The Cancer Chronicles (10 page)

Cells are so particular about where they live that science still struggles to understand metastasis. How do the malignant cells decide where to go, and what counts for them as hospitable soil? Tissue similar to that found in the original tumor would surely be the most desirable, and yet
cancer in one breast rarely moves on to the other breast. Nor does cancer in one kidney often spread to the
opposite one. According to some theories,
cancer cells wandering the corridors of the circulatory system are looking for a particular address—
a molecular “zip code” identifying the organ where they are likely to thrive. Cancers are usually capable of replanting themselves, with varying success, in several kinds of tissue. In the Darwinian struggle inside a tumor different lineages may evolve specific genetic programs,
priming them for survival inside the brain or, alternately, for a new life in the lungs. The primary tumor might smooth the way by secreting chemicals into the blood that help create
a
premetastatic niche downstream, a more hospitable place for the progeny to grow. There is even speculation that
the travelers can bring their own soil with them—healthy cells from home that will assist in the colonization.

Once the cancer cells arrive at a promising location, a whole new cascade of events begins. They
exchange signals with the natives—the cells of the tissue they are set to invade—recruiting their help in coming ashore. If cooperation is not forthcoming, the interlopers might lie dormant for years or decades until they are reawakened. When they have finally established their first colony, some will move on to other sites, and they may even return to the mother tumor to
rejoin the battle at home. This self-seeding might help explain the recurrence of cancers that surgeons are confident they had completely excised.
Metastasis—what would seem to be a messy, haphazard matter of tumors shedding cells willy-nilly into the bloodstream—turns out to be exquisitely and horrifyingly precise.

Besides the blood, there is another course the seeds can follow—from the tumor through the lymphatic vessels, making themselves known, as they did with
Nancy, when they begin congregating inside a lymph node. I don’t remember learning about the lymph system in school, this primitive, insect-like sewer system. It has no heart, sluggishly draining clear, watery waste from the cracks between cells, waste that is filtered along the way by the lymph nodes. Pushed and
pulled by contracting muscles and osmotic pressures, the
lymph eventually makes its way to the rushing blood, connecting with veins in the neck and shoulders.
Evolution in its opportunistic way has found another use for the lymphatic canals: to transport immune cells called
lymphocytes. These collect in the lymph nodes, rapidly mushrooming in number when confronted with foreign tissue—
bacteria, viruses, cancer cells, enemies to destroy.

Malignant cells gain a
pathway to the bloodstream when a tumor acquires
the ability to initiate
angiogenesis, growing its own capillaries. Tumors can also learn to induce
lymphangiogenesis,
creating connections to the lymphatic system. They may even send
signals to a nearby lymph node, instructing it to sprout more vessels to accommodate the forthcoming invasion. The lymphatic system—this key component of the body’s immunological defenses—becomes co-opted. The first sign is a tumor—a lump—growing inside a lymph node, the barrier whose very purpose is to stop such attacks. That apparently is what had happened with Nancy. It was why we were sitting, on what was probably a perfectly good autumn day, in an office at the university cancer center in Albuquerque.

For all the high-tech scanning and laboratory assays, the precise nature of her metastasis was confirmed by a procedure almost medieval in its barbarity: an
endometrial curettage—scraping cells, in this case without an anesthetic, from the lining of the
uterus for pathological scrutiny. To help endure the pain she was given a tongue depressor to clench between her teeth. After all the waiting, the procedure had to be done in a rush. We had been referred to a gynecological
oncological surgeon, a specialist among specialists and a rising star in his field. He was leaving the next day for two weeks. To schedule surgery as quickly as possible the lab work had to be ready for his return. The results were what everyone by now had suspected: The cells from the uterus resembled those that had been found in the lymph node of her right groin.

