Biomedical Engineering Reference
In-Depth Information
environment, the tumor, and the tumor vasculature. The expression of cytokines,
integrins, and growth factors can vary considerably between organs, resulting in
different molecular, biochemical, and physiologic properties of tumors growing in
different environments.
A recent study published by Park et al. [
59
] utilized a “systems” approach to
investigate the microenvironmental influence on gene expression profiles of cell-
line-based tumors growing either subcutaneously, orthotopically (growing in the
appropriate organ) or in the brain. Interestingly, the expression profiles of the
tumors growing subcutaneously and orthotopically generally clustered with the
original cell line. Yet, the tumors growing in the brain had a significantly different
expression pattern than their respective cell lines. The cells from tumors implanted
in the brain had neuronal cell characteristics, clustering with normal mouse brain
samples, indicating a complete “reprogramming” of the cells.
Additional studies have shown that enzymes critical in the processes of invasion
and metastases, such as the extracellular matrix (ECM) degradation enzyme type IV
collagenase and plasminogen activators, are regulated by serum factors, growth
factors, and tumor cell-ECMmatrix interactions [
54
,
58
]. Tumor microenvironment
is also critical in angiogenesis regulation. cDNA expression profiles of endothelial
cells isolated from different organ environments have shown differential expression
of RTKs and chemokine receptors [
48
] and have demonstrated that endothelial cells
originating from different organs exhibited marked differences in response to
stimulation by different mitogens. Evidence to the effect of tumor organ environ-
ment on therapeutic response has been demonstrated in preclinical models [
92
] and
clinical observations also suggest that anatomic location of metastases plays a
critical role in determining response to therapy [
18
].
Despite the known involvement of microenvironment in disease pathophysiol-
ogy, there are currently only a handful of examples of molecular systems biology
models being extended to the tissue, organ, or multi-organ level [
4
,
5
,
17
,
29
]. The
need for integrative multi-scale models for basic and translational cancer research
has been recognized. The National Cancer Institute (NCI) established the Integra-
tive Cancer Biology Program which is focused on the development and use of
computational models to study prevention, diagnostics, and therapeutics in cancer
as a “system” (
http://icbp.nci.nih.gov/
)
. As part of this program, the Center for the
Development of a Virtual Tumor (CViT) was established and their goal is develop-
ing multi-scale models of cancer and the community to carry this out [
16
].
12.4.2 Organism Level
As stated earlier, the most common type of pharmacology modeling at the organism
level is pharmacokinetic or pharmacokinetic-pharmacodynamic modeling. PK-PD
models represent valuable tools that allow us to quantitatively relate dose to
concentration to effect. However, the vast majority of PK-PD studies conducted
assume that the free plasma concentration is reflective of the concentration at the
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