The first clues that cancer has a genetic basis came from several independent
observations. In 1914, the German cell
biologist, Theodor Boveri, noticed that cancer cells often carried abnormal
chromosomes as seen through the microscope. However, the fact that a specific chromosome abnormality was routinely
associated with a particular type of cancer did not come until 1973 when Janet
Rowley showed that chronic myelogenous leukemia (CML) cells carried a
chromosome translocation in which the ends of chromosomes 9 and 22 were
exchanged. Several other studies also showed
that certain types of cancer could run in families, suggesting that the risk for
specific cancers can be inherited. Then,
in 1981 the laboratories of Robert Weinberg and Geoff Cooper showed that DNA
from a human bladder cancer cell line could cause nonmalignant cells in tissue
culture to become cancerous. This was
the first direct demonstration that genes can cause cancer. A cancer-causing gene was called an
“oncogene”.
Since the Weinberg and Cooper observations, dozens of oncogenes have
been identified and characterized. It is
now clear that oncogenes represent normal cellular genes that are either aberrantly
expressed or functionally abnormal. Such
normal cellular genes, called “proto-oncogenes, can be “activated” to become
oncogenes through a variety of different molecular mechanisms.
RNA tumor viruses lead to the discovery of cellular proto-oncogenes.
In 1911, Peyton Rous reported that a class of RNA virus can cause tumors
in animals. These RNA tumor viruses,
called “retroviruses,” carry an RNA genome that, once inside a cell, is reverse-copied
into DNA, which then is inserted randomly into the host cell’s genome. Some retroviruses are slow to cause
tumors. After they infect and spread to
a large number of cells, the DNA copy of
the viral genome, by chance, might integrate into a host cell’s DNA near or
within a normal gene that plays an important role in cell growth. If this viral integration disrupts the expression
or structure of the normal cellular gene, it could induce abnormal growth
signals that cause this single cell to develop into cancer.
In contrast to retroviruses that take a long time to cause cancer, other
retroviruses cause tumors to appear very quickly. In these cases, during the process of reverse-copying
the viral RNA into DNA, RNA in the cells that is expressed from normal cellular
genes is sometimes mistakenly copied into the viral genome. If this captured cellular RNA is from a gene
that is important in stimulating cell growth, the recombined virus can transfer
the captured cellular gene to many other cells where it then causes abnormal growth
stimulation leading to the rapid development of a cancer.
Through molecular cloning, many genes that are activated by the insertion
of retroviruses into the genome, or that are captured by reverse-copying of cellular
RNA into the viral genome have been identified and characterized. Almost three-dozen such retroviral oncogenes
and their related cellular proto-oncogenes are now known.
Proto-oncogenes can be activated in the absence of retroviruses.
The first human oncogene, called Ras, ultimately was identified
in the Weinberg and Cooper experiments mentioned above. We now know that the protein product of the Ras
gene serves as a “switch” that turns growth signals on and off. Normally, the activity of this Ras
switch is tightly regulated in cells. However, single mutations (or “point mutations”) in critical sites of
the Ras gene cause the Ras growth “switch” to remain constantly on, and
this leads to cancer. Thus, some normal proto-oncogenes
can become oncogenes by random genetic point mutation in cells.
Oncogenes also can be activated by structural changes in chromosomes
known as “amplifications” or “translocations.” DNA amplification increases by several-fold a specific region of a chromosome. This can produce many copies of any genes that
lie in the amplified region. If one of
the genes in an amplified region is important in driving cell growth, its
overexpression due to amplification could lead to uncontrolled cell proliferation
and cancer. In the case of chromosome
translocations, a proto-oncogene on one chromosome might be moved to another
chromosome resulting in the gene’s structural alteration and/or aberrant
expression. For example, in the
translocation between chromosomes 9 and 22 that is found in CML, a
proto-oncogene on chromosome 9, called c-Abl, is moved to chromosome 22
where it is fused to another gene called Bcr. Normally, c-Abl is a nuclear “tyrosine
kinase,” which is an enzyme that adds a phosphate molecule to proteins at an
amino acid called tyrosine. Phosphorylation
on tyrosine regulates the function of certain proteins that play important
roles in stimulating cell proliferation. The fusion of Bcr and c-Abl genes creates an oncogene,
called Bcr/Abl, which makes a protein with highly elevated tyrosine
kinase activity and that is found in the cytoplasm instead of the nucleus. These changes in the activity and cellular
location of the c-Abl proto-oncogene lead to chronic myelogenous
leukemia.
Oncogenes cause cancer by “short-circuiting” normal growth control
mechanisms.
Normal cell growth is controlled by the availability of growth factors,
which are hormone-like molecules that bind to specific receptors that usually
sit on the surface of cells. When this
happens, the receptor initiates a signaling cascade from the cell membrane to
the nucleus that ultimately tells the cell to divide. Many of the gene products in such signaling
pathways are proto-oncogenes that can become oncogenes when activated by the
different mechanisms described above. When a signaling proto-oncogene is activated, the signaling cascade
becomes “short circuited” and cells behave as if they are continually in the
presence of their growth factor.
