Biologist Offers New View of Cancer Origin





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Despite the widespread belief that mutations cause cancer, UC Berkeley professor Peter Duesberg has put forth evidence that changes in chromosome number are the true cause of the disease.

Ninety percent of cancers are "solid cancers," which are whole clonal lumps centered in one location. Of these, Duesberg said none has ever been found to have the correct chromosome number, 46. Some have been shown to have almost twice as many chromosomes than are present in normal cells.

The widely held view is that cancers occur as the result of a series of mutations, which eventually lead to uncontrolled cell growth.

"The key here is that we always think about DNA and genes, but we never think on the whole chromosome level," Duesberg said. The professor, an expert in retroviruses, is best known for his view that the Human Immunodeficiency Virus does not cause AIDS.

Aneuploidy occurs when the chromosomes within a cell do not divide evenly, leaving one cell with an extra chromosome and another cell deficient in one chromosome. The condition of aneuploidy has been reported in every documented case of solid cancers, including breast cancers, lung cancers and liver cancers.

"If you look at these cancers, all are aneuploid," Duesberg said. "I am not aware of an example since the development of chromosome analysis of a diploid cancer. The correlation is virtually exact."

One molecular and cell biology professor said that although Duesberg's theory does not offer a replacement for the mutation theory, the two occurrences could work together in the cancer-causing process.

"These are not alternative theories," said Steve Martin, who studies cell biology and tumor virology. "(Duesberg) argues that aneuploidy is the sole cause of cancer. It could very well be the case that it is one of the factors that contributes to tumors, but I certainly do not think that it is the sole cause. The role of mutations in cancer is well established."

In a peer-reviewed article published in the March 21 edition of the Proceedings of the National Academy of Science, Duesberg argues that aneuploidy is the cause of cancer and mutations are correlated with the disease; the prevailing view in the scientific community is that mutations are the cause of malignancies and aneuploidy is a correlation.

"For nearly a century, cancer has been blamed on somatic mutation," the study states. "But it is still unclear whether this mutation is aneuploidy, an abnormal balance of chromosomes, or gene mutation. Despite enormous efforts, the currently popular gene mutation hypothesis has failed to identify cancer-specific mutations with transforming function and cannot explain why cancer occurs only many months to decades after mutation by carcinogens and why solid cancers are aneuploid."

Duesberg compared the workings of the body to a car assembly line. If each chromosome represents one part of the assembly line - producing an engine or a brake - then a mutation would represent a change in the workers in the assembly line - either they work more slowly or faster, or change their function.

If a whole assembly line is deleted or added, then the final car will end up with too many of one part and not enough of another - potentially resulting in a car with three engines, five brakes and no steering wheel.

The machine that was produced through the altered assembly line would not be a viable product - it would not be able to function in the normal way.

If, however, the workers were changed - they began to work more slowly or more quickly - the effect on the final product would be relatively small compared to adding or deleting a whole assembly line.

Duesberg said while aneuploidy - the addition or deletion of entire assembly lines - is known to be present in all cancers, "cancer-causing" mutations have not been demonstrated to be in all malignancies. Furthermore, he said the mutations have been demonstrated to exist in cells that are not cancerous.

But Martin said the relationship between certain genes and the formation of cancer is well documented - especially the connection between mutations in tumor suppressor genes and the development of malignancies.

"That certain mutations cause cancer is very well established for some genes, and there is strong evidence for others," he said. "For example, it has essentially been proven that mutations in certain tumor repressor genes cause cancer."

Martin said although it is true that no single mutation is present in all solid cancers, there are some that are present in approximately half. If mutations occur that alter the activity of one of the genes usually containing a mutation in human cancers, but the usual mutation does not occur, the ultimate cause of the malignancy is still a mutation.

"There are mutations in all cancers," Martin said. "In a certain cancer, you are not going to be able to identify all mutations. The argument that specific mutations are only present in certain cancers is not a good one."

