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Sleeman J.P.,University of Heidelberg | Sleeman J.P.,Karlsruhe Institute of Technology | Christofori G.,University of Basel | Fodde R.,Erasmus University Rotterdam | And 6 more authors.
Seminars in Cancer Biology | Year: 2012

The ability of tumor cells to leave a primary tumor, to disseminate through the body, and to ultimately seed new secondary tumors is universally agreed to be the basis for metastasis formation. An accurate description of the cellular and molecular mechanisms that underlie this multistep process would greatly facilitate the rational development of therapies that effectively allow metastatic disease to be controlled and treated. A number of disparate and sometimes conflicting hypotheses and models have been suggested to explain various aspects of the process, and no single concept explains the mechanism of metastasis in its entirety or encompasses all observations and experimental findings. The exciting progress made in metastasis research in recent years has refined existing ideas, as well as giving rise to new ones. In this review we survey some of the main theories that currently exist in the field, and show that significant convergence is emerging, allowing a synthesis of several models to give a more comprehensive overview of the process of metastasis. As a result we postulate a stromal progression model of metastasis. In this model, progressive modification of the tumor microenvironment is equally as important as genetic and epigenetic changes in tumor cells during primary tumor progression. Mutual regulatory interactions between stroma and tumor cells modify the stemness of the cells that drive tumor growth, in a manner that involves epithelial-mesenchymal and mesenchymal-epithelial-like transitions. Similar interactions need to be recapitulated at secondary sites for metastases to grow. Early disseminating tumor cells can progress at the secondary site in parallel to the primary tumor, both in terms of genetic changes, as well as progressive development of a metastatic stroma. Although this model brings together many ideas in the field, there remain nevertheless a number of major open questions, underscoring the need for further research to fully understand metastasis, and thereby identify new and effective ways of treating metastatic disease. © 2012 Elsevier Ltd.


Raspe E.,Unit of Molecular and Cellular Oncology | Raspe E.,Ghent University | Decraene C.,University Pierre and Marie Curie | Decraene C.,French National Center for Scientific Research | And 2 more authors.
Seminars in Cancer Biology | Year: 2012

Despite advances in chemotherapy, hormone therapy and radiotherapy, not all cancer patients respond favorably to treatment. However, progress in understanding the mechanisms of malignant diseases and the mode of action of therapies are opening opportunities to match treatment to specific patient subpopulations, paving the way for personalized medicine. In this context, high throughput technologies that have been developed to determine gene expression profiles potentially offer an effective tool for dissecting the biology of cancer pathologies, for identifying candidate molecules for the development of new drugs, and for identifying individual patients who are more likely to respond favorably to a given therapy. Here, we overview and discuss the robustness of the deployment of these technologies in these contexts. We conclude that while these technologies are useful for target identification, there are limitations to their use in understanding cancer biology and in routine clinical application. © 2012 Elsevier Ltd.


Gheldof A.,Unit of Molecular and Cellular Oncology | Gheldof A.,Ghent University | Berx G.,Unit of Molecular and Cellular Oncology | Berx G.,Ghent University
Progress in Molecular Biology and Translational Science | Year: 2013

Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells are transcriptionally reprogrammed, resulting in decreased adhesion and enhanced migration or invasion. EMT occurs during different stages of embryonic development, including gastrulation and neural crest cell delamination, and is induced by a panel of specific transcription factors. These factors comprise, among others, members of the Snail, ZEB, and Twist families, and are all known to modulate cadherin expression and, in particular, E-cadherin. By regulating expression of the cadherin family of proteins, EMT-inducing transcription factors dynamically modulate cell adhesion, allowing many developmental processes to take place. However, during cancer progression EMT can be utilized by cancer cells to contribute to malignancy. This is also reflected at the level of the cadherins, where the cadherin switch between E- and N-cadherins is a classical example seen in cancer-related EMT. In this chapter, we give a detailed overview of the entanglement between EMT-inducing transcription factors and cadherin modulation during embryonic development and cancer progression. We describe how classical cadherins such as E- and N-cadherins are regulated during EMT, as well as cadherin 7, -6B, and - 11. © 2013 Elsevier Inc.


Gheldof A.,Unit of Molecular and Cellular Oncology | Gheldof A.,Ghent University | Hulpiau P.,Ghent University | Van Roy F.,Ghent University | And 5 more authors.
Cellular and Molecular Life Sciences | Year: 2012

ZEB1 and ZEB2, which are members of the ZEB family of transcription factors, play a pivotal role in the development of the vertebrate embryo. However, recent evidence shows that both proteins can also drive the process of epithelial-mesenchymal transition during malignant cancer progression. The understanding of how both ZEBs act as transcription factors opens up new possibilities for future treatment of advanced carcinomas. This review gives insight into the molecular mechanisms that form the basis of the multitude of cellular processes controlled by both ZEB factors. By using an evolutionary approach, we analyzed how the specific organization of the different domains and regulatory sites in ZEB1 and ZEB2 came into existence. On the basis of this analysis, a detailed overview is provided of the different cofactors and post-translational mechanisms that are associated with ZEB protein functionality. © Springer Basel AG 2012.


Herfs M.,University of Liege | Hubert P.,University of Liege | Suarez-Carmona M.,University of Liege | Reschner A.,University of Liege | And 5 more authors.
American Journal of Pathology | Year: 2010

TP63 is a p53-related gene that contains two alternative promoters, which give rise to transcripts that encode proteins with (TAp63) or without (ΔNp63) an amino-transactivating domain. Whereas the expression of p63 is required for proper development of epithelial structures, the role of p63 in tumorigenesis remains unclear. Here, we investigated the role of Snail and Slug transcription factors, known to promote epithelial-to-mesenchymal transitions during development and cancer, in the regulation of p63 isoforms in human squamous cell carcinoma (SCC). In the present study, we observed that the expressions of ΔN and TAp63 isoforms were, respectively, down- and up-regulated by both Snail and Slug. However, the induction of TAp63 was not directly caused by these two transcription factors but resulted from the loss of ΔNp63, which acts as dominant-negative inhibitor of TAp63. In SCC cell lines and cancer tissues, high expression of Snail and Slug was also significantly associated with altered p63 expression. Finally, we showed that ΔNp63 silencing reduced cell-cell adhesion and increased the migratory properties of cancer cells. These data suggest that the disruption of p63 expression induced by Snail and Slug plays a crucial role in tumor progression. Therefore, p63 and its regulating factors could constitute novel prognosis markers in patients with SCC and attractive targets for the therapeutic modulation of neoplastic cell invasiveness. Copyright © American Society for Investigative Pathology.

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