The Cancer Chronicles (12 page)

Like the
proto-oncogenes, these
growth-restraining genes were part of a cell’s normal regalia, and they too were discovered when something went wrong.
Retinoblastoma is a childhood cancer marked by runaway growth of the light-sensing cells of the eyes. The first sign might be an eerie white glow in the gaze of a child photographed with a camera flash. If noticed early enough the condition can be treated with
chemo,
radiation,
laser surgery, or removal of the eye. If not the outcome can be horrifying, the expanding tumor expelling the eye from its socket. Pictures in nineteenth-century textbooks show the gruesome results, which still occur among the poor in developing countries. The cancer begins
when a gene called
Rb,
short for “retinoblastoma,” has been taken down by a mutation, losing its ability to curb excessive growth.

But
Rb,
named like so many others because of the accidental
circumstances of its discovery, didn’t exist for the sole purpose of suppressing retinoblastoma. Once scientists started looking for
Rb
genes, they found them throughout the body—and they were missing or crippled in
cancers of the bladder,
breast, and
lung. Unlike an oncogene like
myc
or
ras,
growth-restraining genes like
Rb
are conspicuous by their absence. Because we inherit the chromosomes of both parents, genes exist in pairs. In a single cell, only one oncogene needs to start misbehaving for trouble to begin. With genes like
Rb,
both copies must be knocked out. If only one is lost the other will still be there to send moderating signals.

Dozens of similarly purposed genes have been discovered:
PTEN,
apc,
vhl
,
p53—“
tumor suppressors,” another awkward name thrust on the world by the human tendency to notice things only when they break. In an old-fashioned radio one can reach in with gloves and remove a hot glowing vacuum tube from its socket, unleashing a blasting squeal from the loudspeaker. Someone coming upon the phenomenon for the first time might name the component a squeal suppressor. But the circuitry is so much more complex. So it is with the suppressor genes. Some produce receptors that listen for inhibitory signals—orders from neighbors to stop overstepping their bounds. Others code for enzymes that muffle the commands of growth-stimulating genes. The rhythm of cellular division is governed by the molecular gears of a cell-cycle clock, and tumor suppressor genes are also
involved in the timekeeping.

One of them,
p53
,
sits at the center of a web of chemical pathways controlling the life cycle of a cell. If you want to start a cancer, take down
p53
. If a cell is damaged and dividing too quickly, external sensors will pick up warning signals from crowded neighbors. Internal sensors will detect chemical imbalances or broken DNA. With an emergency declared,
p53
will step in and slow down the clock so that DNA
repair can take place. Proofreading enzymes scan the genome. If one strand of DNA’s
double helix has been corrupted, the other strand can be used as a template to guide repair. Damaged sections can be excised, a replacement synthesized and put into place.

If DNA repair is broken and other measures cannot save a cell
that is mutating beyond control,
p53
initiates
programmed cell death, or
apoptosis. The name is derived from a Greek word describing falling leaves. When an embryo is
developing into a little body, it will produce far more cells than it needs. Apoptosis is the means by which it sheds the excess. Webs between fingers and toes are pared back. Lumps of neurons are sculpted into a thinking brain. Apoptosis is not just one big cellular explosion but an intricate procedure in which death signals set off the molecular equivalent of strategically placed depth charges. The nucleus implodes, the cell’s cytoskeleton crumbles. The microscopic remains are engulfed by other cells and a would-be malignancy is gone.

Through random mutations a few cells will learn to thwart or ignore the death signals—and then double and double and double again. A normal cell can divide only fifty or sixty times—
a principle called the
Hayflick limit.
The count is kept by
telomeres, caps on the ends of
chromosomes that get a little shorter each time around. Once the telomeres fall below a certain size,
mitosis comes to a halt and the worn-out cell is taken offline. Cells like those in the
immune system, which must divide repeatedly, manufacture
telomerase, an enzyme that keeps putting the caps back on the ends of the chromosomes. Cancer cells have also learned this trick, acquiring through the trial and error of mutation the information needed to produce their own telomerase. They can replicate indefinitely.

