genetic dowry?

he most important develop-
ment in cancer research within
the past decade has been the
concept of oncogenes, and
it came from an unexpected direction
the study of viruses.

The first virus found to cause cancer
was the Rous sarcoma virus, discovered
by pathologist Peyton Rous in 191)
in a cancer of chickens. Few believed
the finding, however, until confirma-
tion in the 1960s set off a widespread
search for viruses that could cause
cancer in humans.

The search has been partially suc-
cessful. Hepatitis B virus has been
strongly linked with liver cancer, and
scientists have shown a connection
between cervical cancer and the human
papilloma virus. These cancers are
major world problems. Liver cancer,
for example, is the most prevalent can-
cer in the Third World.

Thanks to the pioneering work of
Hormone Research Institute director
William Rutter, who was first to clone
the gene for the viral coat of the hepa-
titis B virus, a genetically engineered
human vaccine now has been devel-
oped. Unlike conventional vaccines,
which can cause the disease they are
trying to prevent, the synthetic vaccine
mimics the shape of the virus so the
body prepares to fight the real thing
when it appears.

Nevertheless, researchers have been
unable to establish links between
viruses and most other cancers, and the
general view is that most cancers are
not caused by viruses.

The search, in both humans and-ani-
tals, had major consequences, however.
Researchers found many viruses that
cause animal cancers, and one class of
these ~— so-called retroviruses — pointed
to genes in our own chromosomes that
might be involved in cancer.

Retroviruses, like many other medi-
cally important viruses, carry their

Virologist J. Michael Bishop

genetic information in the form of
RNA. Unlike these other viruses, how-
ever, retroviruses also have the ability,
upon infecting a cell, to transcribe their
RNA to DNA and stick the DNA into
the chromosomes of the invaded cell.
The retroviral genes are then treated
like the cell’s own genes.

These retroviral genes often disrupt
the host cell, either by disturbing the
regulation of the cell’s own genes or by
bringing in a gene that runs amok.
When this happens in animals, the cell
sometimes turns cancerous. Usually
only one of the retroviral genes, the
so-called oncogene, is responsible for
the damage, however.

The surprise came in 1976, when
UCSF virologists J. Michael Bishop
and Harold Varmus searched the chro-
mosomes of normal animals and found
a gene very similar to the oncogene
in the Rous sarcoma retrovirus.
Because even humans had this gene,
the question arose as to whether we
carry the potential for cancer in our
own genetic dowry.

The first human oncogene they
found to have a counterpart — a “proto-
oncogene” — was called src. Other
researchers soon found genes similar to
a host of other retroviral oncogenes.
‘Today there are more than 40 known
proto-oncogenes in humans, more than
one-half of which were first found in
retroviruses. But if retroviral oncogenes
can cause cancer in animals, what do
proto-oncogenes do in us? Are these
the switches?

The answer appears to be yes.
Studies in cell culture show that many
different carcinogens can flip these
switches on and turn a normal cell into
a cancer cell. At least nine proto-
oncogenes have been implicated in
human cancers so far, and presumably
damage to them sets cells on the path
to malignancy.

And there are many ways proto-

15
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 

oncogenes can be damaged. A change
in only one of the hundreds of nucleic
acids in the gene could make it go awry,
Occasionally, chromosomes break and
exchange pieces, disrupting a proto-
oncogene. A jumping gene can land in
the middle of a proto-oncogene, or a
gene that controls it, and send it out of
control. And sometimes a cell will gen-
erate hundreds of copies of a proto-
oncogene, presumably causing havoc
by flooding the cell with the protein
product of the gene.

“So far the scientific community has
been able to identify a mutated proto-
oncogene in only 20 percent of human
tumors, though I suspect nearly all
will be found to have at least one,”
Varmus says.“ No one argues that this
single mutation is the sole cause, but it
probably has some role in the origin of
each cancer.

“One of the main questions now is,
“What is the role of the proto-oncogene
in the normal cell?”

In the 11 years since Bishop and
Varmus’ discovery the role oncogenes
play in normal —and cancerous and
leukemic —cells gradually has been
clarified. Research also has led to the
discovery of genes called zz that
may play a role in the evolution of
breast cancer.

Basic research to identify the protein
progeny of specific oncogenes con-
tinues, of course. Once they have that
information, scientists will be able to see
more clearly how best to interrupt the
cancer-causing message at its source.

Virologist Harold Varmus; normal connective-
tissue cells (lower left) become round and
cluster together in piles after infection by
Rous sarcoma virus (lower right)

  
yncogenes may be

 

cancer swit

ince cancer is a disorder of
growth, it is no surprise that
researchers have found a
link with growth factors.
These usually small proteins which
stimulate cells to divide and multiply
and, in embryonic cells, to make them
mature have been known since the
1950s. Since then, more than a dozen
growth factors have been found, each
secreted by a variety of tissues and
each affecting a broad range of cells.

Several oncogenes already have been
identified with growth factors, one
of which is similar to platelet-derived
growth factor, which stimulates the
proliferation of cells in the walls of
blood vessels. Another oncogene,
which causes a tumor in chickens, is
derived from a proto-oncogene that
codes for the receptor for epidermal
growth factor. Epidermal growth factor
causes cells like skin and the lining
of the lung and gut to grow and
proliferate.

According to UCSF cell biologist
Denis Gospodarowicz, a pioneer in the
study of growth factors and the dis-
coverer of fibroblast growth factor in
1974, there is little doubt that this
also will be found to be the product of
a so-far unidentified oncogene.

Given these discoveries, it is no
wonder that cancer researchers are
homing in on growth factors — even to
the point of reversing their strategy
of searching for oncogenes in viruses
and, instead, testing growth factors
to see whether they induce cancer
when inserted into a cell.

Gospodarowicz, who was studying
fibroblast growth factor long before
oncogenes were recognized as being
important in cancer, already has shown
that it is critical not only to the growth
of connective tissue cells, but also to
cell growth in everything from the
brain to bone.

But the substance also has been
found in high levels in several fast-
8rowing and deadly cancers, such as

Cell biologist Denis Gospodarowicz