Cover Page
The handle http://hdl.handle.net/1887/19152 holds various files of this Leiden University dissertation.
Author: Mohseny, Alexander Behzad
Title: Osteosarcoma models : understanding complex disease Date: 2012-06-27
O STEOSARCOMA M ODELS:
U NDERSTANDING C OMPLEX D ISEASE
ii
Osteosarcoma Models: Understanding Complex Disease
Thesis, University of Leiden – with references – with a summary in Dutch
ISBN: 978-94-6203-067-1
Cover art: “lateral thinking” by Irene Sein
Printed by:
WÖHRMANN PRINT SERVICE,Zutphen, The Netherlands
©2012, Leiden University, Leiden, The Netherlands
O STEOSARCOMA M ODELS:
U NDERSTANDING C OMPLEX D ISEASE
Proefschrift
ter verkrijging van
de graad van Doctor aan de Universiteit Leiden,
op gezag van Rector Magnificus prof. mr. P.F. van der Heijden, volgens besluit van het College voor Promoties
te verdedigen op 27 juni 2012 klokke 10:00 uur
door
Alexander Behzad Mohseny geboren te Herat
in 1985
iv
Promotiecommissie
Promotor: Prof. Dr. P.C.W. Hogendoorn Co-promotor: Dr. A.M. Cleton-Jansen Overige leden: Prof. Dr. P. ten Dijke
Prof. Dr. W.E. Fibbe Prof. Dr. A.J. Gelderblom Dr. K. Szuhai
Prof. Dr. J. Kirpensteijn (Universiteit Utrecht) Prof. Dr. A.B. Hassan (Oxford University, UK)
The work presented in this thesis was financially supported by the
Dutch Cancer Society (KWF) [grant number UL2008-4060] and by
EuroBoNet, a European Commission granted Network of Excellence
for studying the pathology and genetics of bone tumours [grant
number LSHC-CT-2006-018814].
“Making the simple complicated is commonplace;
making the complicated simple, awesomely simple, that’s creativity”
Charles Mingus (American jazz bassist and Composer, 1922-1979)
Aan mijn ouders
Table of contents
Chapter 1) Introduction
1.1 Aims and outline 10
1.2 General introduction to osteosarcoma 12
1.3 Osteosarcoma models 20
Chapter 2) Cell of Origin
2.1 MSCs transformation 36
2.2 MSC origin of sarcoma 52
Chapter 3) Etiology
3.1 Loss of CDKN2A/p16 66
3.2 Genomic instability 80
3.3 The WNT pathway 90 3.4 Smad mediated pathways 104
Chapter 4) Progression & Targets for Treatment
4.1 Characterization of Cell Lines 118 4.2 High-throughput Zebrafish Model 132
Chapter 5) Conclusion
5.1 General summary and future perspectives 148 5.2 Nederlandse samenvatting 154
5.3 Dankwoord 160
5.4 Curriculum Vitae 162
5.5 List of publications 163
5.6 Addenda 164
