More and more in recent years, cancer
biologists are pointing their fingers at viruses. Human
papillomavirus, they found, causes cervical cancer;
hepatitis B induces liver cancer; and Epstein-Barr virus
has been implicated in lymphoma. Most recently,
scientists discovered that malignant brain tumors called
glioblastoma multiforme, the late-stage version of the
cancer that has afflicted Senator Edward Kennedy of
Massachusetts, are almost always teeming with
cytomegalovirus (CMV), a common, typically harmless
herpesvirus. Although the nature of the association is
still a mystery, researchers are already taking
advantage of the link to find new cancer treatments.
The
saga began in the late 1990s, when Charles Cobbs, a
neurosurgeon then at the University of California, San
Francisco, started pondering the link between
inflammation and brain cancer. Malignant tumors are
often associated with abnormal immune activity, and he
wanted to know why. “Is it just something that happens
out of the blue, or is it possible that there’s
something maybe driving that inflammatory cascade?” he
recalls wondering.
Because they elicit immune responses,
infections immediately sprang to mind as possible
candidates. Cobbs and his colleagues analyzed
glioblastoma samples from 22 patients and found that all
harbored CMV. Four out of five people have this virus,
which remains in the body for life. Usually a person’s
immune system keeps CMV in a latent state in which it
does not replicate, but Cobbs found the virus actively
reproducing in these tumor cells—and not in healthy
cells nearby. “It was stunningly obvious that these
tumors were infected,” says Cobbs, whose findings,
published in
Cancer Research in 2002, were confirmed in 2007
by Duke University neuro-oncologist Duane Mitchell.
What was not obvious was why, exactly,
the infection was there. Did CMV cause the cancer, or
did it simply proliferate in tumor cells? “It’s a
chicken-and-egg question: What came first, the virus or
the tumor?” Mitchell points out. Glioblastoma patients
have compromised immune systems, which might enable a
latent CMV infection to reactivate, Mitchell says. And
CMV might be frequently found in brain tumor cells
because these cells are easy to infiltrate. A 2008 study
Cobbs published in Nature revealed that a
cell-surface receptor responsible for letting CMV inside
is more frequently found on brain tumor cells than other
cell types.
Cobbs, now at San Francisco’s California
Pacific Medical Center Research Institute, believes that
CMV plays a more active role in generating tumors. He
points to a study published in May in Science
showing that CMV makes proteins that “turn off” human
genes important for preventing unwanted cell growth, a
prerequisite to tumor development. It is as if CMV is
“clipping the brake line,” remarks study co-author
Robert Kalejta, a molecular virologist at the University
of Wisconsin–Madison. Other studies have shown that CMV
can interrupt a cell’s ability to commit suicide when
the cell growth has gone awry. Still, no one has shown
that CMV can turn healthy cells into cancer cells,
Kalejta notes. So although the virus has some of the
tools necessary to cause cancer, there is no proof that
it does.
The good news is that when it comes to
formulating cancer treatments, understanding the details
of CMV’s link to brain cancer is less important than the
link itself. “For our purposes, it doesn’t really
matter,” says Mitchell, whose lab focuses on new cancer
treatments. “We see the presence of the virus as a
unique opportunity to go after it as a target in tumor
cells.” His lab has “trained” immune system cells to
recognize CMV proteins and has used those cells to
identify and kill CMV-infected tumor cells.
Mitchell and his colleagues are currently
testing their vaccine—and a second version using a
different immune cell—in clinical trials, and although
they have not yet published their results, he says that
outcomes look promising. Cobbs, for one, is hopeful.
“I’m holding my breath,” he remarks. “It looks like this
may be a radically new way to consider treating these
tumors.”