Biomedical Engineering Reference
In-Depth Information
tion of cytokine release from the tumor stroma. Cancer cells also are able to
proliferate beyond the normal regenerative capacity of the original untransformed
cell type. Extended replication potential is controlled in part through telomere
maintenance, a property associated with virtually all cancer cells [58]. This mech-
anism is commonly controlled in cancer through upregulation of expression of the
telomerase enzyme.
Cancer cells also exhibit properties associated with inducing and sustaining
angiogenesis, a process that appears to be required for tumor progression. Animal
models of tumorigenesis indicate that angiogenesis is a midstage property, occurring
prior to the appearance of malignancy (see [
55
]). Angiogenesis is mediated through
a complex interplay of regulatory factors, including vascular endothelial growth
factor (VEGF). In fact, many tumors exhibit transcriptional upregulation of VEGF.
The appearance of angiogenesis is often associated with the ability of tumor cells
to invade adjacent tissues and subsequently migrate systemically to preferred sites
(metastasis). Local invasion is mediated by changes in the expression of cell adhesion
molecules and integrins and in changes in the expression of extracellular proteases
such as MMP-2 and MMP-9. In some situations, these matrix-degrading proteases
are produced by tumor-associated stromal and inflammatory cells. Some cancer cells,
for example, induce urokinase expression in stromal cells, which then binds the
urokinase receptor to the cancer cells [59].
Another important mechanism in the progression of certain cancers is the epi-
thelial to mesenchymal transition (EMT) [60,61]. The differentiated epithelial phe-
notype is typically characterized by the polarization of the cell surface into apical
and basolateral domains and by a junctional complex that controls intercellular
adhesion. The occurrence of EMT in cancer is associated with the downregulation
of the expression of E-cadherin, a member of the classic cadherin family, which
controls cell polarity and tight junctions [61].
8.1.5
P
ROMOTION
OF
C
ANCER
BY
I
NFLAMMATION
Scientists have long suspected that chronic inflammation is intimately associated
with the promotion of cancer. In this regard, evidence for the involvement of inflam-
mation in cancer was provided by clinical studies correlating tumor infiltration of
immune cells with poor clinical outcome [62]. A causal role for inflammation and
cancer is suggested by studies reporting reduced cancer incidence in patients under-
going treatment with antiinflammatory drugs [63]. Since many antiinflammatory
compounds inhibit cyclooxygenase-2 activity, this enzyme has been suspected as
the primary target for prevention. Proteolytic enzymes, the transcription factor
NF-
B, and cytokines such as TNF are also believed to be functionally important
in potentiating inflammation-based cancer [62,64,65].
Although there are a number of examples whereby inflammation is implicated
or suspected in cancer progression (e.g., pancreatitis with pancreatic cancer and
gastritis with gastric cancer), probably the best studied link is between inflam-
matory bowel disease and colorectal cancer. Colitis is associated with an approx-
imate ten-fold increase in the risk of developing colorectal cancer, and this risk
κ
