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

CANCER AS A MICROEVOLUTIONARY PROCESS
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development of a tumor relies on a two-way communication between the tumor
cells and the tumor stroma, just as the normal development of epithelial organs
relies on communication between epithelial cells and mesenchymal cells (discussed
in Chapter 22).
The stroma provides a framework for the tumor. It is composed of normal connective
tissue containing fibroblasts and inflammatory white blood cells, as well
as the endothelial cells that form blood and lymphatic vessels with their attendant
pericytes and smooth muscle cells (Figure 20–15). As a carcinoma progresses, the
cancer cells induce changes in the stroma by secreting signal proteins that alter
the behavior of the stromal cells, as well as proteolytic enzymes that modify the
extracellular matrix. The stromal cells in turn act back on the tumor cells, secreting
signal proteins that stimulate cancer cell growth and division as well as proteases
that further remodel the extracellular matrix. In these ways, the tumor and
its stroma evolve together, like weeds and the ecosystem that they invade, and
the tumor becomes dependent on its particular stromal cells. Experiments using
mice indicate that the growth of some transplanted carcinomas depends on the
tumor-associated fibroblasts and normal fibroblasts will not do. Such environmental
requirements help to protect us from cancer, as we discuss next in considering
the critical phenomenon called metastasis.
Cancer Cells Must Survive and Proliferate in a Foreign Environment
Cancer cells generally need to spread and multiply at new sites in the body in
order to kill us, through a process called metastasis. This is the most deadly—and
least understood—aspect of cancer, being responsible for 90% of cancer-associated
deaths. By spreading through the body, a cancer becomes almost impossible
to eradicate by either surgery or local irradiation. Metastasis is itself a multistep
process: the cancer cells first have to invade local tissues and vessels, move
through the circulation, leave the vessels, and then establish new cellular colonies
at distant sites (Figure 20–16). Each of these events is complex, and most of the
molecular mechanisms involved are not yet clear.
For a cancer cell to become dangerous, it must break free of constraints that
keep normal cells in their proper places and prevent them from invading neighboring
tissues. Invasiveness is thus one of the defining properties of malignant
tumors, which show a disorganized pattern of growth and ragged borders, with
extensions into the surrounding tissue (see, for example, Figure 20–8). Although
the underlying molecular changes are not well understood, invasiveness almost
certainly requires a disruption of the adhesive mechanisms that normally keep
cells tethered to their proper neighbors and to the extracellular matrix. For carcinomas,
this change resembles the epithelial–mesenchymal transition (EMT) that
occurs in some epithelial tissues during normal development (see p. 1042).
The next step in metastasis—the establishment of colonies in distant organs—
begins with entry into the circulation: the invasive cancer cells must penetrate the
basal lamina
epithelial cells
precursors to
cancerous cells
capillary
lymphatic
cells
white blood cells
cancer cells
pericyte
endothelial
cell
fibroblast
EXTRACELLULAR
MATRIX
Figure 20–15 The tumor
microenvironment plays a role in
tumorigenesis. Tumors consist of
many cell types, including cancer cells,
endothelial cells, pericytes (vascular
smooth muscle cells), fibroblasts,
and inflammatory white blood cells.
Communication among these and other
cell types plays an important part in tumor
development. Note, however, that only the
cancer cells are thought to be genetically
abnormal in a tumor.
MBoC6 m20.105/20.15