Cancer’s Chromosomal Chaos

KOPS (University Medical Center Utrecht):

This year, 2014, marks the 100th anniversary of an astonishing prediction by one of the great biologists of the past. Theodor Boveri had been observing the many ways in which the development of a sea urchin embryo could go awry when an egg was fertilized by multiple sperm cells. He noticed that those eggs made many errors in how they distributed the chromosomes during the first cell divisions and he deduced that the problems with development were caused by the wrong combination of chromosomes ending up in cells of the embryo. Surely, he thought, these chromosomes must contain information that dictates how a cell should behave. Knowing that another German biologist, David von Hansemann, had seen tumor cells with abnormal amounts of chromosomes, Boveri did what all great scientist do: he merged the two seemingly unrelated observations. Boveri realized that tumor cells might be tumor cells because they lost certain chromosomes that carried information on how to behave.

Not only was this theory of Boveri astonishing because he correctly deduced the existence of tumor suppressor genes (some sixty years before the rest of the world embraced this concept), but it also predicted something that took almost one hundred years to become established in tumor cell biology research: It is now known that the presence of the wrong amount of chromosomes (known as aneuploidy) is the most common genetic alteration in human solid tumors. It is caused by errors in faithful segregation of the chromosomes during the process of cell division, much like in Boveri’s sea urchin eggs. Tumor cells are a sloppy bunch indeed! From their perspective, however, it pays to be sloppy: it allows a population of tumor cells to shuffle the chromosome deck a little every time one of its cells divides, thereby increasing the probability that one of those cells grows just a little more aggressively, for instance. So while sloppiness is deadly to a developing embryo, it benefits a tumor.

Normal, healthy cells have invested a lot in preventing such sloppiness. Our research aims to figure out how one of these error-prevention mechanisms works. This mechanism, known as a ‘checkpoint’, can monitor whether each chromosome is about to travel into the right daughter cell and only allows completion of cell division when all chromosomes have presented their ‘passport’ of good behaviour. Defects at this checkpoint cause chromosomal chaos and cancer in experimental animal models. We discovered that a particular enzyme is the ‘chief executive officer’ of the checkpoint: when it is active, the checkpoint performs its monitoring function properly, but when inactive, the checkpoint does not. The result is chromosomal chaos. One important aspect of our work is understanding where the managing powers of this enzyme come from: what does the enzyme do, how does it do it, who are its foot soldiers, and is it malfunctioning in cancer cells?

Paradoxically, the cancer’s sloppiness might just turn out to be its Achilles’ heel. While cancer cells are sloppy, they are only mildly so, losing one chromosome here, gaining one there, but never gaining or losing many at the same time. Working as a postdoctoral fellow at UCSD in 2004, I showed that various types of cancer cells can be killed when forced to make more severe errors in chromosome distributions than they are used to: death by severe chromosomal chaos. This brought up a new therapeutic possibility: if cancer cells are already tiptoeing on the edge of a cliff by making some errors but not too many, we could give them a little shove to push them over the edge. Healthy cells, on the other hand, have both feet firmly on the ground and may not care too much about that little shove.

You can also think of a cell as a car with four wheels, each wheel representing a process that ensures correct chromosome distribution. In a tumor cell, one of the rear wheels is missing, still allowing the car to move but clearly not as fast or as well-controlled as a normal car. Punching holes in another tire of this cancer car (weakening the checkpoint) would cause the car to stop completely (kill the cell), whereas punching holes would only cause minor problems for the normal four-wheeled car. When we tested this in collaboration with other investigators in the University Medical Center Utrecht, we indeed found that slicing the metaphorical tire stopped cancer cells in their tracks, but left normal cells humming along.

Much work needs to be done before this strategy can be confidently said to have any merit: Can this work in an organism that carries a tumor somewhere in its body? If so, can many types of tumors be killed this way? What is the best way to slice the tire? With recent help from the European Research Council, the Dutch Cancer Foundation, and Cancer Genomics Netherlands, we are now trying to answer these questions and deliver a dose of chaos back to the tumor.

Geert Kops
University Medical Center Utrecht
www.atomiumculture.eu

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