Hypoxia-Inducible Factors in Tumor Cell Differentiation and Tumor Vascularization
Author
Summary, in English
The differentiation stage of tumor cells is recognized as an important clinical factor in several malignancies including neuroblastoma. Tumors with an immature phenotype are more aggressive than differentiated tumors. Moreover, recent hypotheses on tumor progression stipulate that maintenance of tumor growth is dependent on immature cells called tumor-initiating cells (TICs).
Here, we identify HIF-2alpha as a marker of immature neuroblastoma cells and TICs isolated from patient bone marrows irrespective of oxygen levels. We further demonstrate that HIF-2alpha is required to maintain the undifferentiated state, as knockdown of HIF-2alpha induced differentiation. Knockdown of HIF-2alpha revealed a role for HIF-2alpha in recruitment of new blood vessels to experimental neuroblastomas, as the resulting xenograft tumors were highly necrotic.
In addition and in agreement with in vitro data, we show that HIF-1alpha and HIF-2alpha proteins are differentially regulated in clinical neuroblastomas. While both proteins correlated with expression of VEGF, only HIF-2alpha was associated with aggressive disease and only HIF-1alpha correlated with tumor hypoxia.
Finally, we demonstrate a novel mechanism of HIF regulation of endothelial tube formation via Notch regulation. HIF-dependent JAG2 induction in hypoxic tumor cells alters Notch activity in tumor cells and adjacent endothelial cells and thus represents a novel layer of complexity of hypoxia/Notch interplay.
Together, our findings reveal novel roles of HIFs in regulation of tumor cell differentiation and tumor vascularization.
Department/s
- Department of Translational Medicine
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
Publishing year
2010
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2010:16
Document type
Dissertation
Publisher
Lund University
Topic
- Cancer and Oncology
Keywords
- HIF-2alpha
- cancer
- notch
- angiogenesis
- tumor-initiating cells
- hypoxia
- neuroblastoma
- differentiation
Status
Published
Supervisor
- Sven Påhlman
- Helen Pettersson
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-86443-30-6
Defence date
12 March 2010
Defence time
09:00
Defence place
Main lecture hall, Pathology Building, Entrance 78, 2 fl. UMAS, Malmö
Opponent
- Randall Johnson (Professor)