C h a p t e r 7
Neoplasia
133
grade. Accordingly, on a scale ranging from grade I to IV,
grade I neoplasms are well differentiated and grade IV
are poorly differentiated and display marked anaplasia.
2
Genetic Instability and Chromosomal Abnormalities.
Most cancer cells exhibit a characteristic called
genetic
instability
that is often considered to be a hallmark of
cancer.
3,4
The concept came about after the realization
that uncorrected mutations in normal cells are rare
due to many cellular mechanisms to prevent them. To
account for the high frequency of mutations in cancer
cells, it is thought that cancer cells have a genotype
that is highly divergent from the genotype of normally
transformed cells. Characteristics of genetic instability
are alterations in growth regulatory genes and genes
involved in cell cycle progression and arrest.
Genomic instability most commonly results in gross
chromosomal abnormalities. Benign tumors usually have
a normal number of chromosomes. By contrast, malig-
nant cells often display a feature called
aneuploid,
in
which they have an abnormal number of chromosomes.
2–4
The chromosomes may be structurally abnormal due to
insertions, deletions, amplifications, or translocations
of parts of their arms (see Chapter 6). They may also
display microsatellite instability, which involves short
repetitive sequences of DNA, and point mutations.
Growth Properties.
The characteristics of altered prolif-
eration and differentiation are associated with a number
of growth and behavioral changes that distinguish cancer
cells fromtheir normal counterparts. These include growth
factor independence, lack of cell density–dependent
inhibition, impaired cohesiveness and adhesion, loss of
anchorage dependence, faulty cell-to-cell communication,
and an indefinite cell life span or immortality.
Cell growth in test tubes or culture dishes is referred
to as
in vitro cell culture
because the first containers used
for these cultures were made of glass (
vitrium
, mean-
ing “glass” in Latin). It is assumed that the in vivo (in
the body) growth of tumor cells mimics that of in vitro
studies. Most normal cells require a complex growth
medium and survive for only a limited time in vitro. In
the case of cancer cells, the addition of serum, which is
rich in growth factors, is unnecessary for the cancers to
proliferate. Some cancer cells produce their own growth
factors and secrete them into the culture medium, while
others have abnormal receptors or signaling proteins
that may inappropriately activate growth-signaling
pathways within the cells. Breast cancer cells that do not
express estrogen receptors are an example. These cancer
cells grow even in the absence of estrogen, which is the
normal growth stimulus for breast duct epithelial cells.
Normal cells that are grown in culture tend to dis-
play a feature called
cell density–dependent inhibition,
in
which they stop dividing after the cell population reaches
a particular density.
5
This is sometimes referred to as
con-
tact inhibition
since cells often stop growing when they
come into contact with each other. In wound healing, for
example, contact inhibition causes fibrous tissue growth
to cease at the point where the edges of a wound come
together. Malignant cells show no such contact inhibition
and grow rampantly without regard for adjacent tissue.
There is also a reduced tendency of cancer cells to stick
together (i.e., loss of
cohesiveness
and
adhesiveness
)
owing, in part, to a loss of cell surface adhesion molecules.
This permits shedding of the tumor’s surface cells; these
cells appear in the surrounding body fluids or secretions
and often can be detected using cytologic examination.
Cancer cells also display a feature called
anchorage
independence
.
5,6
Studies in culture show that normal cells,
with the exception of hematopoietic cells, will not grow
and proliferate unless they are attached to a solid sur-
face such as the extracellular matrix. For some cell types,
including epithelial tissue cells, even survival depends
on such attachments. If normal epithelial cells become
detached, they often undergo a type of apoptosis known
as
anoikis
due to not having a “home.” In contrast to nor-
mal cells, cancer cells often survive in microenvironments
different from those of the normal cells. They frequently
remain viable and multiply without normal attachments
to other cells and the extracellular matrix. Another charac-
teristic of cancer cells is faulty
cell-to-cell communication
,
a feature that may contribute to the growth and survival
of cancer cells. Impaired cell-to-cell communication may
interfere with formation of intercellular connections and
responsiveness to membrane-derived signals. For exam-
ple, changes in gap junction proteins, which enable cyto-
plasmic continuity and communication between cells,
have been described in some types of cancer.
7
Cancer cells also differ from normal cells by being
immortal
; that is, they have an unlimited life span. If nor-
mal noncancerous cells are harvested from the body and
grown under culture conditions, most cells divide a lim-
ited number of times, usually about 50 population dou-
blings, then achieve senescence and fail to divide further.
In contrast, cancer cells may divide an infinite number
of times, and hence achieve immortality. Telomeres are
short, repetitive nucleotide sequences at the outermost
extremities of chromosome arms (see Chapter 2). Most
cancer cells maintain high levels of telomerase, an enzyme
that prevents telomere shortening, which keeps telomeres
from aging and attaining a critically short length that is
associated with cellular replicative senescence.
Functional Features.
Because of their lack of differen-
tiation, cancer cells tend to function on a more primitive
level than normal cells, retaining only those functions
that are essential for their survival and proliferation.
They may also acquire some new features and become
quite different from normal cells. For example, many
transformed cancer cells revert to earlier stages of gene
expression and produce antigens that are immunologi-
cally distinct from the antigens that are expressed by cells
of the well-differentiated tissue from which the cancer
originated. Some cancers may elaborate fetal antigens
that are not produced by comparable cells in the adult.
Tumor antigens may be clinically useful as markers to
indicate the presence, recurrence, or progressive growth
of a cancer. Response to treatment can also be evaluated
based on an increase or decrease in tumor antigens.
Cancers may also engage in the abnormal production
of substances that affect body function. For example,
