Serous ovarian adenocarcinoma (SOC) is one of the most devastating diseases among women worldwide. Despite improvements in early diagnosis and therapy in the last decades, the five-year survival rate remains at 30%. Poor prognostic outcome can be mainly explained by the fast relapse rate observed in most patients after cytoreductive surgery and chemotherapeutic treatment. Of note here is that intrinsically resistant cell populations, the so-called cancer stem cells, have been recently associated with tumor recurrence, treatment failure and subsequent disease relapse. However, the lack of models that faithfully recapitulate the heterogeneity of serous ovarian cancer hindered so far the study of these phenotypically and functionally heterogeneous cancer cells. Hence, the aim of this thesis was to establish and to evaluate a personalized model system that fully mimics SOC. Furthermore, this novel model system serves as a platform to study the cellular and molecular processes involved in metastasis development and drug resistance, as well as to identify tumor initiating cell populations. Our advanced model system combines serum-free culture of primary cancer cells with xenotransplantation assays. Xenograft tumors established upon transplantation of primary SOC cells show histopathological features of SOC and express the two clinically used SOC specific markers CA125 and WT1. We were able to demonstrate that this model system displays major hallmarks of SOC such as the development of ascites and metastatic colonization of the diaphragm. Additionally, the molecular characteristics of the respective tumor are preserved throughout our models and the recently identified four transcriptional subtypes of SOC are conserved within our in vitro cultured primary cell lines as well as the corresponding xenograft tumors. Using this model system, we were able to identify the heterogeneously expressed surface marker CD151, which defines a functionally different subpopulation within the tumor. Xenotransplantation assays demonstrated that exclusively CD151+ cells possess tumor initiation capacity whereas CD151- cells do not. Gene expression profiling predicted a selective subpopulation-specific activation of various proliferation-associated pathways in CD151+ cells. Determination of the phosphorylation status of key pathway members of the JNK/MAPK- and EGFR signaling as well as members of the Src kinases (SFKs) verified these findings. Ablation of CD151 almost completely abrogated the activating phosphorylation suggesting CD151 to play a central in regulation of described pathways. Analysis of a patient cohort, comprising 489 SOC patients, resulted in a significant correlation of CD151 expression with an advanced disease stage and a shorter overall survival in low-grade tumor patients. Taken together, our data indicate that CD151 defines a tumor initiating subpopulation of cells in SOC and also plays a functional role in mediating the activation of various proliferative pathways. Thus, CD151 should be evaluated as a prognostic marker as well as a target of therapeutic treatment in SOC.
|Supervisor:||Trumpp, Prof. Dr. Andreas|
|Date of thesis defense:||17 September 2013|
|Date Deposited:||11 Oct 2013 08:48|
|Faculties / Institutes:||The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences|
|Subjects:||570 Life sciences|
|Controlled Keywords:||Tumor Initiating Cells, Ovarian Cancer, Ovarian Cancer Subtypes, CD151|