Understanding Cancer: Mosaicism, Metastasis, and the Immune System

Advances in technology have led to research producing improved understanding of the nature of cancer, how it can grow and spread, and new ways in which to combat it.  This new knowledge is both exciting and troubling.  It does provide options for prolonging the lives of those who suffer from cancer, but instead of producing a hope that cancer will one day be conquered, it raises the specter of a process that is inevitable and ultimately unavoidable.  One is led not to the conclusion that cancer will one day be cured, but to recognize that all of us are lucky to still be alive.

A mosaic is a plant, animal, or human with two or more populations of cells with different genetic makeup.  This situation can develop when a mutation occurs which produces daughter cells that are able to reproduce and propagate that mutation.  Carl Zimmer, in his book She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity, provides a detailed description of mosaicism and how science gradually learned not only that mosaicism was very common in the human population, but that cancer was a form of mosaicism

Zimmer tells us that mosaics were first recognized in plants where a tree or a shrub might suddenly send off an unusual branch that was obviously dissimilar to the rest of the structure.  Scientists recognized that cellular reproduction was not a perfect mechanism and observed that mosaicism was often accompanied by variations in the chromosomal content of daughter cells.  If such variations existed in plants, why wouldn’t they be expected in animals, including humans.

“A single fertilized egg will multiply into roughly 37 trillion cells by the time a person reaches adulthood.  Each time one of those cells divides, it must create a new copy of its three billion base pairs of DNA.  For the most part our cells manage this duplication with stunning precision.  If they make a mistake, one of their daughter cells will acquire a new mutation that is not present at conception.  And if that daughter cell produces an entire lineage a potentially vast pool of cells will inherit it too.  Based on estimates of the somatic mutation rate, some researchers have estimated that there might be over ten quadrillion new mutations scattered in each of us.”

Zimmer concludes that scientists were so concerned with genetic variations between individuals, that they gave scant thought to the notion of genetic variability within an individual. 

“But modern science was slow to recognize that we humans were mosaics as well.  It’s not as if human mosaics were invisible.  Some were downright impossible to miss.  Human mosaics might be born with port-wine stains on their face.  Others looked as if a charcoal artist had applied stripes and checkerboards to their skin (a condition that came to be known as the lines of Blaschko…).  One human mosaic even became a celebrity in Victorian England.  He called himself the Elephant Man.”

The evidence is beginning to accumulate that indicates mosaicism is common to all of us—and it begins early in our development.

“In the first few days of an embryo’s existence, over half of its cells end up with the wrong number of chromosomes, either by accidently duplicating some or losing them.  Many of these imbalanced cells either can’t divide or do so slowly.  From their initial abundance, they dwindle away while normal cells create their own lineages.  If the supply of chromosomes is too abnormal—a condition called aneuploidy—then the mother’s body will sense trouble and reject the embryo altogether.”

“But a surprising number of embryos can survive with some variety in their chromosomes.  Markus Grompe, a biologist at Oregon Health and Science University, and his colleagues looked at liver cells from children and adults without any liver disease, most of whom had died suddenly, by drowning, strokes, gunshot wounds, and the like.  Between a quarter and a half of their liver cells were aneuploids, typically missing one copy of one chromosome.”

He notes that a particularly prescient researcher named Theodor Boveri recognized that cancer is a form mosaicism in 1902.  It would be 1960 before Boveri would finally be proved correct.

“It would take until 1960 for scientists to observe chromosomes carefully enough to test Boveri’s theory.  David A. Hungerford and Peter Nowell discovered that people with a form of cancer called chronic myelogenous leukemia were missing a substantial chunk of chromosome 22.  It turned out that a mutation had moved that chunk over to chromosome 9.  The altered chromosomes drove cells to become cancerous.”

As technology improved, scientists were able to detect small mutations that were capable of producing cancerous cells as well.  What this picture of widespread mutations suggests is that cancer is inherent in bodily function.  However, if it is so prevalent, how do most of us get to live to a ripe old age?  Humans and other animals could not have evolved as they have without mechanisms to protect themselves from the development of dangerous levels of cancer.  The issue is not whether we will encounter cancer, it is how will the cancer evolve in our particular bodies.

An article produced by Siddhartha Mukherjee for The New Yorker provides a deeper look into these issues.  It is titled Cancer’s Invasion Equation and begins with this lede.

“We can detect tumors earlier than ever before. Can we predict whether they’re going to be dangerous?”

Much effort has gone into early detection of cancerous tumors, but what if cancer is prevalent but not always dangerous.  What if most cancers never become a health issue?