For example, the v-sis oncogene from a monkey cancer virus known
as the simian sarcoma retrovirus (SSV) comes from a gene that encodes
platelet-derived growth factor, which stimulates growth of different cell
types. Cells infected with SSV are,
therefore, constantly bathed in the v-sis growth factor and stimulated
to proliferate. Other oncogenes are
mutated growth factor receptors where mutation leaves the receptor permanently
“on” even in the absence of the growth factor. Two examples of mutated receptor oncogenes include v-erbB found
in a bird retrovirus that causes various cancers and v-fms, which is carried
by a mouse retrovirus that causes leukemia.
Inside the cell, components of the signaling cascade that connect cell
surface growth receptors to the nucleus also can cause cancer when their
activity is altered by mutation or overexpression. The Ras proto-oncogene that was mentioned
above is an example of a signal-transmitting molecule that is found inside
cells that can be mutated into an oncogene.
In the nucleus, normal growth signals trigger the expression and activity
of yet other proteins, called “transcription factors,” that regulate gene expression
needed for cell growth. Many of these transcription
factors also are proto-oncogenes. Two
examples of proto-oncogene transcription factors are c-Fos and c-Jun,
both of which were first identified as retroviral oncogenes.
“Tumor suppressor genes” inhibit the development of cancer.
In 1983, Raymond White and Webster Cavanee, using a technique called
“chromosome mapping,” learned that the loss of a small segment of human
chromosome 13 was a recurring feature in retinoblastoma, a rare childhood cancer
of the retina that can run in families. In this deleted region of chromosome 13 they discovered a gene that they
named RB (for retinoblastoma), both copies of which were inactivated
either by DNA deletion or by a mutation within the gene that destroyed its function. Interestingly, such inactivation of both
copies of the RB gene occurs in about forty percent of all human cancers.
The product of the normal RB gene functions as a brake to cell
division, so that loss of this brake can lead to unregulated cell growth. Another gene that also is associated with
cancer when both copies are inactivated by mutation is the p53 gene,
which acts as a “guardian” of the genome. This gene product induces a cell suicide program called “apoptosis” in
cells with damaged DNA. Normally, this
protects the body from cells whose DNA is damaged. However, loss of p53 activity allows
cells with damaged DNA to grow and pass DNA mutations to their daughter cells, thereby
contributing to the growth of tumors. A
third type of gene that plays a role in cancer when it is inactivated is NF1. This gene encodes a protein that turns off
the Ras growth signal mentioned above. Thus,
loss of NF1 function is another way that the Ras growth signal can be
left constantly on.
Since the discovery of RB, researchers have identified several
additional genes in which both copies are inactivated due to mutation or chromosomal
deletion. These genes normally block
cell growth and prevent tumors from growing; hence they are called “tumor
suppressor” genes. Since both copies of
these genes need to be inactive in order to release cancer cells from growth
inhibition, tumor suppressor genes act recessively. This contrasts to the oncogenes described above,
where only one copy needs to be activated in order to promote cancer. Therefore, in contrast to tumor suppressor
genes, oncogenes act in a dominant fashion.
Cancer usually arises after multiple genetic “hits.”
In 1971, Alfred Knudson, Jr. proposed that retinoblastoma resulted from
at least two separate genetic defects. In families with a high risk of retinoblastoma, the first defect was inherited,
while the second occurred sometime during childhood. This came to be known as Knudson’s “two-hit
theory”. We now know that the “first
hit” is the inheritance of a copy of chromosome 13 that carries a small
deletion in the region that carries RB. The “second hit” occurs when a random
mutation inactivates the remaining copy of RB
in a single cell making the cell susceptible to unregulated proliferation.
Subsequent research has shown that most, if not all, cancer arises from
multiple genetic events or “hits.” Bert
Vogelstein and coworkers first showed this in colon cancer in the late 1980s. Colon cancer begins with a pre-cancerous
stage, called a benign polyp. Left
untreated, this will progress through successively more cancerous stages until
it becomes an aggressive carcinoma. Vogelstein’s group found that the progression of colon cancer through
these different stages was associated with the acquisition of genetic changes
in oncogenes such as Ras, as well as in a number of different tumor
suppressor genes including p53. Together, sequential activation of different oncogenes along with
inactivation of various tumor suppressor genes drives the step-wise progression
of pre-cancerous cells to highly cancerous tumors.
Bibliography:
Bishop,
J. Michael. “Oncogenes.” Scientific
American 246 (1983):80-92.
Cavenee,
Webster K., White, Raymond L. “The Genetic Basis of Cancer.” Scientific
American March (1995):72-79.
Croce,
Carlo M., Klein, G. “Chromosome Translocations and Human
Cancer.” Scientific American 252 (1985):54-60.
Varmus,
Harold. “Retroviruses.” Science
240 (1988):1427-1435.
Weinberg,
Robert A. “A Molecular Basis of Cancer.” Scientific American
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-- “Tumor Suppressor Genes.” Science
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This article was originally published in Genetics, vol 3, R. Robinson, ed. 2003.
+++++++++++++++++++++++++++++++
Steven S. Clark,
Ph.D., a former professor and medical researcher at the University of Wisconsin School of Medicine provides consulting services
for investors and biotechnology companies. He encourages contributions to this page. Email him with story pitches.
________________________________________________________________________________________
© 2008 Steven S. Clark, PhD. All Rights
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