Glioblastoma Multiforme (GBM), the most prevalent and lethal primary brain tumor,
typically shows the formation of hypercellular regions called pseudopalisades which usually
surround necrotic cores and thrombosed vessels and are almost exclusive of this tumor
type. In addition, pseudopalisades over express hypoxia‐inducible factors and secrete
prothrombotic factors such as tissue factor [1].
We discuss how these regions represent a wave of tumor cells actively migrating away from
central hypoxia after a vascular insult as it was proposed in [2]. The irreversible impact of
hipoxia events in tumor evolution will also be discussed as well as the therapeutical
implications of our results and how the combination of antioxidants and antithrombotics,
with very low or none toxicities, reduces tumor invasion and sensitizes GBM cells to
conventional radiotherapy and chemotherapy, hopefully increasing median patient survival
times.
Our results suggest that therapeutic approach targeting blood coagulation decreases tumor
invasion although its effect is limited in monotherapy [3].This is mainly due to the fact that
an inefficient local tumor oxygenation in the tumor even during very short periods of time
may lead to irreversible tumor cell transformation to more aggressive phenotypes [4].
Finally, we show that an appropriate combination of antioxidants and antithrombotics, with
minor toxicity, may substantially slow down tumor invasion and sensitize GBM to
conventional therapies such as radiotherapy and temozolamide [5].
The theoretical approach is based on different mathematical models constructed on the
basis of the migration/proliferation dichotomy hypothesis, and incorporate the interplay
among several cell phenotypes, a necrotic core and the vasculature that evolves with the
tumor progression. The experimental verification of our ideas, to be discussed in this talk, has used: (i) experiments in controlled microfluidic devices and (ii) Different stainings of
tumor tissue and pathology analysis to test the pseudopalisading hypothesis, (iii) in vitro and
in vivo experiments to test the effectivity of the combined therapies (xenografts in mice and
orthotopic tumor transplants with rats and mice).
The potential application of these results into the clinical practice is under study.

[1] Louis, D. N., Ohgaki, H., Wiestler, O. D. & Cavenee, W. K. (2007) World Health
Organization Classification of Tumours of the Central Nervous System, 4th edn. Geneva:
Renouf Publishing Co. Ltd.
[2] Rong, Y., Durden, D. L., Van Meir, E. G. & Brat, D. J. (2006) ’Pseudopalisading’ necrosis in
glioblastoma: A familiar morphologic feature that links vascular pathology, hypoxia, and
angiogenesis. J. Neuropathol. Exp. Neurol., 65, 529–539.
[3] A. Martínez‐González, G. F. Calvo, L. Pérez‐Romasanta, V. M. Pérez‐García. Hypoxic cell
waves around necrotic cores in glioblastoma: A mathematical model and its therapeutical
implications, Bulletin of Mathematical Biology 74, 2875‐2896 (2012).
[4] V. M. Pérez‐García and A. Martínez‐González. Hypoxic ghost waves accelerates the
progression of high‐grade gliomas. Journal of Mathematical Biology (submitted) (2013).
[5] A. Martínez‐González, M. Durán‐Prado, G. F. Calvo, F. J. Alcaín, L. Pérez‐Romasanta, V. M.
Pérez‐García. Combined therapies of antithrombotics and antioxidants delay in silico brain
tumor progression Mathematical Medicine and Biology, doi: 10.1093/imammb/dqu002
(2014).