“In 1985, pathologists in Finland assembled a group of a hundred and one men and women who had died of unrelated causes—car accidents or heart attacks, say—and performed autopsies to determine how many harbored papillary thyroid cancer. They cut the thyroid glands into razor-thin sections, as if carving a hock of ham into prosciutto slices, and peered at the sections under a microscope. Astonishingly, they found thyroid cancer in more than a third of the glands inspected. A similar study regarding breast cancer—comparing breast cancer incidentally detectable at autopsy with the lifetime risk of dying of breast cancer—suggests that a hyperzealous early-detection program might overdiagnose breast cancer with startling frequency, leading to needless interventions. Surveying the results of prostate-cancer screening, Welch calculated that thirty to a hundred men would have to undergo unnecessary treatment—typically, surgery or radiation—for every life saved.”

Studies like this corroborate the notion that cancer is very common, but that most incidences do not become a threat to us.  The real issue according to Mukherjee is prediction not detection.

Mukherjee also provides us with some startling data related to the issues of metastasis, the spread of a cancer from one location to other organs.  Women who die from breast cancer will generally die because the cancer had metastasized and spread to other organs rather than from the effect of the original breast tumor.  By inducing breast cancer in mice, researchers were able to tally cancerous cells that might be shed by the tumor.  The results were startling.

“The results baffled the investigators. On average, they found, the tumor was sloughing off twenty thousand cancer cells into every milliliter of blood—roughly three million cells per gram of tumor every twenty-four hours. In the course of a day, the tumor molted nearly a tenth of its weight. Later studies, performed with more sophisticated methods and with animal tumors that had arisen more ‘naturally,’ confirmed that tumors continually shed cells into circulation. (The rate of shedding from localized human tumors is harder to study; but available research tends to confirm the general phenomenon.)”

The issue with metastasis is not how cancer cells get from one organ to another, it was what happened to cancerous cells that prevented them from flourishing on other organs.

“The real conundrum wasn’t why metastases occur in some cancer patients but why metastases don’t occur in all of them.”

There is additional data on metastasis that suggests breast cancer cells find more welcoming terrain on some organs than on others.  This effect was first documented by a doctor named Stephen Paget in the late nineteenth century.

“But when Paget collected the case files of seven hundred and thirty-five women who had died of breast cancer, he found a bizarre pattern of metastatic spread. The metastases didn’t appear to spread centrifugally; they appeared in discrete, anatomically distant sites. And the pattern of spread was far from random: cancers had a strange and strong preference for particular organs. Of the three hundred-odd metastases, Paget found two hundred and forty-one in the liver, seventeen in the spleen, and seventy in the lungs. Enormous, empty, uncolonized steppes—anatomical landmasses untouched by metastasis—stretched out in between.”

“Why was the liver so hospitable to metastasis, while the spleen, which had similarities in blood supply, size, and proximity, seemed relatively resistant? As Paget probed deeper, he found that cancerous growth even favored particular sites within organ systems. Bones were a frequent site of metastasis in breast cancer—but not every bone was equally susceptible.”

The most likely explanation for this collection of observations was that most of the cancer cells being shed by a tumor were killed in passage and the ones that made it to another organ were mostly unwelcome in that environment and either went dormant or were subsequently destroyed.  Yet a small fraction could reach an environment in which they were capable of interacting with the surrounding tissue and media and cultivating another tumor. 

Two words appear frequently in Mukherjee’s discussion: environment and ecology.

“Paget coined the phrase ‘seed and soil’ to describe the phenomenon. The seed was the cancer cell; the soil was the local ecosystem where it flourished, or failed to. Paget’s study concentrated on patterns of metastasis within a person’s body. The propensity of one organ to become colonized while another was spared seemed to depend on the nature or the location of the organ—on local ecologies. Yet the logic of the seed-and-soil model ultimately raises the question of global ecologies: why does one person’s body have susceptible niches and not another’s?”

“Paget’s way of framing the issue—metastasis as the result of a pathological relationship between a cancer cell and its environment—lay dormant for more than a century.”

With this view of the cancer cell-tissue interaction comes the need to understand not just the nature of the cancer cell, but also the nature of the environment in which the interaction takes place.  One needs to understand why some people are susceptible to tumor formation and others are not.

“For decades, our standard explanation for those…people who meet the criteria of the diagnostic test, who are at risk for a disease, but who may not actually have it—was stochastic: we thought there was a roll-of-the-dice aspect to falling ill. There absolutely is. But what Medzhitov calls ‘new rules of tissue engagement’ may help us understand why so many people who are exposed to a disease don’t end up getting it. Medzhitov believes that all our tissues have ‘established rules by which cells form engagements and alliances with other cells.’ Physiology is the product of these relationships…There are tens of trillions of cells in a human body; a large fraction of them are dividing, almost always imperfectly. There’s no reason to think there’s a supply-side shortage of potential cancer cells, even in perfectly healthy people. Medzhitov’s point is that cancer cells produce cancer—they get established and grow—only when they manage to form alliances with normal cells.”

