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CHA PTE R

On the Simulation of Organ-on-Chip

Cell Processes

Application to an In Vitro Model of Glioblastoma Evolution

,†
Jacobo Ayensa-Jim enez* , Mohamed H. Doweidar* ,†,‡,§ ,
,†
Teodora Randelovic* , Luis. J. Ferna ´ndez* ,†,‡,§ , Sara Oliva ´n* ,†,‡,¶ ,
Ignacio Ochoa* ,†,‡,¶ , Manuel Doblar e* ,†,‡,§
†
*Arago ´n Institute of Engineering Research (I3A), University of Zaragoza, Zaragoza, Spain Institute of Health Research of
‡
Aragon (IIS), Zaragoza, Spain Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine
§
(CIBER-BBN), Madrid, Spain Mechanical Engineering Department, School of Engineering and Architecture (EINA),
¶
University of Zaragoza, Zaragoza, Spain Human Anatomy and Histology Department, Faculty of Medicine, University of
Zaragoza, Zaragoza, Spain

16.1 INTRODUCTION

Cancer is the leading cause of death in developed countries and second in the developing ones [1]. Out of the 14.1
million new cancer diagnoses in 2012 worldwide, there were 8.2 million deaths and, at that time, 32.6 million people
living within 5 years of diagnosis. Furthermore, the Globoscan 2012 database [2] estimates a 27% overall increase in
cancer incidence by 2035, whereas the death count will rise 78% by that year. This means that approximately 15–20
million people will die of cancer every year in the upcoming two decades. And all this, despite the immense research
effort made in recent years. The main reason for this is the extreme complexity of the processes involved in cancer
development. In fact, the cancer landscape has dramatically changed in recent years, demonstrating that it is much
more complex than initially thought. Old paradigms focused only on tumor cells and genetics have now turned into
a new scenario that integrates different cell populations, extracellular matrices, chemotactic gradients (oxygen or nutri-
ents), and physical cues such as local deformation [3–6], all conforming a complex, dynamic, and multiple interactive
tumor microenvironment (TME) [7].
Furthermore, tumor cells evolve differently within the same tumor, with different evolution paths and specific
microenvironments for each type of cancer and tissue, thus explaining their high heterogeneity [8]. Whereas normal
cells require specific physiological signals to proliferate, tumor cells can divide independently of these signals and
ignore antigrowth ones. Besides, they acquire limitless replicative potential and are capable of evading apoptosis sig-
nals [9]. In this situation, exacerbated consumption of oxygen and nutrients leads to hypoxia and nutrient starvation,
thus subjecting cells to extreme stress. This harsh environment favors survival of cells capable of resisting and adapting
themselves to these highly demanding conditions. This lack of nutrients and oxygen also activates other mechanisms,
such as autophagy or regulation of oxidative stress [10]. Moreover, tumor cells are also able to change their TME, for
example, by promoting new blood vasculature that increases the supply of oxygen and nutrients to maintain their
growth as well as colonizing new tissues through metastasis [11]. Finally, when a given treatment (surgery,
chemo-, radio-, immune-, hormone, or combination therapy) is applied, the tumor and its TME undergo significant
alterations.
Due to the complexity, heterogeneity, and dynamic changes that take place in the TME, it is difficult to investigate,
in vivo, in a precise way, all interactions in the tumor and the surrounding stroma. A good reproduction in vitro of the

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