On the scale of medical horrors learning that one has
uterine cancer can be relatively good news (that is how far life had plunged).
Most cases by far are endometrioid adenocarcinomas—cancer of the epithelial cells of glandular tissue. Unlike
ovarian cancer, it is usually noticed early and the five-year
survival rate can be as high as 90 percent if the malignancy has not advanced beyond the uterine lining. If it has the odds are lower. When there is
metastasis to the nearest lymph nodes (
sentinel nodes, they are called, for they are the first line of defense against the errant cells) the likelihood of survival can drop to 45 percent—and if the cancer has advanced as far as an inguinal node, as it had with
Nancy, to 15 percent. But those were just averages.
Nancy’s youth gave hope for a better than normal outcome. She was strong and could tolerate a regime of
treatment—“regime” is precisely the right word—at least as aggressive as the cancer: multiple rounds of sickening chemo followed by burning
radiation. But first would come the surgery. A
hysterectomy, of course, and removal (“
dissection”) of suspect lymph nodes. The surgery would also be exploratory with the aim of identifying and excising any other tissues the cancer might have invaded.

The operation was scheduled for early November, still weeks away. All that time to imagine the cells as they continued to multiply, trying out new combinations of mutations. We went to a lawyer to draw up living wills and medical powers of attorney. Nancy’s youngest brother flew in from the East Coast to be with us. One night shortly before surgery we were sitting together in a Thai restaurant (it’s strange the details one remembers) pretending to be enjoying dinner. During the meal Nancy mentioned that she had noticed a lump that day in the inguinal node of her left leg. The good one. Remembering this now I think of that 1868 paper by Thomas
Ashworth: One thing was certain. Moving through her lymphatic system, the cancer cells had reached the other side of her body. And they had found hospitable soil.

As I learned about metastasis, I thought about the years before the cancer when Nancy and I worked so hard to turn a desiccated,
junk-strewn weed patch—our backyard—into a xeriscape garden. Not a zeroscape—those gravel and cactus afterthoughts one sees in Phoenix or Las Vegas—but something akin to a dry highland meadow. We started with one small patch, clearing it of brush and scattering a packet of
Beauty Beyond Belief wildflower seeds, a mix recommended for northern New Mexico. There were seeds for Colorado aster, goldfields, arroyo lupine, desert lupine, desert marigold, California poppy, alyssum, baby blue eyes, baby’s breath, bachelor button, black-eyed Susan, candytuft, catchfly, columbine, purple coneflower, yellow coneflower, coreopsis, cosmos, African daisy, Shasta daisy, blue flax, scarlet flax, mountain garland, gaillardia, larkspur, perennial lupine, Mexican hat, Rocky Mountain penstemon, corn poppy, sweet william pinks, and wallflower. We raked them into the dirt and let nature take its course.

When the rains came it was clear that all we were going to get was blue flax, coneflower, and Mexican hat. They overflowed the garden and over the years found niches throughout our irregularly shaped quarter acre of land. The yellow coneflower and Mexican hat, both members of the genus
Ratibida,
mated to form hybrids that still appear each season. On Saturday mornings we would come home from the nursery with flats of new wildflowers to try. For all our efforts some would die not long after planting, but those that survived would set seed in the fall. The winds would come, then the rain, and we would find Rocky Mountain penstemon and red pineleaf penstemon in surprising new places. They would grow there and thrive in a way they never did when we were the ones to choose the locale.

Some wildflowers native to the foothills where we lived flourished along the trails. Yet they were nearly impossible to cultivate:
Hymenoxys argentea
with its silvery leaves and yellow flowers,
Phlox nana
(locally called Santa Fe phlox), which bloomed little violet stars. A local nursery managed to grow only a few of the plants and there was a waiting list each spring. It took years of trial and error until the phlox finally found a spot, shaded by a pine tree, where it
deigned to grow.
Nancy had majored in biology and would show me how a leaf of a wildflower began to change at the tip, gradually in shape and color, until one day there was a blossom. It had never occurred to me that the same green cells that formed the leaf were
differentiating into colorful petals—genes switched on and off, signaled by sunlight, temperature, moisture, whatever told the plant that it was time to bloom.
Differentiation and development could occur at astonishing speeds.

What adapted far more readily were the weeds. After our first summer rain in Santa Fe, a bluish green carpet that we welcomed as some unidentified native ground cover turned out to be seedlings of kochia, a member of the goosefoot family that originated in the harsh climate of the Russian steppes. For all its aridity, New Mexico must seem to this immigrant like a tropical paradise. The tiny plants rapidly shot up to form ugly, spindly weeds.

