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

1096 Chapter 20: Cancer
connective tissue epithelium
NORMAL
EPITHELIUM
LOW-GRADE
INTRAEPITHELIAL
NEOPLASIA
HIGH-GRADE
INTRAEPITHELIAL
NEOPLASIA
(A) (B) (C) (D)
INVASIVE
CARCINOMA
50 µm
Figure 20–8 Stages of progression in the
development of cancer of the epithelium
of the uterine cervix. Pathologists use
standardized terminology to classify the
types of disorders they see, so as to guide
the choice of treatment. (A) In a stratified
squamous epithelium, dividing cells are
confined to the basal layer. (B) In this
low-grade intraepithelial neoplasia (right
half of image), dividing cells can be found
throughout the lower third of the epithelium;
the superficial cells are still flattened and
show signs of differentiation, but this is
incomplete. (C) In high-grade intraepithelial
neoplasia, cells in all the epithelial layers
are proliferating and exhibit defective
differentiation. (D) True malignancy begins
when the cells move through or destroy the
basal lamina that underlies the basal layer
of epithelium and invade the underlying
connective tissue. (Photographs courtesy
of Andrew J. Connolly.)
genetic or epigenetic changes. In the subsequent acute phase, cells that show not
only the translocation but also several other chromosomal abnormalities overrun
the hemopoietic (blood-forming) system. It appears that cells from the initial
mutant clone have undergone further mutations that make them proliferate even
more vigorously, so that they come to outnumber both the normal blood cells and
their ancestors with the primary chromosomal translocation.
Carcinomas and other solid tumors evolve in a similar way (Figure 20–8).
Although many such cancers in humans are not diagnosed until a relatively late
stage, in some cases it is possible to observe the earlier steps and, as we shall see
later, to relate them to specific genetic changes
Tumor Progression Involves Successive Rounds of Random
Inherited Change Followed by Natural Selection
From all the evidence, therefore, it seems that cancers arise by a process in which
an initial population of slightly abnormal MBoC6 m20.09/20.08
cells—descendants of a single abnormal
ancestor—evolve from bad to worse through successive cycles of random
inherited change followed by natural selection. Correspondingly, tumors grow in
fits and starts, as additional advantageous inherited changes arise and the cells
bearing them flourish. Tumor progression involves a large element of chance and
usually takes many years, which may be why the majority of us will die of causes
other than cancer.
At each stage of progression, some individual cell acquires an additional mutation
or epigenetic change that gives it a selective advantage over its neighbors,
making it better able to thrive in its environment—an environment that, inside
a tumor, may be harsh, with low levels of oxygen, scarce nutrients, and the natural
barriers to growth presented by the surrounding normal tissues. The larger
the number of tumor cells, the higher the chance that at least one of them will
undergo a change that favors it over its neighbors. Thus, as the tumor grows, progression
accelerates. The offspring of the best-adapted cells continue to divide,
eventually producing the dominant clones in the developing lesion (Figure 20–9).
Just as in the evolution of plants and animals, a kind of speciation often occurs:
the original cancer cell lineage can diversify to give many genetically different vigorous
subclones of cells. These may coexist in the same mass of tumor tissue; or
they may migrate and colonize separate environments suited to their individual
quirks, where they settle, thrive, and progress as independently evolving metastases.
As new mutations arise within each tumor mass, different subclones may
gain an advantage and come to predominate, only to be overtaken by others or
outgrown by their own sub-subclones. The increasing genetic diversity as a cancer
progresses is one of the chief factors that make cures difficult.