The Cancer Chronicles (18 page)

A physics of cancer! In the decade and more that has passed since this immodest prediction, scientists have continued to uncover whole new layers of complications. Inside the biological microchip called a cell there are components inside components and wiring so dense and so fluid that it sometimes seems impossible to tease the strands apart. Moving up a level, what is happening inside a cancer cell cannot be fully understood without considering its place within an intricate communications network of other cells. By the time the “Hallmarks” paper was published, scientists were already finding that
tumors are not homogeneous masses of malignant cells—that they also contain healthy cells that help produce the proteins a tumor needs to expand and attack tissue and to plug into the blood supply. This aberrant ecosystem has come to be called the
cancer microenvironment, and entire conferences and journals are devoted to understanding it.

Complicating matters further has been the gradual realization that the genetic changes that can lead to cancer
don’t necessarily have to occur through mutations—deletions, additions, or rearrangements of the
nucleotide letters in a cell’s DNA. The message can be altered in more subtle ways. Think of what happens during normal
development. Every cell in the fetus carries the DNA inherited from its parents—the genetic instructions a body requires to manufacture its many parts. As cells divide and
differentiate the entire script remains intact, but only certain genes are activated to produce the proteins that give a skin cell or a kidney cell its unique identity. That much is familiar biology. What hadn’t occurred to me is that as the cell proliferates, this configuration must be locked in place and passed on to its progeny.

Scientists have been piecing together a rough picture of how this works. Molecular tags can bind to a gene in a way that causes it to be permanently disabled—incapable of expressing its genetic message.
(The tags are methyl groups, so this process is called
methylation.) Genes can also be enhanced or suppressed by twisting the shape of the
genome. In the iconic image, DNA’s interwoven coils float elegant as jellyfish in lonely isolation. But in the messiness of the cell, the two helical strands are wrapped around clusters of proteins called histones. Methyl groups and other molecules can bind to the helix itself or to its protein core and cause the whole assembly to flex. As that happens some genes are exposed and others are obscured. Alterations like these, which change a cell’s function while leaving its DNA otherwise unscathed, are called
epigenetic. “Epi-,” coming from ancient Greek, can mean “over,” “above,” “upon.” Just as a cell has a genome, it also has an
epigenome—a layer of software overlying the hardware of the DNA. Like the genome itself the epigenome is preserved and passed on to daughter cells.

What all this suggests is that
cancer may not be only a matter of broken genes. Disturbances to a cell—carcinogens, diet, or even stress—might rearrange the epigenetic tags without directly mutating any DNA. Suppose that a methyl group normally keeps an
oncogene—one that stimulates cellular division—from being expressed. Remove the tag and the cell might start dividing like crazy. On the other hand, the production of too many tags might inactivate a
tumor suppressor gene that would normally hold mitosis in check. Freed to proliferate, the cell would be vulnerable to more copying errors. So epigenetic changes would lead to genetic changes—and these genetic changes could conceivably affect methylation, triggering more epigenetic changes … and round and round it goes.

Outside the laboratory enthusiasm for this scenario is driven both by hope and by fear. Epigenetics might provide a way for a substance to act as a carcinogen even though it has been shown incapable of breaking DNA. But unlike genetic damage, these changes might be reversible. How big a role epigenetics plays remains uncertain. Like everything that happens in a cell, methylation and the modification of histones are controlled by genes—and these have been found to
be mutated in different cancers. Maybe it all comes down to mutations after all. On the other hand, a few scientists have
proposed that cancer actually begins with epigenetic disruptions, setting the stage for more wrenching transformations.

Even more unsettling is
a contentious idea called the
cancer stem cell theory. In a developing embryo,
stem cells are those with the ability to renew themselves indefinitely—they are essentially immortal—dividing and dividing while remaining in an undifferentiated state. They are agents of pure potentiality. When a certain type of tissue is needed, genes are activated in a specific pattern and the stem cells give rise to specialized cells with fixed identities. Once the embryo has grown into a creature, adult stem cells play a similar role, standing ready to differentiate and replace cells that have been damaged or reached the end of their life. Since healthy tissues arise from a small set of these powerful forebears, why couldn’t the same be true for some tumors?

