There is an article about cancer in this month’s issue of Scientific American written by pioneering the virologist, Peter Duesberg. For those of you to whom his name sounds vaguely familiar, Duesberg became famous by claiming that HIV doesn’t cause AIDS. Fortunately, this article does not go into his radical ideas about HIV. Instead, this piece explores his more plausible hypothesis regarding the cause of cancer, which proposes that the source for many cancers is aneuploidy: a condition where the cell’s chromosomes are scrambled — duplicated, broken, structurally rearranged or missing entirely. In contrast to Duesberg’s unconventional ideas about the HIV-AIDS connection, his argument is compelling for the link between this observed chromosomal chaos and cancer. I thought you would enjoy reading my summary of this article since the original is behind a subscription wall.
Duesberg’s group arrived at their hypothesis by rethinking the basic biological features about what makes a human cell “normal,” or even “human.” Basically, individual genes can be quite variable within a species but chromosomal structure is not. For example, the genes for eye color can encode a variety of colors from one individual to the next, but the actual genes for eye color are always found on precisely the same location on exactly the same chromosome in every individual of the species.
A normal human somatic cell is diploid; it carries two complete sets of each chromosome (pictured, above). However, solid tumor cells are not diploid. According to the author, cancer cells are always aneuploid — hosting one or more severely damaged, missing or extra chromosomes. As a result of aneuploidy, the total DNA content of a cancer cell can either be more than twice or less than half of what is found in a normal cell. This imbalance makes the cells cancerous because they cause the cell to produce wildly skewed amounts of those proteins that are encoded by the thousands of genes that were either gained or lost. This disrupts normal functioning of these cells, leading to cancer.
Because of their structural complexity, the most vulnerable proteins in the cell are those that comprise the mitotic spindle fiber apparatus that is responsible for segregating chromosomes during cell division. The failure of the mitotic spindle fibers can cause aneuploidy, thereby contributing to additional derangements of chromosome number (see above and below).
Abnormalities in the spindle proteins reveal how cancerous cells within the same tumor can exhibit different combinations and alterations in their chromosomal make up, or karyotype. This variance in karyotype effectively makes each cell a new species. Further, this inherent instability also allows individual cancer cells to evolve new traits and behaviors, unlike normal cells in an organism, which are destined to develop predetermined characteristics depending upon the organ or tissue type they belong to. Thus, an aneuploid cell can dispense with more and more of its normal social obligations within a multicellular organism and multiply wildly at the expense of normal cells.
As Duesberg observes, cancerous cells tend to evolve from bad to worse. This process is referred to as carcinogenesis and is characterized by the cells developing their own unique sizes, shapes, metabolisms and growth rates. Malignancy is defined by the cancerous cells’ abnormal ability to invade neighboring tissues and to travel to distant organs, a phenomenon known as metastasis. The evolutionary plasticity of cancerous cells is the reason that cancer is an intractible problem, scientifically and medically. Soon after a toxic drug is found to kill tumor cells, those cells that are resistant to the drug will multiply and grow in their place.
Despite their differences, the entire population of malignant cells came from a single unstable mother cell. This clonal origin of cancerous cells is easily seen by tracing unique chromosomal rearrangements that could only have arisen from one source. So the challenge facing scientists is to determine how one normal cell out of trillions in the human body can become so chromosomally and phenotypically unstable that it gives rise to cancer.
To understand this phenomenon, the author’s group began to collect and analyze cellular exceptions to the popular gene mutation theory of cancer. This allowed them to identify six main features of cancer that are inexplicable by gene mutation alone but are explained by gross chromosomal changes.
Cancer risk increases with age. Basically, cancer is primarily a disease of old age and is almost completely unknown in the young. This is consistent with chromosomal disturbances hypothesis because gene mutations accumulate over generations. Thus, even though newborns can harbor enough gene mutations to trigger cancer, they rarely have cancer. Additionally, lab mice that are intentionally engineered to carry an assortment of carcinogenic mutations from birth can live and propagate with no higher risk of developing tumors than normal lab mice. So this suggests that something other than simple genetic mutations are the likely cause of cancers.
Also consistent with these observations, and a rare exception to cancer’s age bias, are children that suffer from congenital aneuploidy, such as Down’s Syndrome, or from an inherited chromosomal instability syndrome, such as mosaic vareigated aneuploidy (MVA), both of which cause mental retardation. These inborn errors result in disturbances to chromosomal structure or number. For example, it is known that defects of the spindle assembly in the cells of MVA children produce random aneuploidies throughout their bodies, and nearly one third develop leukemia or unusual solid cancers. Thus, being born aneuploid or with the propensity towards aneuploidy accelerates the process that leads to cancer.
