BioWorld International Correspondent

LONDON - A discovery by researchers in the Netherlands has forced a rethinking of the scientific dogma relating to how cancer cells differ from normal cells. Put simply, cancer cells are less protected than normal cells against uncontrolled proliferation, and the new research describes a novel strategy by which cancer cells can evade the normal controls.

Ultimately, the finding could lead to new ways of making cancer drugs more effective.

Hein te Riele, head of the division of molecular biology at The Netherlands Cancer Institute in Amsterdam, told BioWorld International: "As a general principle, cell cycle checkpoints protect normal cells from uncontrolled proliferation, and cancer cells have lost those checkpoints. We have now described a new and previously unknown checkpoint, which may contribute to finding improved therapies for cancer."

The work is described in the Dec. 12, 2005, issue of Cancer Cell in a paper titled "Mitogen requirement for cell cycle progression in the absence of pocket protein activity."

Te Riele and his colleagues were investigating the processes that led to the arrest of cell division in cells in culture. Such cells normally need growth factors, supplied in the growth medium. Without those growth factors, the cells arrest at the G1 checkpoint.

If growth factors are present, conversely, the cells enter S phase of cell division and begin synthesizing DNA.

Te Riele's group, and others, already had shown that for the G1 checkpoint to operate, the cells need three proteins, all members of the retinoblastoma protein family. Scientists predicted that cells that did not have these three proteins would proceed to synthesize their DNA independently of growth factors and progress through the cycle of cell division.

The work reported in Cancer Cell, however, showed that this is not the case. Instead, while cells do indeed pass through the S phase and enter the G2 phase, they subsequently die.

Graduate student Floris Foijer, first author on the Cancer Cell paper, decided to inactivate the pathway leading to apoptosis by overexpressing the protein BCL2 and thus modeling an event that also is frequently seen in human cancer. To his surprise, he found that the cells no longer die; instead they arrest their growth in the G2 phase.

The team has drawn two conclusions from that finding. "First," said te Riele, "this tells us that the idea that once cells have passed through the G1 checkpoint they continue to proliferate is not correct, because the cells arrest in G2. Secondly, our cells are apparently better protected from uncontrolled proliferation than we thought, because of this previously unnoticed checkpoint."

Experiments carried out by the Dutch team showed that two small molecules, called p21 and p27, inhibit the progression of the cell cycle through the G2 checkpoint, by inhibiting cyclins - particularly cyclins A and B1.

"As long as these cyclins are inactive," te Riele said, "the cells cannot pass through G2. We believe that, somehow, this inhibitory effect of p21 and p27 is at the heart of the mechanism that arrests cells in G2."

They also showed that the well-known tumor suppressor protein p53 plays a role in that mechanism. Loss of p53 reduces the levels of p21 and p27 and causes the G2 checkpoint to fail.

That finding provides a novel explanation for earlier observations that combined loss of the retinoblastoma proteins (abrogating the G1 checkpoint) and loss of p53 (abrogating the G2 checkpoint) accelerates tumor development.

"It was for a long time thought that loss of the G1 checkpoint was mandatory for the development of cancer, and this is still true," te Riele said. "But what we have shown is that loss of the G1 checkpoint alone is not sufficient for cancer to develop, because there is another checkpoint in G2. For cancer to develop, additional events are needed that remove the G2 checkpoint. Loss of p53 may be such an event."

In certain types of premalignant lesions, he added, the cells are arrested, and it is possible that they are arrested in the G2 phase of the cell cycle.

The team is planning follow-up studies in animal models to see if they can find evidence that loss of the G2 checkpoint turns such lesions into malignant tumors.