Role of E-cadherin in tumor metastasis and discovery of compounds targeting metastatic cancer cells
Başlık çevirisi mevcut değil.
- Tez No: 400443
- Danışmanlar: PROF. ROBERT A. WEINBERG
- Tez Türü: Doktora
- Konular: Biyoloji, Biology
- Anahtar Kelimeler: Belirtilmemiş.
- Yıl: 2008
- Dil: İngilizce
- Üniversite: Massachusetts Institute of Technology
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Biyoloji Ana Bilim Dalı
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: 178
Özet
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Özet (Çeviri)
The epithelial cell adhesion molecule E-cadherin is often downregulated duringcarcinoma progression and metastatic spread of tumors. However, the precise mechanism andmolecular basis of metastasis promotion by E-cadherin loss is not completely understood. Toinvestigate its role in metastasis, I utilized two distinct methods of E-cadherin inhibition thatdistinguish between E-cadherin's cell-cell adhesion and intracellular signaling functions. Whilethe disruption of cell-cell contacts alone does not enable metastasis in vivo, the loss of E-cadherinprotein does, through induction of an epithelial-to-mesenchymal transition (EMT), invasivenessand anoikis-resistance. E-cadherin binding partner f3-catenin is necessary but not sufficient forthese phenotypes. In addition, gene expression analysis shows that E-cadherin loss results in theinduction of multiple transcription factors, at least one of which, Twist, is necessary for Ecadherinloss-induced metastasis. These findings indicate that E-cadherin loss in tumorscontributes to metastatic dissemination by inducing wide-ranging transcriptional and functionalchanges.In addition to promoting metastasis, loss of E-cadherin and the accompanying EMTrenders cells resistant to conventional chemotherapeutic drugs. As the cells that have undergonean EMT represent the pool of cancer cells most competent to metastasize and lead to tumorrecurrence, it is of vital importance to find therapies that effectively target such cells. Paired celllines that differ in their differentiation state were utilized to discover compounds with selectivetoxicity against cells that have undergone an EMT. High-throughput screening of small moleculelibraries resulted in a number of compounds that specifically affect the viability of cells that haveundergone an EMT while having minimal cytotoxic effects on control epithelial cells. Thesestudies establish a proof-of-principle for discovering compounds that target highly metastatic andotherwise chemotherapy resistant cancer cells.
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