. Molecular mechanisms underlying functional effects of T-cadherin involve ?1 integrin activation status and the Rho family of small GTPases. Effects of T-cadherin on EGFR activity are due to altered accumulation of EGFR within lipid raft domains; T-cadherin upregulation retains, while T-cadherin loss releases EGFR from these domains. Thus, T-cadherin acts as a negative auxiliary regulator of EGFR. EGFR activation in SCC promotes T-cadherin redistribution to intercellular contacts, supporting a reciprocal nature of cross-talk between EGFR and T-cadherin. We postulated that modulation of EGFR activity by T-cadherin could be a regulatory mechanism common to other RTKs. Using prostate cancer cells DU145 (which express comparable levels of EGFR and IGF-1R) we found that T-cadherin regulates activity of both EGFR and IGF-1R and their cross talk. Therefore modulation of growth factor receptor tyrosine kinase activity and cross-talk may be a common mechanistic principle underlying T-cad-dependent control of carcinoma cell behavior. In summary, the findings of this thesis have advanced knowledge on the functional role of T-cadherin in cancer and the participating molecular mechanisms.
Advisors:Resink, Therese
Committee Members:Fabbro, D.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Further Research Groups at DBM > Signal Transduction (Resink/Erne)
Item Type:Thesis
Thesis no:10853
Bibsysno:Link to catalogue
Number of Pages:98 Bl.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:56
Deposited On:29 Jul 2014 14:14

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