| dc.description.abstract | Carcinomas are most prevalent type of cancers and arise from an epithelial layer. Epithelial layers have a strict organization; cells are tightly linked through different junctions. The Epithelial to Mesenchymal Transition (EMT) developmental program enables epithelial cells to transform into mesenchymal cells and break free from neighboring epithelial cells in order to migrate though the body. Also in carcinomas, EMT enables cells to invade into healthy tissue. EMT also aids cancer progression in other manners by suppressing senescence, anoikis, apoptosis, oncogene addiction and modulating the immune response. Furthermore, EMT can lead to the formation of mesenchymal cancer stem cells. Mesenchymal cancer stem cells seem to be more resistant to chemotherapy than epithelial cancer cells. All of these traits increase the chance of an invading cancer cell being successful in setting up a metastatic niche. The cadherin switch from E-cadherin to N-cadherin is considered a mark of EMT. Cadherins are cell-cell adhesion proteins. E-cadherin inhibits invasion by protecting epithelial integrity and N-cadherin increases invasion. It seems that a part of carcinomas has an E- to N-cadherin switch during EMT. However, other carcinomas show other cadherin switches and E- and N-cadherin expression is not always mutually exclusive. In the HMLE cancer cell line E-cadherin knockdown is enough to induce EMT. By knocking out E-cadherin and p53 in a tissue specific manner they show an increase of invasion and metastases. In gastric carcinoma model E-cadherin and p53 knockout leads to EMT, however, in an invasive lobular carcinoma model EMT has not been observed. If EMT could be inhibited in carcinomas, the chance of metastasis would decrease and the formation of new cancer stem cells would be inhibited. Since chemotherapy mainly targets epithelial cancer cells, combining an EMT inhibitor might lead to more efficient chemotherapy. There are some compounds capable of inhibiting EMT or promoting the reverse process Mesenchymal to Epithelial Transition (MET). The identified compounds either inhibit a pathway which induces EMT or lead regaining epithelial identity and re-expression of E-cadherin. These compounds need to be further tested using in vivo models. Antibodies targeting mesenchymal marker proteins are being developed as well. An anti N-cadherin antibody shows a decrease of tumor growth and metastases in mice, perhaps by targeting mesenchymal cancer stem cells. Since chemotherapy does not efficiently target cancer stem cells, screens were performed to find compounds that target cancer stem cells. In the future, there may be a combined anticancer therapy developed which inhibits EMT and targets cancer stem cells. This type of therapy could be combined with chemo-, radiotherapy or surgery to treat carcinomas more efficiently. | |
