Scientists have long known of the tumor suppressors and oncogenes that kick-start cancer. Now researchers report that downstream genes affected by such mutations act synergistically to further promote cancer progression, according to a study published online in Nature on Sunday (May 25).

"When cells convert from normal to cancer," said Hartmut Land from the University of Rochester Medical Center, an author of the study, "you have a forest of [genetic] changes that arise. It's difficult to understand which are important in the conversion."

So Land and colleagues examined the changes in genes regulated by two known oncogenic genes, p53 and Ras. Mutations in p53 and Ras changed the expression patterns of 548 genes. The researchers then looked for the subset of those genes that acted synergistically -- whose response to the both mutations was more than the sum of their response to Ras or p53 alone.

They then functionally tested these cooperative effects by using short hairpin RNA and cDNA insertions to reverse changes in these "cooperation response genes." They found that in 14 out of 24 cases, reversing the change caused by Ras and p53 mutations reduced tumor formation, with some combinations having a greater effect than others.

"To some people this doesn't come as a big surprise," said Wafik El-Deiry a professor of molecular genetics at the University of Pennsylvania School of Medicine who was not involved in the study. The idea that many genes act together to spur cancer is not new. In fact, 25 years ago, in a paper that has been cited nearly 2,500 times, Land himself showed that a skin cell needed more than a single oncogenic mutation to become cancerous. This research shows "some evidence experimentally," for that mechanism, said El-Deiry.

Land noted that the current study also "generates a rational approach to find targets" for new treatments, by using existing therapies to modulate the genes downstream of the p53 mutation.