Mitochondria in a personalized cancer treatment approach

259 Pages·2017·8.83 MB·English

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van Gisbergen, M. W. (2017). Mitochondria in a personalized cancer treatment approach. Maastricht:
Datawyse / Universitaire Pers Maastricht. https://doi.org/10.26481/dis.20170329mvg
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Published: 01/01/2017
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10.26481/dis.20170329mvg
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Mitochondria in a personalized cancer
treatment approach
UNIVERS

Cover
Cover design: Anna Karlström

Production
Printing: Datawyse | Universitaire Pers Maastricht
ISBN 978 94 6159 67 2 UM
PERS MAASTITRAICIRHET
©Copyright: Marike W. van Gisbergen, Maastricht, 2017.

P
Mitochondria in a personalized cancer
treatment approach

Proefschrift

ter verkrijging van de graad van doctor aan de Universiteit Maastricht,
op gezag van de Rector Magnificus, Prof. dr. Rianne M. Letschert,
volgens het besluit van het College van Decanen
in het openbaar te verdedigen
op woensdag 29 maart 2017 om 14:00 uur

door

Marike Willemijn van Gisbergen
Promotor
Prof. dr. P. Lambin

Copromotores
Dr. L.J. Dubois
Dr. A.M. Voets, Universiteit Hasselt

Beoordelingscommissie
Prof. dr. F.C.S. Ramaekers (voorzitter)
Prof. dr. R.P. Coppes, UMC Groningen
Dr. P. Willems, Radboud UMC Nijmegen
Prof. dr. L.P.A.J. Schrauwen
Dr. F. van Tienen
Contents
Chapter 1 General introduction and thesis outline 7
Chapter 2 How do changes in the mtDNA and mitochondrial dysfunction
influence cancer and cancer therapy? Challenges, opportunities and
models 25
Chapter 3 Distinct radiation responses after in vitro mtDNA depletion are
potentially related to oxidative stress 63
Chapter 4 Mitochondrial dysfunction inhibits hypoxia-induced HIF-1α
stabilization and expression of downstream targets 83
Chapter 5 New approach of delivering cytotoxic drugs towards CAIX expressing
cells: A concept of dual-target drugs 103
Chapter 6 Nitroglycerin`s influence on tumor hypoxia and perfusion in non-
small cell lung cancer: a window-of-opportunity trial 153
Chapter 7 Chemical reactivity window determines prodrug efficiency toward
glutathione transferase overexpressing cancer cells 179
Chapter 8 General discussion 213
Summary 231
Samenvatting 237
Valorization Addendum 243
Acknowledgements / Dankwoord 249
Curriculum Vitae 255
List of publications 257

5
Chapter 1
General introduction and thesis outline

7
General introduction and thesis outline
General introduction
Now-a-days cancer is one of the leading causes of death worldwide. In the Netherlands
alone already 43.214 deaths from cancer were registered for the year 2014 [1]. Cancer
is a generic term for many types of diseases, which all involve several common
characteristics and is used for both benign and malignant tumors. A cell mass that is
rapidly dividing and could potentially invade its surrounding tissues is often referred to
as a cancer. The abnormal growth of this cell population starts by sequential
accumulation of different DNA mutations inherited by cell division. Under normal
physiological conditions tissues have the capability to replace mutated cells. However,
when the normal cellular functions are compromised a benign tumor mass could arise.
Cells from a benign tumor are able to evade apoptosis; however, they don’t have the
capability to invade other tissues yet. When a cell population acquires additional
mutations, the rise of a malignant tumor may occur. Tumors display several
characteristics which enable the tumorigenic and/or metastatic potential of the cell
population and include sustained proliferative signaling, evading growth suppressors,
avoiding destruction by the immune system, enabling replicative immortality, tumor
promoting inflammation, invasion and metastatic potential, inducing angiogenesis,
genomic instability and genomic mutations, resisting cell death and deregulated cellular
energetics. Often these characteristics are referred to as the ‘Hallmarks of cancer’,
which have been comprehensively described by Hanahan and Weinberg [2, 3].
Treatment of malignancies is of great importance in order to increase survival and
quality of life of cancer patients. Now-a-days many cancer treatment options are
available in the clinic although the majority of the patients are currently still treated by
surgery, chemotherapy or radiotherapy, or a combination of those. The choice of
therapy is dependent on several factors such as the patient’s condition, the tumor’s
histopathology, stage and location. Different cancer types often do benefit from
additional hormone therapy [4, 5] or even immunotherapy [6]. Heterogeneity amongst
patients, but also amongst tumors and their microenvironment influence treatment
outcome. Also, heterogeneities in nutrient supply, proliferation, pH levels and oxygen
supply or consumption influence the treatment response. Knowledge of a tumor’s
status and the predictive power of treatment response could therefore improve
treatment efficacy and reduce treatment costs [7].
The role of the tumor microenvironment in tumor survival
The tumor and its microenvironment (TME) is a very complex but important system,
from which our understanding is gradually increasing. The TME consists out of blood
vessels, signaling molecules, the extracellular matrix and many cell types such as
9