Biomedical Engineering Reference
In-Depth Information
primary tumor, evading the immune system, homing to and colonizing the
distant organ. It is widely appreciated that formation of metastasis is an
inefficient process. Estimations of cells that are shed into the vasculature are
as high as 10
6
cells per gram of cancer tissue daily (Chang et al., 2000).
Fortunately, this high frequency of tumor cell shedding into the vasculature
does not result in an equally high rate of metastasis. Other, ethically contro-
versial, experimental data show that upon autotransplantation of human tumor
cells only a small fraction is capable of initiating an orthotopic tumor (Southam
and Brunschwig, 1960).
These indications of the inefficiency of the metastatic process have been
explained mainly in a genetic framework. It is believed that the additive genetic
alterations required for successful metastasis are a relatively infrequent event.
This might explain the low frequency of tumor cells capable of forming a
metastasis. However, the new insights gained into cancer stem cell research
may suggest an additional explanation. If only the cancer stem cells are in
principle capable of founding a metastasis possibly this would explain the low
numbers of metastasis-initiating cells. Furthermore this cancer stem cell model
of metastasis is also supported by recent experimental data using gene expres-
sion micro arrays (Cardoso et al., 2007). It has been shown that the gene
expression profile of the primary colorectal cancer is predictive for the occur-
rence of a metastasis later on in the disease. This suggests that the capacity to
initiate a metastasis is possibly a feature of the dominant clone more than of a
small fraction of cells that accumulated the right to mutations. Moreover, the
gene expression profiles of metastasis closely resemble the expression profiles of
primary colorectal cancers (Cardoso et al., 2007). These experimental data hint
toward a model in which the small fraction of 'migratory' cancer stem cells is
capable of invasion, extravasation, and establishment of a new tumor mass at a
distant site (Brabletz et al., 2005). This metastasis then resembles the original
malignancy in morphology, marker expression, and gene expression. Moreover
this tumor contains again a cancer stem cell compartment from which colon-
cancer stem cells can be isolated (O'Brien et al., 2007).
8 Consequences of the Cancer Stem Cell Model for Therapy
If the cancer stem cells are the only tumor cells capable of driving tumor
progression and metastasis, every therapy should be aimed at successful eradi-
cation of the cancer stem cell compartment. However, evidence is accumulating
that the population with cancer stem cell features is also more resistant to
chemotherapeutic agents and radiotherapy (Al Hajj et al., 2004; Jordan et al.,
2006). This putative chemo- and radio-resistance of the colon-cancer stem cells
could possibly explain why such therapeutic interventions in CRC patients are
of limited value. The identification of cancer stem cells as drivers of colon-
cancer growth and the proposed resistance of
these cells
to existing
