Role of transforming growth factor beta in human glioblastoma multiforme cancer stem cells and in tumorigenesis
Year: 2013
Type: dissertation
Abstract: The function of TGF-beta in glioblastoma cancer stem cells (GBM CSC) was unknown at the beginning of this thesis. In a series of 9 different CSC lines, I observed varying response of the cell lines to TGF-beta incubation. Most of the cell lines were completely resistant, 2 cell lines showed growth inhibition and surprisingly in one of the cell lines there was growth promotion. A detailed characterization of the effects of TGF-beta showed that TGF-beta did not modulate bona fide stem cell properties but rather proliferation and migration in vitro. In vivo TGF-beta significantly modulated the tumor size of TGF-beta treated and orthotopcially implanted CSC. However, the responsiveness to TGF-beta was not random. Earlier reports of my group suggested that different types of CSC lead to the formation of GBM. These two groups show distinct transcriptional profiles and display substantial differences with respect to TGF-beta related transcripts. The experiments in this thesis now prove that the assignment to a specific CSC type was associated with the role of TGF-beta in the respective CSC lines in vitro and in derived GBM in vivo. In summary, TGF-beta acts either as paracrine immunosuppressor in CD133+ proneural-like CSC and GBM or as tumorpromoter/-suppressor in CD133- mesenchymal-like CSC and GBM. This heterogeneity in response to TGF-beta has substantial implication for various anti-TGF-beta therapies presently underway as it could be counter-productive in GBM in which it acts as tumor suppressor. In addition, the reduced immune-paralysis in mesenchymal GBM makes them optimal targets for immunotherapies. In the second part I focused on the role of TGF-beta in the NSC from SVZ of mice lacking p53 and compared the results with similar NSC from mice that had p53. In line with the published results it was observed that the p53-/- cells proliferated faster than p53+/+ cells. Importantly, the p53+/+ but not p53-/- cells showed proliferation arrest in response to TGF-beta treatment. This lack of response was observed even though the major components of TGF-beta signaling were intact. Conversely, the blocking TGF-beta signaling in p53+/+ cells showed enhanced proliferation whereas there was no change in case of p53-/- cells suggesting that the loss of inhibitory autocrine TGF-beta signaling on NSC contribute to the proliferation of NSC after loss of p53 activity. Given that mounting evidence suggest the origin of GBM CSC from NSC, this study provides cues to the initial steps in the origin of GBM from NSC. Taken together, alteration of TGF-beta signaling is an early event in the genesis of GBM and remain of relevance in GBM although with variable biological function.
Source: RWTH Publications (RWTH Aachen)
Authors: Praveen Kumar, Christoph P. Beier
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2697924476