Biomedical Engineering Reference
In-Depth Information
classified into different disease types by the type of cell it originates from.
65
In
neuroepithelial tissues there are more than 100 entities that have been
discovered.
66
This cancer heterogeneity has been imaged in tissue specimens
using antibody staining combined with quantum dots.
67
Heterogeneity in the
tumor environment also explains how EPR is not equally present in all tumors.
Variability in the environment is apparent in the tumor vasculature
(Figure 1.4). Beyond shape, architecture, and density, tumors show differences
in vascular permeability based on the type of tumor, location in the body,
location in the tumor, hormone concentrations, and state of growth or
regression of the tumor.
68-70
Unfortunately, heterogeneity in tumor vascu-
lature makes it difficult to know specific size cutoffs for carrier sizes targeting
the EPR effect. Still, it may be possible to try to increase permeability in the
tumor with hyperthermia or with iRGD peptides, the latter having been
classified as tumor penetrating peptides.
71,72
It also may help to artificially
increase the vascular pressure to slightly improve tumor extravasation.
73,74
Once the particle extravasates, it is confronted with a wall of dense packing
in the tumor environment. Part of this environment is the ECM that is found
in a state of flux, where the ECM of normal tissue is being broken down to
make room for cancer cells that are secreting proteins for new ECM to support
the growing tumor.
75
The support comes in the form of survival signals,
inhibition of the immune system, limited diffusion of drug particles, and
enabling cancer invasion and metastasis.
76-78
This new ECM is analogous to
the biofilm that bacterial colonies will form for protection and continued
growth. The ECM has a higher stiffness and viscosity due to more fibronectin,
collagen I, and crosslinking agents which limit diffusion and also have an effect
on the interstitial fluid pressure (IFP).
79-81
While absolute values will vary patient to patient, the IFP is higher towards
the center of the tumor environment.
82,83
The pressure results from both
hydraulic and osmotic factors. There is a constant hydraulic pressure from the
arterioles and capillaries that drives fluid and solutes into the tumor
environment. Solutes flow into the interstitium from the blood vessels and
accumulate into the dense packing of matrix and cells to create an osmotic
pressure. Lack of functional lymphatics prevents an outlet and equalization of
these pressures. Hence, the high IFP presents an opposition for macro-
molecules that could otherwise be transported by bulk flow and penetrate into
the tumor core.
84
Interstitial pressure also seems to be affected by contractile
stromal cells in the tumor environment.
85-87
There is a diverse collection of cells, cancerous and noncancerous, in the
tumor environment. This diversity in cell types plays a role in how cancers
resist treatment. For example, immune cells such as myeloid-derived
suppressor cells and CD25+ T cells can be present in tumors and suppress
the immune response against cancer cells.
88,89
While there are different types of
cells in the tumor environment, there are also differences among the cancer
cells. Among the cancer cell population, there is a subdivision of cells that are
cancer stem-like cells.
90
d
n
4
y
3
n
g
|
1
The properties of stem-like cancer cells make them a