Carcinogens take a very long time to cause cancer. After exposure to numerous chemicals and forms of radiation that are known to be carcinogeonic, it is known that even the strongest carcinogens at the highest survivable doses do not cause cancer immediately. Instead, cancer only shows up years or decades later. However, when bacteria are exposed to substances that cause gene mutations, they begin to display their new phenotypes within hours, and in larger organisms, such as fruit flies, this effect is seen within days. Thus, the gene mutation scenario does not explain why cells exposed to carcinogens become cancerous.
Carcinogens, whether or not they cause gene mutations, induce aneuploidy. Some of the most potent carcinogens, such as asbestos, tar, aromatic hydrocarbons, nickel, arsenic, lead, plastic and metallic prosthetic implants, particular dyes, urethane and dioxin, do not typically produce any mutations at all. Moreover, the dose required to mutate any one gene can be a thousand times greater than that required to induce malignant tumors years later. But it was noted in all cases that the chromosomes of cells treated with these carcinogens displayed higher than usual rates of breakage and disruption. Thus, carcinogens function as “aneuploidogens” rather than mutagens.
Patterns of aneuploidy are seen in different tumors. If aneuploidy is a side effect of cancer, then chromosomal changes in the cancers of different people should be random. But in fact, based on findings using several chromosome painting technologies, scientists are detecting distinct non-random chromosomal patterns in cancer cell genomes. These technologies allow scientists to tag specific regions of chromosomes with colored DNA-specific probes and to construct pictures of the chromosomal pieces that have been gained, lost of rearranged in each cell. For example, a group at Karolinska University Hospital in Sweden found that patients suffering from Burkitt’s lymphoma had translocations involving chromosomes 3, 13 and 17, as well as specific losses or gains in chromosomes 7 and 20.
Additionally, researchers have found that specific chromosomal changes are associated with the particular stage of the cancer, its metastatic potential, and drug resistance. For instance, the Karolinska group found that translocations of a particular region of chromosome 17 and gains on parts of chromosomes 7 and 20 were associated with drug resistance.
Gratuitous traits do not contribute to cancer’s survival. Individual gene mutations, which rarely occur, would only be selectively conserved in tumor cells if the mutation gave those cells an advantage. So the chances of an untreated cancer developing resistance to a drug it has never been exposed to before and metastisis, which does not help the cell to successfully compete with normal cells at the site of origin, is practically zero. But because chromosomes contain thousands of genes, they can be selectively retained for their contribution to some cancer-specific phenotype, and many other unselected traits, such as drug resistance and metastic potential, also located on that same chromosome, would tag along. Because of this, cancer cells can evolve all sorts of new and unexpected traits very rapidly.
Cancer cells change much faster than genes. As you might have surmised from the previous point, cancer cells can evolve new phenotypes and lose old ones very rapidly — much more rapidly than normal gene mutations occur. In fact, the mutation rate for each individual gene remains normal in more than 90 percent of all cancers. Instead, aneuploid cells reshuffle their chromosomes and phenotypes much faster than mutatation can alter their genes. Further, those cells that were more aneuploid were quicker to alter their chromosomes, a pattern that strongly supports the conclusion that chromosomal instability in cancer cells is catalyzed by cellular aneuploidy itself.
These collective observations were summed up nicely by Leslie Foulds of the Royal Cancer Hospital in London: “no two tumors are exactly alike … even when they originated from the same tissue … and have been induced experimentally in the same way.” This individuality of cancers cannot be explained by the activity/inactivity of specific genes, which would be expected to have consistent effects each time in the each cell.
Instead, by recognizing cancer as a chromosomal rather than a genetic disease, medicine can act accordingly. So once a cancer has been identified, this aneuploid scenario shows how random chromosomal reshuffling can rapidly generate lethal properties such as drug resistance and metastasis. As a result, treatment paradigms that rely on using one drug, for instance, especially those drugs that target one gene, will not be effective. Additionally, this can help in diagnosis: by determining the level of aneuploidy in a given cell population, scientists can detect and distinguish early cancers from morphologically similar benign tumors. Further, in the case of more advanced tumors, identifying the level of aneuploidy can be used to guide treatment choices.
Finally, screening for chromosome-damaging substances in food, drugs and in the environment could significantly improve cancer preventiion by identifying pottential carcinogens. This knowledge will provide a basic understanding of cancer, yielding effective prevention, management and even cures.
Chromosomal Chaos and Cancer, by Peter Duesberg. Scientific American, May 2007, pp. 115-122.