This would be an unexpected twist on the conventional view in which any cancer cell that has acquired the right combination of mutations is capable of generating a new tumor. Imagine if instead the growth and spread of a cancer is driven by a fraction of special cells, those that have somehow become endowed with an intrinsic quality called “
stemness.” Just as normal stem cells generate skin, bone, and other tissues, the cancer stem cells would generate the variety of cells that form the rest of a tumor. But only the cancer stem cells would have the ability to replicate endlessly, metastasize, and seed another malignancy. How much easier that might make things for oncologists. Maybe
chemotherapies fail because they spare the cancer stem cells. Remove these linchpins and the malignancy would collapse.

It is a promising possibility, but the further I ventured into the subject,
the more confusing it seemed. Do the other cells in the tumor perform functions like
angiogenesis that would aid in sustaining the malignancy? Or are they just filler material? And where would the cancer stem cells come from? Do they begin as normal
stem cells (like those that generate skin) that become damaged by mutations? Or are they fetal stem cells that survived into adulthood and then went berserk? Or, like the other cells jostling for position inside a tumor, did they also arise through random variation and selection? Maybe the all-powerful cells began as “ordinary” tumor cells that
shed their identity and reverted to this primal form. Some experiments suggest that in the turmoil of a tumor, cells are constantly shifting their identity between cells with stemlike properties and cells without.

As I struggled to fit this all into the big picture, I was relieved to find researchers who seemed as baffled as I was. Some scientists were convinced the hypothesis was
the wave of the future, others that it was of limited
importance—a footnote to the standard theory. However it all pans out, the underlying view of cancer as a
Darwinian process—arising like life itself through random variation and selection—would remain largely unshaken. But as an outsider trying to understand the essence of cancer, I felt daunted by the possibility of even more convolutions.

The place to take in the full sweep of what is happening on the frontiers is
the annual meeting of the
American Association for Cancer Research, the largest and most important of its kind in the world. It was being held early one spring in Orlando, Florida, and as I changed planes in Atlanta I could already see the ripple effect. Young scientists rushed through the airport carrying long cardboard tubes protecting their posters. Each, unfurled, would describe a tiny piece in the expanding puzzle. Altogether
more than 16,000 scientists and other specialists from sixty-seven countries were converging on Orlando, where more than six thousand new papers would be presented—in poster sessions and symposiums—over a span of five days. There were few distractions. Orlando’s mammoth convention center and its environs form an insular world of hotels, chain restaurants, and meeting halls, a kind of boring version of Las Vegas.
Inside this air-conditioned bubble I hoped to absorb as much as I could.

While there had been three simultaneous sessions at the modest
developmental biology meeting I had attended in Albuquerque, here there were more than a dozen—beginning at 7:00 a.m. and running into the evening with major lectures and educational sessions overlapping and in between. Carrying a copy of the proceedings as thick as a telephone book (or the weightless equivalent on their cell phones), the informavores plotted their hunting strategies. As the clock began to run out on a speaker’s 10:30 a.m. talk, there would come a rustling of chairs with people quietly hurrying to a presentation scheduled in another room for 10:45. Geography was a consideration. Going from “Guts, Germs and Genes” (recent findings on the role bacteria play in the onset of some tumors) to catch the end of “Ubiquitin Signaling Networks in
Cancer” required a brisk ten-minute walk indoors. Beckoning one floor below was the exhibit area, where
pharmaceutical companies with huge steampunk espresso machines tempted passersby—a cappuccino and biscotti in return for listening to a presentation by Merck or Lilly on a new cancer drug. At the Amgen booth, visitors wearing 3-D glasses watched
an amazing video flythrough of a tumor undergoing
angiogenesis. For more than a decade
Amgen had been working on an angiogenesis inhibitor. Combined with
paclitaxel in a clinical trial, it
extended the lives of women with
recurrent
ovarian cancer from 20.9 months to 22.5 months, or about forty-eight days.