Martin added, however, that the presence of aneuploidies in human cancers has been well documented.

"It is certainly true that aneuploidies are present in the large majority of cancers," Martin said. "Whether they are the cause of cancer or the consequence of other mutations is what is unresolved. They could play a causal role."

Aneuploidies have long been known to have wide-ranging effects, Duesberg said. For example, the addition of a single chromosome causes Down's Syndrome, which not only causes mental disabilities but can render sufferers sterile and increase their risk of cancer.

Further, if one compares the chimpanzee genome to that of the human, there are very few differences, Duesberg said. But if one considers the number of chromosomes, the differences between the two species can be accounted for.

"Down's Syndrome provides proof of principle," he said. "Aneuploidy clearly changes phenotype, (which are the observable traits expressed in a given organism)."

Duesberg said while it is clear that the number of chromosomes in a cell has an effect on the way the cell functions, the way that mutations work has not yet been determined.

He said many genetic tests that induce certain types of mutations have not yielded cancerous cells. In addition, a change in the number of chromosomes is much more profound than a change caused by a simple point mutation.

When genetic mutations occur, small changes in the phenotype result - for example, a person's hair color changes from red to blond. But when a change in the number of chromosomes occurs, the change is much more dramatic, he said.

"If you look at household genes - the ones that are involved in key cellular processes - they are all basically the same, from E-coli all the way up to humans," Duesberg said. "The difference appears to be in the number of chromosomes. When nature wants to create a new species, it changes the number of chromosomes. Gene mutations are usually just for small adjustments within one species."

Duesberg said the big difference between organisms within a species and organisms between species is the ploidy - the actual number of chromosomes present changes between species, but not within a species. He added that changing the number of chromosomes randomly would likely produce an organism that does not function in its normal capacity.

"The difference appears to be in the way that the chips are put together - you can build a Mac or a PC with the same pieces," Duesberg said. "But if you have five chips with the same function and leave another one out entirely, you will create a system that cannot be read. A similar thing occurs in cancers. Some breast cancers have five copies of the same chromosome."

One of the reasons that scientists have not focused on the question of ploidy is that many cancer studies use bacteria, which cannot have ploidy because they only have one chromosome, Duesberg said. Without the one chromosome, the bacterium could not exist at all.

He theorizes that carcinogens, which are generally all considered to also be mutagens, can alter the way spindle microtubules form during mitosis. The spindles are the part of the cell responsible for separating the chromosome pairs and pulling them to separate ends of the cell.

If spindle fibers form incorrectly, the chromosomes may not separate properly, yielding cells with incorrect ploidies.

The theory is supported by the fact that scientists have found carcinogens that do not cause gene mutations, Duesberg said. These carcinogens have not been studied in association with the development of aneuploidies.

Many have argued that the presence of aneuploidy in cancer cells occurs as a result of mutations, but Duesberg's paper states that the presence of aneuploidy in noncancerous cells overturns this hypothesis.

"Most cancer researchers have abandoned the aneuploidy hypothesis in favor of gene mutation," the study states. "Their reasoning is that aneuploidy must be a consequence of transformation, although this view is incompatible with aneuploidy in noncancerous cells."

Whether or not Duesberg's theory pans out, one biologist stated that it is important that the prevailing views in science constantly be questioned - if they are not, then the entire community becomes stuck.

"(Duesberg) won't let the field stand still," stated Avery Sandberg, the chief editor of the journal Cancer Genetics and Cytogenetics. "Once scientists think of one theory as being the de facto theory, we're in great trouble."

Sandberg added that while Duesberg's hypothesis is not widely accepted, there is little evidence currently available that could eliminate the theory.

"There's a lot to be said for (Duesberg's) theory," Sandberg said. "No one has disproved it, and since the genetic mutation theory was proposed 15 years ago, people have found lots of exceptions. I predict that both theories will turn out to be right, because cancer will be found to result from multiple pathways."

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