September 22, 2002	Sunday	Rajab 14, 1423

LOS ANGELES: One of the fundamental riddles of cancer — how a single cell can accumulate enough mutations to become malignant — may now be solved, scientists report.

The answer seems to lie in the availability of road-kill. By slurping up the parts and pieces of cells that have died nearby, ordinary cells may consume another cell’s damaged DNA, then lose control of their own growth and become cancerous.

Until now it was suspected that all the mutations that lead to cancer must occur within one cell, which then grows like a clone to form a tumour. In colorectal cancer, for example, as many as six different mutations are needed to reach malignancy.

But “that has been very difficult to explain,” said tumour biologist Lars Holmgren. “How can all of these mutations occur within a short period of time, and within one cell?”

His new idea is that mutations can be occurring independently, in numerous cells, “but by sharing, they may all end up in a single cell,” he added. So if cells pick up genes from dying cells, perhaps “there’s a continuous scrambling of the genome,” Holmgren said. Such a process “would increase the genetic diversity of the tumour,” allowing cells in the tumour to try new gene combinations that let them escape being poisoned by drugs. This is how multi-drug resistance arises, causing treatments to fail.

After experimenting with cells growing in culture dishes, Holmgren and his colleagues at the Karolinska Institute in Sweden now think they have the answer. They suspect it’s a phenomenon called horizontal transfer, cells using the mutant DNA spilled from dying neighbours.

Cancer biologist Doug Hanahan said, “This is a very provocative observation, an interesting notion. We know that cancer cells have genomic instability, and can rearrange and scramble their genomes.”

Hanahan, at the University of California Medical School in San Francisco, added, “The notion that a cell can sort of take up the body of one of its neighbours and assimilate” the genes “is a very intriguing result.”

But, he said, “We don’t know yet how important it is.”

According to Holmgren, it seems important indeed, offering a new way to understand what’s occurring in cancer.

“We were surprised to see that entire chromosomes, or fragments of chromosomes, were transferred” into the cells near dying tumour cells. And it’s now clear, he said, that “the oncogenes (cancer genes) are piggybacking on these fragments.”

The so-called oncogenes, given names like myc and ras, are known to be central players in the process of carcinogenesis, touching off the uncontrolled growth that is cancer. And it is such loss of genetic stability, scrambling the cell’s internal blueprints, that allows this to happen.

“The amazing thing was that we found fusions of chromosomes,” joinings between the cell’s normal gene carriers and those picked up from the dying cancer cells, Holmgren said in an interview. “So that was how it was propagated, as independent chunks of DNA, or as fusions, or as whole chromosomes” released from the dying cells and then consumed.

This suggests that the mutations needed to get cancer going can be occurring in many different cells, without necessarily doing immediate damage. Then as these cells die and their mutant genes are released, the excess DNA can be scavenged and get into other cells. In time, a nearby cell may pick up enough damaged DNA to get cancer going, or to accelerate the cancer process.

The scavenging scenario might also show how, and why, tumours evolve rapidly enough to escape assault by the patient’s immune system, how they can resist all the drugs that doctors try, become immune to radiation, and “learn” to send out deadly metastases that take root elsewhere. The instructions are accumulating, thanks to contributions from dying neighbours.

Thus, like a virus, mutant DNA from cancer cells is, in a sense, “infecting” well-behaved normal cells. And if the normal cells’ defences are down, they soon begin showing the signs of cancer. So in one sense this resembles the spread of an infectious disease, from cell to cell to cell.

The new studies in Sweden also show that the debris from dying cells rapidly disappears, which means that “all of the tumour cells that were dying were being cleared by the neighbouring cells,” Holmgren explained.

“From that came the idea that the neighbouring cells are eating the dying cells, and could be rescuing the DNA. Is that how they get the mutant genes, or chromosome fragments?” he asked.

The answer is yes. And now “we’ve proven that hypothesis in cell culture systems,” Holmgren said.

To be certain, however, Holmgren and his colleagues are trying to verify their findings in other systems, such as living mice.—Dawn/The LAT-W.P News Service (c) The Washington Post.