Another hated intruder from Eurasia was western
salsify, and we thought at first that it was no worse than a larger version of the American dandelion. We quickly learned better. One morning we were showing our fledgling gardens to our neighbor
Vivian when she spotted one of these weeds, now more than a foot tall, with a podlike bud protruding outward that was about to open into a flower. Vivian shrieked melodramatically and pulled it up by its roots, advising us to kill every one we found. As we soon learned, the pretty yellow petals would turn, seemingly overnight, into a cloud of feathery white seeds, each so viable that western salsify would quickly spread throughout the yard outcompeting almost everything. It spread so viciously that we imagined it, in the dark of night, expectorating its deadly spores in one explosive burst. We thought of the pods in
Invasion of the Body Snatchers,
landing from some distant star to take over the earth. We nicknamed the weed “space plant,” and I learned to recognize and destroy the seedlings when they were barely half an inch high.

That was a few years before Vivian died of ovarian
cancer. The spreading of weeds became linked in my mind with metastasis. But
maybe that was the wrong metaphor. Cancer, as
Paget realized so long ago, is more discriminating in the way it propagates. Honed for life in a specific tissue, a metastasizing cancer cell had more in common with those delicate wildflowers—until it found its roost. Then it was more like the pods.

The first hint that cancer is a
disease of information came in a laboratory at the University of Texas, where in the late 1920s
Hermann J. Muller was
experimenting with
fruit flies. He was working in a long tradition that had begun with
Mendel, who
discovered in his monastery garden that certain traits like flower color are passed down among generations of pea plants according to predictable patterns. Purpleness is a dominant factor and whiteness is a recessive one. If a pea plant inherits the purple factor from each parent, its flowers will be purple. The same rule holds true if both inherited factors are white. But if one is white and the other is purple, they do not blend to make lavender. Purple trumps white so that is the color that appears in the progeny. The modern way of saying this is that there is a gene for flower color—a microscopic kernel of hereditary information—and that it comes in two forms. With fruit flies, which breed so rapidly, the shuffling of these tokens unfolds in fast-forward. Eyes red or white, bristles straight or forked—these
genetic traits, as discrete as the ones and zeroes of binary code, can be followed and plotted as they travel down the family line.

As a student, Muller had studied how the Mendelian process
sometimes spits out a wild card. After many generations, purebred red-eyed flies would spontaneously produce a mutant with white eyes. Other kinds of
mutations would also appear. This was long before
DNA was identified as the stuff of genes, the helically shaped molecule that carries genetic information in a four-symbol alphabet—the
nucleotides abbreviated G, C, A, and T. If a letter is changed, the meaning can be corrupted. The signal becomes noise or is silenced altogether.
That kind of clarity would come decades later with the discoveries of
Oswald Avery in 1944,
Alfred Hershey and
Martha Chase in 1952, and a year later when
James Watson and
Francis Crick cobbled together from cardboard, sheet metal, and wire their model of the
double helix. For now Muller’s contribution was to show that whatever genes were made of and however they worked, you didn’t have to wait for mutations to occur. They could be produced at will by exposing the flies to x-rays.

Most often the mutations sterilized the flies or killed them. That, he speculated, might explain why the rays were so effective at destroying rapidly dividing
cancer cells—a therapy that had come into use almost as soon as
x-rays were first produced in the laboratory of
Wilhelm Röntgen in 1895. With each cellular division the genes had to be copied. The energy from a penetrating x-ray could damage the microscopic structure, inducing a lethal mutation and removing the cell from the game. Far more telling was that Muller’s x-rays could also create living mutants: albino fruit flies or fruit flies with forked bristles or shrunken wings. This ability to alter genetic material, he suggested, might explain a paradox: why the cancer-killing rays could also
produce
cancers, transforming normal cells into malignant ones. Cancer, this seemingly amorphous disease, this sprawl of hyped-up cells, might be the result of precise genetic mutations.