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As a cell grows, so may cancer

Size may be as important as division, say fruit-fly researchers who pursue trend in basic sciences
Macro images of fruit fly eye one normal and one greatly reduced.
A fruit fly that produces too much of the tumor suppressor called brat (left) has eyes greatly reduced in size compared to those of a normal fly (right). Images courtesy Dr. Mark Roth

Even in the microscopic world of cells, size sometimes matters. In fact, for cells in organisms as diverse as fruit flies and humans, getting too big can have a disastrous consequence: the onset of cancer.

Biologists have long recognized that unrestrained cell division, the process by which one cell divides into two, is a hallmark of cancer.

More recently, the laboratories of Drs. Mark Roth, Bruce Edgar and Bob Eisenman in the Basic Sciences Division have shifted their attention to cell growth, a process that plays an equally important role in cancer development.

"Until the last few years, people used the words 'growth' and 'division' interchangeably," said Dr. Deborah Frank, a postdoctoral fellow at Washington University in St. Louis who recently completed her graduate work in Roth's lab. "Now we treat the two words separately, because it's become clear that growth - that is, how big a cell gets - is subject to its own regulation. If that regulation becomes abnormal, it can lead to cancer."

Frank, Roth and Edgar used the tiny fruit fly Drosophila to illustrate how cell size and tumor formation are linked by studying a fly gene called brat, for brain tumor. Their findings appeared in the Jan. 15 issue of Development.

With life spans of roughly one month, fruit flies don't live long enough for their cells to amass enough mutations to cause true cancer. Yet some strains of flies harbor mutations that cause tumors to form as a result of unregulated cell division or growth.

A gene called brat

One such mutation results in a deficiency in the brat gene, which is known as a tumor suppressor. When intact, brat prevents tumor formation. In contrast, flies lacking the brat gene die prematurely with greatly enlarged brains, the characteristic giving rise to the gene's name. Such genes aren't unique to flies: In humans, tumor suppressor genes are frequently mutated in a variety of human cancers.

Frank was drawn to study cell growth in flies after a discovery she made in the roundworm Caenorhabditis elegans. She found that a worm gene, known as ncl-1, helps to keep cell growth in check by keeping cells from manufacturing too much of the cell machinery used to make proteins. Cells lacking ncl-1 have enlarged compartments in which these protein-making components are produced.

The fly gene with a sequence most similar to ncl-1 is brat, an observation that prompted Frank to test whether both organisms use similar means to control cell growth. In fact, they do: she found that when the fly gene is introduced into ncl-1 mutant worms, it compensates for the ncl-1 defect.

Frank also observed that flies deficient for brat have bigger-than-normal cells. Like the worms with cell-growth defects, cells from brat mutant flies have enlarged compartments that are characteristic of the overproduction of protein synthesis machinery.

Too much brat also causes abnormalities. Flies engineered to overproduce brat have unusually small organs. For example, excess brat production in the fly eye causes a dramatic reduction in eye size relative to normal flies.

Frank postulates that excessive cell growth may be an important precursor to enhanced cell division, which ultimately leads to tumor formation.

"Cells may have to reach a certain size before they can divide," she said.

"We know that's true in yeast, where you can see a new cell bud from the mother cell when the mother reaches a certain size. But there hasn't been the same proof for cells from more complex organisms."

The idea that enhanced growth triggers division is supported by studies in mammalian cells that have focused on myc, one of the best-known oncogenes (genes that when improperly regulated can cause cancer). For example, research in Dr. Robert Eisenman's Basic Sciences laboratory on the role of myc in mice has shown that excess cell growth occurs prior to enhanced cell division.

"Based on all these findings, I would argue that to make a cancerous cell, you need to lose control of both cell growth and division," Frank said.

Close relatives

Although Frank has been unable to detect a human gene identical to brat, human cells do possess close relatives.

"There are several human genes that have regions within them similar to brat," she said. "Although their exact function is unclear, it is intriguing that some of these genes are known to play a role in cancer."

Miller, a postdoc in Dr. Kathryn Miller's lab at Washington University, continues to study cell growth in flies. She analyzes the role that the cell cytoskeleton - a network of proteins important for cell shape and movement - plays in growth control and tumor formation.

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