Stem cell based therapy of malignant brain tumors
Författare
Summary, in English
First, we investigated the frequency and properties of cancer stem cell (CSC)-like cells in the rat glioma models used in the present thesis. Virtually all cells within both glioma models concomitantly express CD133, nestin as well as the neural lineage markers glial fibrillary acidic protein, βIII-tubulin and CNPase in vitro and in vivo. Unsorted tumor cells displayed very high clonogenic capacity in vitro and robust tumorigenicity in vivo. Thus, CSC-like cells do not reside within a rare sub-population of cells in these glioma models but constitute most, or all, cells.
We next examined the subventricular zone (SVZ) response to growth of malignant glioma. Tumor growth resulted in decreased numbers of SVZ proliferating cells, increased SVZ neuroblast immunoreactivity, and migration of striatal neuroblasts from the SVZ toward glioma. Although endogenous neuroblast migration toward gliomas was of moderate magnitude, this indicates a region specific reparative mechanism in response to tumor growth. We continued by implanting rat SVZ-derived neural precursor cells (NPCs) and rat multipotent mesenchymal stroma cells (MSCs) into gliomas. Intratumorally implanted NPCs and MSCs migrated specifically within gliomas and largely avoided normal brain tissue. Importantly, implanted NPCs and MSCs did not proliferate within tumors. This indicates a low risk of development of secondary malignancies. A comparative analysis revealed higher survival and better intratumoral migratory capacity of implanted MSCs, compared to NPCs.
Intratumorally implanted MSCs migrated to the majority of the invasive glioma extensions and to a substantial fraction of distant tumor microsatellites. Furthermore, implanted MSCs integrated into tumor blood vessel walls and expressed pericyte markers but not endothelial cell markers. The pericyte marker expression profile and perivascular location of implanted MSCs indicate that these cells act as pericytes within tumors. MSC implantation did not, however, affect tumor microvessel density or the survival of glioma-bearing animals.
In summary, gliomas can attract endogenous striatal neuroblasts from the SVZ. However, intratumoral implantation of NPCs and MSCs yields a much more powerful, and tumor-specific, infiltration within gliomas. In particular, pericyte-like MSCs represent a well suited vector system for the delivery of therapeutic transgenes to vascularized and invasive gliomas.
Avdelning/ar
Publiceringsår
2008
Språk
Engelska
Publikation/Tidskrift/Serie
Lund University Faculty of Medicine Doctoral Dissertation Series
Volym
2008:123
Fulltext
- Available as PDF - 18 MB
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Dokumenttyp
Doktorsavhandling
Förlag
Avd för Neurokirurgi, Inst för kliniska vetenskaper, Medicinska fakulteten, Lunds Universitet.
Ämne
- Surgery
- Neurology
Nyckelord
- neural stem cell
- pericyte
- mesenchymal stem cell
- neuroblast
- subventricular zone
- cancer stem cell
- rat
- glioma
- cancer
Status
Published
Handledare
ISBN/ISSN/Övrigt
- ISSN: 1652-8220
- ISBN: 978-91-86059-76-7
Försvarsdatum
17 december 2008
Försvarstid
09:15
Försvarsplats
Segerfalksalen, BMC A10, Lunds Universitet
Opponent
- Bengt Westermark (Professor)