We would like to acknowledge and thank the NCI Physical Science and Oncology Centers and the Tri-Institutional

Training Program in Computational Biology and Medicine for funding this work.
Yu-Kang Cheng
123
, Eric C. Holland
2
, Franziska Michor
1
1
Dana-Farber Cancer Institute and Harvard School of Public Health,
2
Memorial Sloan-Kettering Cancer Center,
3
Weill Cornell Medical College and Tri-Institutional Training Program in Computational Biology and Medicine
Spatial Modeling of the
Brain Tumor Perivascular Niche
Abstract
Glioblastomas are heterogeous in nature, intermingling with
a wide range of stromal cells. These cells include vascular
cells, microglia, and other cell types that provide a
specialized niche for stem-like tumor cells (BTSCs). These
interactions result in spatio-temporal dynamics that are not
well characterized by population averages. Current
mathematical models of cancer, derived at the population
level, are not well suited for examining the effects of
intercellular signaling with this perivascular niche. Here we
propose a multiscale agent-based model of perivascular
niche dynamics that links phenomena occurring at the
subcellular, cellular, and tissue levels. This model can be
used to test hypotheses concerning the role of
microenvironmental signals in the maintenance of the brain
tumor stem cell population and their effects on therapeutic
interventions.
Purpose
Methodology
Develop a spatially accurate model of the perivascular
zone in brain cancers
Optimize radio- and chemo-therapy given drug
diffusivity and cell type sensivity
Consider the effects of spatial variation in and
interaction between cell types across the PVN, and
changes in population structure during mutation
accumulation
Chaste
Parameters
Further Directions
Incorporate further micorenvironment factors
Add mutation-dependent effects to cells
Build an array of blood vessels to consider regions of
pseudopalisading necroses
Extend the model into 3D space
d
RADIUS
2.5-3.5 Width of blood vessel
d
MICRO
3-5 Microenvironment width
t
STEM
20-30 hours Stem cell cycle length
t
TUMOR BULK
12-14 hours Progenitor cell cycle length
m
TUMOR BULK
4-6 Number of tumor bulk cell divisions
p
REVERT
0.2 Probability of dedifferentiation
p
MICRO
0.2 Probability of microenvironment
d
CHEMO
5 Spread of drug
1 Drug distribution parameter

STEM
0.001 Radiation death in stem cells

TUMOR BULK
0.1 Radiation death in tumor bulk cells
Initial State
Cells are initialized at varying times in their cell cycle, and a
200 hour time is given to allow full development of the
PVN.
Chemotherapy: Continuous low dose
Radiotherapy: Pulsed, 1 hour every 24 hours
Cell Division
Microenvironment
BTSC
Tumor Bulk: i m
TUMOR BULK
Terminal Differentiation: i = m
TUMOR BULK
+ 1
+
i i+1 i+1
+
i i+1 i+1
+
1
Apoptosis
Reversion
pREVERT
The Perivascular Niche
Blood Vessel
tSTEM
tTUMOR BULK
tTUMOR BULK
References
1. Hambardzumyan D, Becher OJ, Rosenblum MK, Pandolfi
PP, Manova-Todorova K, et al. (2008) PI3K pathway
regulates survival of cancer stem cells residing in the
perivascular niche following radiation in medulloblastoma in
vivo. Genes Dev 22: 436-448.
2. Charles N, Holland EC (2010) The perivascular niche
microenvironment in brain tumor progression. Cell Cycle 9:
3012-3021.
3. Pitt-Francis J, Bernabeu MO, Cooper J, Garny A, Momtahan
L, et al. (2008) Chaste: using agile programming techniques
to develop computational biology software. Philos Transact A
Math Phys Eng Sci 366: 3111-3136.
Chaste (Cancer, Heart and Soft Tissue Environment) is an
agent-based modeling simulation package designed for
multi-scale, computationally demanding biological problems
involving cellular interaction and physiology. For our
purposes, this framework provides various C++ classes for
a variety of cell cycle models, cell types, population
structures, cellular mechanics, and cell killers, which can
then be extended to fit the tissue of interest. The package
is being developed by a team mainly based in the
Computational Biology Group at Oxford University
Computing Laboratory [3].
0 hr 50 hr 100 hr
150 hr 200 hr

STEM

TUMOR BULK
e-/dCHEMO
Blood Vessel Microenvironment BTSC Tumor Bulk Differentiated Apoptotic
Results
Radiation has no effect on stem cell counts.
Chemotherapy maintains stem cell counts, but does not
decrease them.
Both treatments decrease cell counts in the tumor bulk,
however, the combination is more effective than the sum of
their effects.
Stem cell distance remains consistent with or without
treatment.
Both treatments decrease tumor bulk size, however, the
combination is more effective than the sum of their effects.
Endothelial (CD34)
[2]
Macrophage
Astrocyte Fibroblast BTSC
Microglia
Tumor Bulk
Endothelial
Tumor Bulk (DAPI)
Stem (nestin)
[1]