Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

1120 Chapter 20: Cancer
escape from
parent tissue
invasiveness
causes
entry into
vessel
DIFFICULT
survival in the
circulation
travel through
circulation
arrest in
capillary or
other small
vessel
EASY
exit into
remote tissue
or organ
survival of
cells in
foreign
tissue
colonization of
remote site
initial growth
of cells in
foreign
tissue
DIFFICULT
persistence
of growth
must escape the normal confines of their parent epithelium and begin to invade
the tissue immediately beneath. Second, they must travel via the blood or lymph
to lodge in distant sites. Third, they must survive there and multiply. It is the first
and last steps in this sequence that are the most difficult to accomplish for most
cancers (Figure 20–31).
The first step, local invasiveness, requires a relaxation of the mechanisms that
normally hold epithelial cells together. MBoC6 m20.44/20.31
As mentioned earlier, this step resembles
the normal developmental process known as the epithelial–mesenchymal transition
(EMT ), in which epithelial cells undergo a shift in character, becoming less
adhesive and more migratory (discussed in Chapter 19). A key part of the EMT
process involves switching off expression of the E-cadherin gene. The primary
function of the transmembrane E-cadherin protein is in cell–cell adhesion, binding
epithelial cells together through adherens junctions (see Figure 19–13). In
some carcinomas of the stomach and of the breast, E-cadherin has been identified
as a tumor suppressor gene, and a loss of E-cadherin may promote cancer development
by facilitating local invasiveness.
The initial entry of tumor cells into the circulation is helped by the presence of
a dense supply of blood vessels and sometimes lymphatic vessels, which tumors
attract to themselves as they grow larger and become hypoxic in their interior.
This process, called angiogenesis, is caused by the secretion of angiogenic factors
that promote the growth of blood vessels, such as vascular endothelial growth
factor (VEGF; see Figure 22–26). An abnormal fragility and leakiness of the new
vessels that form may help the cells that have become invasive to enter and then
move through the circulation with relative ease.
The remaining steps in metastasis, involving exit from a blood or lymphatic
vessel and the effective colonization of remote sites, are much harder to study. To
discover which of the later steps in metastasis present cancer cells with the greatest
difficulties, one can label the cells with a fluorescent dye or green fluorescent
protein (GFP), inject them into the bloodstream of a mouse, and then monitor
their fate (Movie 20.5). In such experiments, one observes that many cells survive
in the circulation, lodge in small vessels, and exit into the surrounding tissue,
regardless of whether they come from a tumor that metastasizes or one that
does not. Some cells die immediately after they enter foreign tissue; others survive
entry into the foreign tissue but fail to proliferate. Still others divide a few times
and then stop, forming micrometastases containing ten to several thousand cells.
Very few establish full-blown metastases.
What, if anything, distinguishes the survivors from the failures? A clue may
come from the fact that in many types of tumors, the cancer cells show a kind
of heterogeneity that resembles the heterogeneity seen among the cells of those
normal tissues that renew themselves continually by a stem-cell strategy, as we
discuss next.
Figure 20–31 The barriers to metastasis.
Studies of labeled tumor cells leaving a
tumor site, entering the circulation, and
establishing metastases show which steps
in the metastatic process, outlined in Figure
20–16, are difficult or “inefficient,” in the
sense that they are steps in which large
numbers of cells fail and are lost. It is in
these difficult steps that cells from highly
metastatic tumors are observed to have
much greater success than cells from a
nonmetastatic source. It seems that the
ability to escape from the parent tissue, and
an ability to survive and grow in the foreign
tissue, are key properties that cells must
acquire to become metastatic. (Adapted
from A.F. Chambers et al., Breast Cancer
Res. 2:400–407, 2000. With permission
from BioMed Central Ltd.)
A Small Population of Cancer Stem Cells May Maintain Many
Tumors
Self-renewing tissues, where cell division continues throughout life, are the breeding
ground for the great majority of human cancers. They include the epidermis