As I watched the video, I thought of the excitement thirteen years earlier when a
Harvard scientist,
Judah Folkman, had discovered what briefly appeared to be the makings of a silver bullet. For every mechanism in a cell there is a countermechanism to keep it in check. Angiogenesis is a normal means through which blood is supplied to newly created tissues. Molecules called
angiostatin and endostatin, which are naturally produced to inhibit angiogenesis—you don’t want new blood vessels growing just anywhere—had shown striking effects in choking off tumors in
mice.
James Watson, the celebrated
molecular biologist, was quoted on the front page of
The New York Times:
“
Judah is going to cure
cancer in two years.” He followed up with a letter to the editor insisting that he had spoken more cautiously to the reporter—and then went on to declare, just as enthusiastically, that what was happening in Folkman’s laboratory was “
the most exciting cancer research of my lifetime, and it gives us hope that a world without cancer may yet be attainable.” Watson was not alone. The director of the
National Cancer Institute called Folkman’s results “
remarkable and wonderful” and “the single most exciting thing on the horizon,” before adding the usual caveat that what worked for mice wouldn’t necessarily work for people.

It didn’t, of course. The experiments were difficult to replicate and later research suggested that some angiogenesis inhibitors might make matters worse—with the tumor fighting back by
metastasizing more vigorously toward safer ground. There are now inhibitors on the market, but the results are nothing like what had been envisioned. Used along with the standard blunt-edged poisons,
Avastin can
add a few months to a patient’s life at a cost of tens of thousands of dollars. Side effects include gastrointestinal perforation and severe internal bleeding. Inhibiting angiogenesis can interfere with the healing of surgical incisions and other wounds. Several months after the Orlando meeting, the
Food and Drug Administration, weighing the risks and the benefits, revoked approval for Avastin as a treatment for metastatic
breast cancer.

Such grim realities seemed far away at the grand opening session, where
Arthur D. Levinson, a pioneer in the design of
targeted therapies, was honored for “leadership and extraordinary achievements in cancer research.” He was cited specifically for his role in developing “
blockbuster drugs” like Avastin. Levinson is the chairman of
Genentech, which also makes
Herceptin to treat the 15 to 20 percent of breast cancers that are
HER2 positive—those with an overabundance of the growth-stimulating receptors. For metastatic breast cancer, Herceptin can add a few months to a woman’s life. Used in the early stages of the illness, the drug’s effects are more striking.
When
standard
chemotherapy was accompanied by Herceptin, 85 percent of women were found free of the cancer after four years. That compared with 67 percent who had not taken the drug. The trial was stopped early so that women in the control group could benefit (and so
Genentech could reduce the time to market). As word spread of the new therapy, breast cancer patients who once dreaded learning that their
tumor was HER2 positive—a particularly vicious and aggressive kind—came almost to welcome the news.

No cancer drug, however, is as good as it sounds. Herceptin can also affect healthy cells with a normal number of HER2 receptors, and there is
a serious risk of congestive heart failure. Even
Gleevec,
the “crowning achievement” of targeted therapy, has its dark side. With the drug, chronic myeloid
leukemia can almost always be held in check, but Gleevec must be taken indefinitely to keep the cancer from coming back. There are also problems with another class of pharmaceuticals that aim to suppress tumors
by strengthening the body’s immunological defenses. Immune system
boosters called
cytokines are infused into the bloodstream—or
the patient’s own immune cells are removed, modified to enhance their killing powers, and then reinjected. The danger with these experimental therapies is keeping the immune system from becoming so vigilant that it wildly overreacts, mistaking the body itself for an interloper and initiating a catastrophic
autoimmune response.