Biomedical Engineering Reference
In-Depth Information
2. At the G1 cell cycle checkpoint, also termed the restriction point, normal cells detect the
composition of growth/antigrowth signals including cytokines and nutrients in their envi-
ronment, and then decide whether or not to enter another round of cell division. One key
effector halting the cell cycle at G1 is the retinoblastoma protein (pRb). Hypophosphorylated
pRb blocks cell proliferation by sequestering E2f family transcription factors, thereby
inhibiting the binding of these to DNA so that the genes required for entry into the
S
phase of the cell cycle are not expressed. Deletion of pRb is frequent in cancers and thus
represents one of the most common means by which cancer cells obtains resistance to
antigrowth signals.
3. Evading apoptosis, or programmed cell death, is also a key acquired capacity of can-
cer cells. In normal cells, apoptosis targets cells for self-destruction when their DNA is
damaged beyond repair, or when the cells do not receive the proper prosurvival signals
from their environment. A key family of regulatory proteins involved in regulating apop-
tosis is the Bcl-2 family containing proapoptotic (Bax, Bak, Bid, and Bim) as well as
antiapoptotic (Bcl-2, Bcl-XL, and Bcl-W) regulatory proteins. The Bcl-2 protein itself is
frequently unregulated in cancer cells leading directly to resistance toward drug-induced
apoptosis. Furthermore, deletion or mutational inactivation of the tumor suppressor gene
p53 represents another way of evading apoptosis, because p53 normally induces up regu-
lation of proapoptotic Bax protein upon DNA damage. p53 is inactivated in 50% of all
human tumors.
4. Normal cells have the capacity to divide only a i nite number of times, typically 60-70
doublings before they die due to senescence, a cell fate different from apoptosis. This
is because the telomeres, DNA sequences at the end of the chromosome arms, shorten
a little at each mitotic cell division. Loss of telomeres results in DNA recombination
and end to end fusions of chromosomes leading to cell senescence. More than 90% of
human cancers avoid telomere shortening by expressing the catalytic subunit of telom-
erase hTERT, thereby avoiding senescence. The remaining use DNA recombination for
this purpose.
5. Angiogenesis is the process of developing new blood vessels. In order to grow beyond
the size of a few 100
m, tumors must develop neovascularization through the process
of angiogenesis. However, the tumor cells do not directly participate in neovasculariza-
tion, which is mediated only by endothelial cells. Instead tumor cells produce the factors
required for endothelial cells to perform angiogenesis in that they secrete growth factors
like vascular endothelial growth factor (VEGF) or i broblast growth factor (FGF1/2), which
can be produced by different mechanisms as shown for VEGF in Figure 23.1. Angiogenesis
is attractive in anticancer therapy because its inhibition is expected to have no implications
for normal cells in the body regardless of their proliferation rate.
μ
6. Primary tumor growth is seldom the direct cause of death in cancer patients. Instead,
the spreading of tumors known as metastasis is the most frequent cause of death (90%).
Invasion is penetration of tumor tissue through basal membranes allowing a tumor to grow
out from its original site into the surrounding tissue; whereas metastasis is the spreading
of cancer cells to other sites in the body, and the subsequent establishment of secondary
tumors in other tissues. Both processes involve changing the interaction of cancer cells
with the extracellular environment/matrix.
23.1.3 E
NABLING
C
HARACTERISTICS
OF
C
ANCER
C
ELLS
In addition to these hallmarks, cancer cells display a number of additional alterations enabling
cancer growth. One of the most important alterations is genome instability. The number of indi-
vidual mutations required to induce all six hallmarks of cancer would not normally accumulate in a
