C h a p t e r 7
Neoplasia
137
Etiology of Cancer
The cause or causes of cancer can be viewed from two
perspectives: (1) the genetic and molecular mechanisms
that characterize the transformation of normal cells into
cancer cells and (2) the external and more contextual
factors such as age, heredity, and environmental agents
that contribute to its development and progression.
Together, both mechanisms contribute to a multidimen-
sional web of causation by which cancers develop and
progress over time.
Genetic and Molecular Basis
of Cancer
The pathogenesis of most cancers is thought to originate
from genetic damage or mutation with resultant changes
that transform a normally functioning cell into a cancer
cell. Epigenetic factors that involve silencing of a gene or
genes may also be involved. In recent years, the role of
cancer stem cells in the pathogenesis of cancer has been
identified. Finally, the cellular microenvironment that
involves the extracellular matrix and a complex milieu
of cytokines, growth factors, and other cell types is also
recognized as an important contributor to cancer devel-
opment and its growth and progression.
Cancer-Associated Genes
Most cancer-associated genes can be classified into two
broad categories based on whether gene overactiv-
ity or underactivity increases the risk for cancer. The
category associated with gene overactivity involves
proto-oncogenes,
which are normal genes that become
cancer-causing genes if mutated.
2,3
Proto-oncogenes
encode for normal cell proteins such as growth fac-
tors, growth factor receptors, transcription factors
that promote cell growth, cell cycle proteins (cyclins or
cyclin-dependent proteins), and inhibitors of apoptosis.
The category of cancer-associated underactivity genes
includes the
tumor-suppressor genes
, which, by being
less active, create an environment in which cancer is
promoted.
Genetic Events Leading to Oncogene Formation or
Activation.
There are a number of genetic events that
can cause or activate oncogenes.
16
A common event is
a point mutation in which there is a single nucleotide
base change due to an insertion, deletion, or substitu-
tion. An example of an oncogene caused by point muta-
tions is the ras oncogene, which has been found in many
cancers.
2
Members of the ras proto-oncogene family are
important signal-relaying proteins that transmit growth
signals to the cell nucleus. Hence, activation of the ras
oncogene can increase cell proliferation.
Chromosomal translocations have traditionally been
associated with cancers such as Burkitt lymphoma and
chronic myeloid leukemia. In Burkitt lymphoma the
c-myc gene, which encodes a growth signal protein,
is translocated from its normal position on chromo-
some 8 to chromosome 14, placing it at the site of an
immunoglobulin gene.
2
The outcome of the transloca-
tion in chronic myeloid leukemia is the appearance of
the so-called
Philadelphia chromosome
involving chro-
mosomes 9 and 22 and the formation of an abnormal
fusion protein that promotes cell proliferation
3
(see
Chapter 11, Fig. 11-6). Recent advances in biotechnol-
ogy and genomics are enabling the identification and
increased understanding of how gene translocations,
even within the same chromosome, contribute to the
development of cancer.
Another genetic event that is common in cancer is
gene amplification. Multiple copies of certain genes
may cause overexpression with higher than normal
levels of proteins that increase cell proliferation. For
example, the human epidermal growth factor receptor-2
(HER-2/neu) gene is amplified in up to 30% of breast
cancers and indicates a tumor that is aggressive with
a poor prognosis.
17
One of the agents used in treat-
ment of HER-2/neu overexpressing breast cancers is
trastuzumab (Herceptin), a monoclonal antibody that
selectively binds to HER-2, thereby inhibiting the prolif-
eration of tumor cells that overexpress HER-2.
Genetic Events Leading toLoss of Tumor-Suppressor
Gene Function.
Normal cells have regulatory genetic
mechanisms that protect them against activated or
newly acquired oncogenes. These genes are called tumor-suppressor genes. When this type of gene is inactivated,
a genetic signal that normally inhibits cell proliferation is
removed, thereby causing unregulated growth to begin.
2,3
Mutations in tumor-suppressor genes are generally reces-
sive, in that cells tend to behave normally until there is
homologous deletion, inactivation, or silencing of both
the maternal and paternal genes.
Two of the best-known tumor-suppressor genes are
the p53 and retinoblastoma (RB) genes. The p53 gene,
named after the molecular weight of the protein it encodes,
is the most common target for genetic alteration in
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The spread of cancer occurs through three
pathways: direct invasion and extension, seeding
of cancer cells in body cavities, and metastatic
spread through lymphatic or vascular pathways.
Only a proportionately small clone of cancer cells
is capable of metastasis.To metastasize, a cancer
cell must be able to break loose from the primary
tumor, invade the surrounding extracellular
matrix, gain access to a blood vessel, survive its
passage in the bloodstream, emerge from the
bloodstream at a favorable location, and invade
the surrounding tissue. Once in the distant
tissue site, the metastatic process depends on
the establishment of blood vessels and specific
growth factors that promote proliferation of the
tumor cells.
