At the Centrosome:
An Answer to How Cancer Begins

In the 19th century and the early part of the 20th, German biologist Theodor Heinrich Boveri first described the centrosome and its critical role in cell division or mitosis. He also theorized that somehow, a malfunctioning centrosome begins the process that leads to cancer.

As scientific thought about cancer evolved, however, it turned away from Boveri’s notions and the centrosome and toward the idea that cancer evolves because a gene in the tissue changes or becomes mutated.

“The trouble is that no one has found that specific gene,” said Bill R. Brinkley, Ph.D., vice president and dean of the Graduate School of Biomedical Sciences at Baylor College of Medicine.

In recent years, the importance of the centrosome has come to the fore again, and Brinkley, who is also a distinguished service professor in the department of molecular and cellular biology, is among those leading the move.

The centrosome, a small organelle located outside the nucleus of the cell, divides during cell division and the result is two centrosomes, which move to opposite ends of the nucleus. From each centrosome, microtubules grow into a “spindle” which is responsible for separating replicated chromosomes into the two daughter cells.

Without the correct number of centrosomes, human cells could not divide normally, resulting in a gain or loss of chromosomes within the genome. What happens when the centrosome malfunctions is a matter of dispute.

Brinkley leads a group that thinks that the centrosome’s malfunction is an early and critical event in the initiation of cancer. It has long been known that the genomes or genetic blueprints of cancer cells are unstable and that there are chromosomal abnormalities as well. Some cells may lack one chromosome and have too many of another and vice versa.

Those on the other side of the issue feel that the problem begins with a genetic change and genomic instability occurs much later.

Recent research in the area has brought back “the idea that one of the earliest events (in a cell that becomes malignant) is the actual rearrangement of the genome caused by the aberrant centrosome,” said Brinkley.

In an experiment at Baylor, Brinkley and Dennis Roop, Ph.D., another professor in molecular and cellular biology, blocked the action of the tumor suppressor gene p53 in the skin cells of living mice. The gene p53 is the guardian of the genome and wards off genetic changes that could lead to cancer.

Without the gene working in their skin, the animals develop skin cancers when they were exposed to carcinogens. In 75 percent of the tumor cells, there were too many centrosomes.

“You are supposed to have one or two,” he said. “We are finding anywhere from three to 15 in the cell. It led us back to Boveri’s idea.”

One day he received a call from Subatra Sen, Ph.D., a scientist at The University of Texas M.D. Anderson Cancer Center. He was cloning a gene that had come from extra DNA found at a particular spot on chromosome 20 in breast cancer. He said he didn’t yet have the complete sequence of the gene he was cloning, but he had an antibody to a partial sequence and wanted Brinkley to take a look at it on Baylor’s sophisticated microscopy system.

Brinkley admits his first response was lackadaisical, but then Sen said, “By the way, it looks as though it is staining right at the spindle poles.” Spindle poles and centrosomes are closely linked. The stain was used to locate the position of the antibody in the cell.

Brinkley grins as he said, “I told him to bring it right on over – now. We put in our system and we found that it lights up the centrosomes.”

Sen had found that the gene and its enzyme product – aurora A kinase – was overactive or as geneticists put it, overexpressed, in cancer cells. Brinkley knew there were too many centrosomes in cancer cells.

“I told him that I wondered it there was a connection,” said Brinkley.

Sen went back to determining the DNA sequence of the gene and Brinkley and his laboratory looked at a wide range of cancers.

“At every point, we found that aurora A kinase was found in that region near the centrosome,” he said.

Then they undertook the ticklish task of what caused the gene to overexpress in a normal cell. If they got extra centrosomes, it seemed as though it would prove that centrosome defects and genomic instability were early cancer events.

“We did it,” said Brinkley, “We took mouse cells and transfected them with Dr. Sen’s aurora A kinase cDNA (the portion of a gene that carries its message). Within two days, we had induced extra centrosomes in the cells.”

They have duplicated the achievement in human cells, and Brinkley thinks it has shown that actual rearrangement of the genome caused by aberrant mitosis or cell division could be one of the earliest events in cancer.

With multiple centrosomes, there are multiple poles and each affects the way the spindle achieves its task of separating chromosomes among daughter cells. That effect is bad.

Now Sen is attempting to understand the biochemistry of the enzyme. He wants to know how aurora A kinase causes the centrosomes to become abnormal. His work is being done in human cells.

“We are looking at the centrosome in rats,” said Brinkley. He is using a special experimental rat model developed by Dan Medina, Ph.D., also a professor in the department of molecular and cellular biology. When these rats are pregnant or are given the appropriate dose of pregnancy hormones when they are young, they rarely get breast cancer.

With the help of Thea Goepfert, Ph.D., one of Brinkley’s lab associates, Brinkley attempted to determine if this ability to block cancer with hormones and promote it with carcinogens affects centrosomes.

It turns out that it does. About two months after rats were given a carcinogen, a “hot spot” with cells that have many centrosomes appears. At the same time, production of the aurora A kinase goes up.

“When we give hormones, it doesn’t happen,” he said. “We think there is a hormone connection, at least in breast cancer.”

How do cells with abnormal numbers of centrosomes survive and produce a cancer?

“They survive by bunching the centrosomes together,” he said.

Most of the cells in such clusters die because they cannot divide with abnormal numbers of centrosomes, but in a few there is a set of genes that not only keep the cell alive but actually cause it to grow better than the other cells. Those that do that evolve into cancer cells.

Not every scientist agrees with Brinkley’s theories or those of his colleagues. Science is a process of disagreement and experiment. That’s what makes it exciting – and the right answer might be no more than another experiment away.

– Reprinted from Baylor College of Medicine’s From the Laboratories online newsletter, available at http://www.fromthelab.net.

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©2006 Texas Medical Center

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