According to modern biology textbooks, a single genetic mutation is rarely enough to cause cancer. It is generally thought that cells must accumulate a series of mutations that work together to trigger tumor development. Now, Howard Hughes Medical Institute (HHMI) researchers have shown that distinct cancer-causing mutations in neighboring cells can cooperate to produce tumors.
Cancer biologists have long known that it takes the cooperation of multiple cancer-causing genes - or oncogenes -- to cause cancer. "It was assumed that these mutations have to occur in the same cells to drive tumorigenesis," said HHMI researcher Tian Xu at Yale University. "We have now discovered that the oncogenic mutations don't have to be in the same cells to drive development of cancer. Distinctive mutations occurring in different neighboring cells could cooperate to promote tumorigenesis."
Xu, graduate student Ming Wu, and postdoctoral researcher Jos- Carlos Pastor-Pareja, both of whom work in Xu's lab at Yale University, are coauthors of the study published in Nature on January 13, 2010. The findings may open up a new avenue of research into the molecular origins of cancer. They also help to clarify how ordinary cellular stresses, such as wounds or inflammation, may promote cancer development.
Xu's team set out to study the interaction of two mutant genes often detected together in tumors. One of these, RasV12, is a growth-promoter. Ras mutations are well known for their ability to cooperate with other mutations to cause cancer. On its own, however, RasV12 causes only a mild overgrowth of cells. The other gene, scrib-, a non-functioning mutant of a tumor-suppressor gene known as scrib, by itself causes cells to die. When the two mutant genes are found in single cell, they cooperate to produce tumors.
Xu and his colleagues were curious about what would happen when RasV12 exists in one group of cells, and scrib- exists in a nearby group of cells. They decided to find out, using the fruit fly Drosophila melanogaster, a model organism that has been a workhorse of geneticists over the years. To its surprise, Xu's group discovered that the two mutations, existing in adjacent clusters of Drosophila larval eye cells, somehow interacted to turn the entire group of cells into a large invasive tumor. The results were dramatic, Xu says. It was just as if the two mutations had existed in a single cell.
"No one has ever shown before that different oncogenic mutations in different cells can interact to produce a tumor," said Xu. "People have just assumed that when they take the DNA from a tumor, the various mutations they see are combined in each cell. But they could be in different cells. Nobody really knows."
The team observed a similar result when they grew cells with the RasV12 mutation together with cells that harbored a dysfunctional mutant of another tumor-suppressor gene, lgl. That led them to wonder whether the old paradigm of oncogenesis - that cancer-causing mutations must exist in the same cell -- might be in need of revision.