German biologist Theodor Boveri observed early in the last century that cancer cells often harbor multiple copies of a subcellular structure that he had previously named the centrosome. He was also the first to suggest that the extra centrosomes drive cancer. Biologists have since learned a great deal about the structure and many functions of Boveri's "special organ of cell division." But why cancer cells harbor multiple copies of this organelle -- and whether they are "addicted" to having so many -- has remained unanswered. So has the question of whether healthy human cells even require centrosomes to divide. Now, 101 years after Boveri aired his suspicions, a Ludwig Cancer Research paper published in advance online in Science may have some answers.
A team of researchers led by Karen Oegema and Andrew Shiau of Ludwig San Diego reports that while cancer cells are not addicted to multiple centrosomes, healthy cells absolutely require them to proceed with cell division. In the absence of centrosomes, healthy cells enter a state of latency, while malignant cells continue dividing. "Our results have settled a long-running debate in cell biology," says Oegema, a member of the Ludwig Institute for Cancer Research, San Diego. "Centrosomes make things so much better for healthy dividing cells, that they have a protective mechanism that halts their division if they lose these organelles."
Ordinarily, the resting cell's single centrosome serves as an organizing center for the cell's protein filament-based skeleton. When a cell divides, however, the centrosome takes on another function. It duplicates and plays a role in ensuring equal distribution of chromosomes to the two daughter cells. Many cancer cells contain multiple centrosomes, and this aberration contributes to the misdistribution and abnormal numbers of chromosomes in daughter cells.
Still, it wasn't clear that centrosomes are absolutely needed for cell division. Biologists have long known that other mechanisms exist to separate chromosomes. "The growing feeling among a number of cell biologists is that the 'centrosome is like the appendix of the cell'," says Shiau, director of the Ludwig Institute's Small Molecule Discovery Program in San Diego. His team, which is part of a broader Technology Development program at Ludwig, specializes in developing compounds that can be used to advance cancer research and have potential as therapies.
Earlier studies had sought to resolve the issue by cutting centrosomes out of cells or destroying them with lasers. But both normal and cancer cells treated this way simply remade their lost centrosomes, and then continued dividing.
To get around this limitation, the researchers designed and synthesized a molecule that specifically and reversibly inhibits an enzyme named Plk4, which controls the assembly of centrioles -- barrel-like protein structures from which centrosomes are made. They then showed that exposure to this inhibitor, centrinone, eliminates centrosomes from both healthy cells and cancerous ones. When the compound was removed, cancer cells reverted to precisely the number of centrosomes they had before exposure to the molecule. Those lacking centrosomes, however, did not stop dividing -- though fewer survived the ordeal.
"This was in marked contrast to what normal cells would do when we persistently removed centrosomes," says Oegema. "Normal cells arrested their growth when their centrosomes were absent. This suggests that they absolutely require centrosomes for division, which was not at all the thinking in the field."
The researchers show that the pause in the division of healthy cells is governed by a protein named p53, which is mutated in about half of all cancers. Levels of p53 were elevated in cells treated with centrinone. When the protein was temporarily inactivated in normal cells, they too failed to arrest upon exposure to centrinone.
The new ability to reversibly eliminate centrosomes is likely to benefit research in a wide variety of biomedical fields, given the organelle's multiple roles -- from organizing the cytoskeleton to sprouting hair-like structures known as cilia on certain cells. The findings might also have applications for cancer therapy, even if cancer cells aren't addicted to centrosomes.
"The idea," says Shiau, "is that you trigger p53 in normal cells and have them stop multiplying -- and then introduce another agent that only kills continuously dividing cells." This concept, dubbed cyclotherapy, was conceived several years ago by David Lane, Ludwig's Scientific Director and a co-discoverer of p53. Working with their colleagues in San Diego, the Ludwig Small Molecule Discovery team is developing more drug-like variants of centrinone with the goal of identifying combination therapies that can be tested in clinical studies.
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