Conferred with the closest that nature has come to immortality, the cell and its descendants increase exponentially in number, each division giving rise to a new branch of the family tree. The branches divide fractal-like into more branches, and each of these lineages—these many-forking paths—is
accumulating mutations. Equipped with different routines and survival skills, the clans compete for dominance.

As this evolution unfolds, the tumor that is emerging acquires more of the tools of
carcinogenesis. Enzymes called
proteases eat into healthy tissue.
Cell adhesion molecules hold the expanding mass in place. Taking the invasion to a whole new level,
signals are
sent to healthy cells recruiting them to join the attack. Cells called
fibroblasts obediently synthesize proteins for the tumor’s structural support.
Endothelial cells—those that line the circulatory and lymphatic systems—are summoned to help make the vessels that nourish the tumor and provide avenues for metastasis.
Macrophages and other inflammatory cells, flocking to fight the invasion, are persuaded instead to aid in its expansion—producing substances that stimulate
angiogenesis,
lymphangiogenesis, and the creation of more malignant tissue. Here lies another
paradox of cancer. The panoply of devices normally employed to heal a wound—destroying old diseased tissue and replacing it with healthy new growth—is turned on its head, subverted to promote malignancy.

All of these mechanisms are so intertwined that it can be difficult to tell where one leaves off and another begins. What is being done by the cancer cells and what is being done by its minions? Tumors were once thought of as homogeneous clumps of malignant cells. Now they are
compared to bodily organs—systems of interlocking parts. There is a crucial difference. Organs are linked into a network of other organs, each playing an established role. A tumor is attempting to become independent, as though a kidney had decided to break free and set out on a life of its own.

In a very creepy way,
an embryo is so much like a
tumor that the early days of pregnancy resemble the incursion of a malignant growth. Once an egg is fertilized, it travels down the fallopian tube, dividing and dividing along the way. After several days it has become a ball of dozens of identical cells, which proceed to gather themselves into two regions. The outer layer will become the
placenta, while the inner cell mass will give rise to the
fetus.

Exchanging signals with the uterine wall, this expanding mass, called the
blastocyst, prepares to implant itself, the next step in a successful pregnancy. To carve out an opening, protein-dissolving
enzymes erode the surface of the uterine lining. As the blastocyst digs in, a process embryologists call
invasion, cell
adhesion
molecules help ensure a tight grip. Normally such an interloper would be rejected as foreign tissue, but
messages are sent to the immune system enlisting its cooperation. If all goes as planned, blastocyst becomes embryo, and it
begins stimulating
angiogenesis—growing vessels to hook into the mother’s blood supply. Every step of the way the molecular interactions of pregnancy are like those that occur during the genesis of a tumor.

As the occupation continues, the cells inside the fetus begin spreading in a well-orchestrated metastasis. First they gather themselves into three layers—the endoderm, mesoderm, and ectoderm (inner, middle, and outer). Cells from each of these primordial regions then strike out on their own, moving into new positions. As they travel they begin to
differentiate. Bone and cartilage go here, dermis goes there, with nerves and
blood vessels strung through. What began as identical totipotent
stem cells—blank slates—become the specific cells of the body. There is no central overseer. Every cell contains the entire genome, and as the diaspora continues genes are turned on or off in different combinations, producing the unique set of proteins that gives a cell its identity. The endodermal cells give rise to the lining of the digestive and respiratory tracts and form the
liver, gallbladder, and
pancreas. The cells of the mesoderm form muscles, cartilage,
bones, spleen, veins, arteries, blood, and
heart. The cells of the ectoderm form skin, hair, and nails and also the neural crest, which develops into the nervous system and brain.

While tumors evolve through
random mutations, fetuses do so according to a plan. But the deeper biologists look,
the more parallels they find. As the fetus develops, tightly connected
epithelial cells—the kind that form tissues—must loosen their grip so they can move to new locations. They become wanderers called
mesenchymal cells. When they reach their destination they can turn back into epithelial cells and regroup into new tissues. This process, called the
epithelial-mesenchymal transition, or
EMT, also occurs during healing, when cells are dispatched to repair wounds at distant sites. It seems only natural that
cancer would find a way to adopt EMT as a vehicle of metastasis, and there is compelling evidence that it does. Carcinomas, the most common cancers, are derived from epithelial cells. By temporarily changing identity they could more easily disperse through the body. During the transition they might even acquire properties like those of fetal stem cells—the ability to replicate profusely and generate a new tumor. There would be no need for the cancer cell to stumble upon these chameleon talents through
random mutations. The program, left over from early days, would be waiting ready-made in the
genome like a book forgotten on a shelf. It would simply have to be reread.