“Once we think of diseases in terms of ecosystems, then, we’re obliged to ask why someone didn’t get sick. Yet ecologists are a frustrating lot, at least if you’re a doctor. Part of the seduction of cancer genetics is that it purports to explain the unity and the diversity of cancer in one swoop. For ecologists, by contrast, everything is a relationship among a complex assemblage of factors.”

This “seed and soil” approach to metastasis is beginning to bear fruit.  Our immune system is undoubtedly the reason why many cancer cells are destroyed before they can do harm.  After all, it is designed to detect cells that are not part of our normal tissues and destroy them.  The question then becomes why do some cancer cells manage to take root?  It turns out that there are chemical signals that inform immune system cells when tissue it encounters is “normal” tissue not to be attacked.  If cancer cells are capable of producing the correct chemical signals, they can trick the immune system into leaving them alone.  Researchers have moved in the direction of developing what has become known as immunotherapy.

“There are important consequences of taking soil as well as seed into account. Among the most successful recent innovations in cancer therapeutics is immunotherapy, in which a patient’s own immune system is activated to target cancer cells. Years ago, the pioneer immunologist Jim Allison and his colleagues discovered that cancer cells used special proteins to trigger the brakes in the host’s immune cells, leading to unchecked growth.  When drugs stopped certain cancers from exploiting these braking proteins, Allison and his colleagues showed, immune cells would start to attack them.”

Such an approach can be useful, and it is a good beginning, but immunity can only be one factor in a complex problem.

“Such therapies are best thought of as soil therapies: rather than killing tumor cells directly, or targeting mutant gene products within tumor cells, they work on the phalanxes of immunological predators that survey tissue environments, and alter the ecology of the host. But soil therapies will go beyond immune factors; a wide variety of environmental features have to be taken into account. The extracellular matrix with which the cancer interacts, the blood vessels that a successful tumor must coax out to feed itself, the nature of a host’s connective-tissue cells—all of these affect the ecology of tissues and thereby the growth of cancers.”

Jerome Groopman provides a discussion of the status of immunotherapy in countering cancer in The Body Strikes Back, an article that appeared in the New York Review of Books.

Both Allison and a Japanese scientist independently discovered “braking” molecules that restrain our immune system from attacking tumors.  For that they shared the Nobel Prize in Physiology and Medicine in 2018.  Notably, they discovered two different molecules that served this function.  Groopman describes some successes that have been achieved with therapies that block the effectiveness of those “brakes.”  One of the issues with these therapies are that they succeed slowly and can take many months to exhibit a success.  Treatment of metastatic melanoma was one of the first attempts at therapy.

“Instead of assessing efficacy in the short term, as was usual for radiation and chemotherapy, the researchers measured patient survival over a period of years. In 2010 the study results were presented at a major cancer meeting: a quarter of the patients treated with blockers for widespread melanoma were alive after two years; their predicted survival had been a mere seven months.”

Former President Jimmy Carter was the most famous recipient of this therapy and provided an example of a “miracle” drug that worked.

“One of the most stunning successes of this treatment is the case of President Jimmy Carter. In the summer of 2015 he was diagnosed with melanoma that had spread to his liver and brain. With standard radiation and chemotherapy his prognosis was dismal, measured in weeks to a few months. Carter received a new PD-1 blocker and remains in remission nearly four years later.”

Turning off brakes to our immune system to allow it to attack cancer tumors also puts normal tissues at risk.

“The advent of successful immune therapy for cancer comes with a price. It often causes toxic side effects, as the unleashed immune system attacks not only the tumor but normal tissues as well. Patients can suffer intense inflammation of the bowels, skin, and thyroid and adrenal glands. Then there is the cost of the treatments, typically more than $100,000 per year.”

As exciting as these developments are, they remain consistent with Mukherjee’s warning that immunity can be only part of the solution.

“Metastatic melanoma has proved to be one among several previously intractable cancers that has yielded to immune therapy. Clinical trials in lung cancer, Hodgkins lymphoma, bladder cancer, Merkel cell carcinoma, and others have shown dramatic remissions and raised the prospect of some patients being cured. In general, a quarter to a third of treated patients react positively.”

 The notion of “winning” a war on cancer seems ever less appropriate.  Perhaps the best we can hope for is that we will die more slowly than we did in the past.