Wanting to learn more about the complex processes of life and anti-life, I drove down to Albuquerque one morning where the
Society for
Developmental Biology was
holding its annual meeting. The essence of the science is to tamper with
genes that play a role in embryonic unfolding and then see what kind of deformities occur. Experimenting with insects, worms, fish, and other laboratory creatures, biologists are slowly piecing together the steps that lead from a fertilized egg to a fully formed adult. Like ants in amber, the same cellular processes have been preserved and carried through evolution’s forking paths. When activated at the wrong time they can bring on human cancer.

There was a flood of new results to impart since the previous year’s meeting. The only way to accommodate them all was by running sessions simultaneously.
“Organogenesis,” “Spatiotemporal Control in Development,” “Branching and Migration,” “Generation of Asymmetry”—a feast of strange, enticing ideas. Darting from one room to another, I could sample the latest reports about the genes directing the development of the liver in the zebrafish or the brain of the sea squirt, or those that ensure that the trachea properly separates from the digestive tract in the embryonic mouse. One could learn about how sex is determined in the worm
C. elegans,
or how
apoptosis—programmed cell death—sculpts the genitals of
fruit flies. There were talks about how amphibians and planaria regenerate amputated body parts—and speculation about why that is something mammals cannot do.

Many of the genes directing development were first discovered in fruit flies. When mutated or destroyed, they cause deformations, and so they have been given names like
wingless, frizzled, smoothened, patched, and disheveled. Mutations in a gene called hedgehog can cause bristles to grow unexpectedly on the undersides of fruit fly larvae. (A human
hedgehog gene is involved in the sprouting
of hair from follicles, suggesting
possible treatments for baldness.)
Genes called snail, slug, and twist are invoked in the gyrations of the epithelial-mesenchymal transition.

As scientists discovered variations, they went even wilder with the nomenclature. Desert hedgehog, Indian hedgehog, and sonic hedgehog. A gene called fringe was soon joined by manic fringe, radical fringe, and lunatic fringe. When mutated during the formation of an embryo the result can be deformities and neonatal cancer. The silly nomenclature has caused some uneasiness among people dealing with the heartbreaking outcome of developmental defects. One medical researcher put it like this: “
The quirky sense of humour … often loses much in translation when people facing serious illness or disability are told that they or their child have a mutation in a gene such as Sonic hedgehog, Slug or
Pokémon.” The latter, proposed as a name for an
oncogene, was withdrawn after the threat of a lawsuit from Nintendo, the maker of the Pokémon game.
It now goes by the less evocative name
Zbtb7.

No lawsuits were filed by Sega when its video game character, Sonic the Hedgehog, was appropriated by biologists. Even if the company had been inclined to sue, it was soon too late.
Since it was discovered in 1993, sonic hedgehog has rapidly emerged as one of the most powerful components of animal development. The first hints came in the 1950s when
sheep grazing in the mountains of Idaho were giving birth to deformed lambs. In the most hideous cases, there was a single eye in the center of the forehead, and oftentimes the brain had not completely divided into left and right hemispheres. After spending three summers communing with the sheep, a Department of
Agriculture scientist discovered the cause. Drought was prodding them to wander higher up the mountains, where they dined on a lily called
Veratrum californicum.
Laboratory experiments confirmed that pregnant sheep that ate the plant gave birth to
cyclopean mutants. The mutagenic chemical was isolated and named cyclopamine. It worked, biologists went on to discover, by suppressing the signals of the
sonic hedgehog gene. (Sheep also played a part
in the episode of the
Odyssey
where Odysseus and his men visit the island of the Cyclopes. Trapped in a cave they are devoured, one by one, by the one-eyed monster Polyphemus, until Odysseus blinds him with a homemade spear. He and his soldiers escape by tying themselves to the underside of Polyphemus’s flock.)