Navigation Links
Mutations in different cells cooperate to set the stage for cancer
Date:1/13/2010

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.

Since their results indicated that the genetic "cooperation" long thought to be necessary for tumor formation could actually occur between cells, Xu's team wanted to find out how this could happen. By sifting through some of the genes activated in the RasV12 plus scrib- combination, they found the signaling pathway that mediates the interaction. They showed that cells that contain the scrib- mutation activate a signal protein called JNK, which in turn drives a signaling pathway that promotes cellular proliferation. When this JNK-driven activity reaches cells that contain RasV12, the combination of these two cell-proliferating influences appears to be enough to push the cells into tumorigenesis.

Intriguingly, the JNK activity seems to spread from scrib- cells via a mysterious, domino-type effect. "The signal is relayed from cell to cell," Xu said. "So if we stop it in one cell, then the signal no longer propagates."

Xu and his colleagues say that the scrib- mutation is not the only thing that can spur JNK signaling. JNK is a stress-response signal, which is activated when tissues are wounded or inflamed, and it appears to be necessary for wound healing. Thus relatively ordinary stress, in concert with a RasV12 mutation, might be enough to trigger cancer.

"It has been suspected that stress contributes to cancer because individuals that are frequently exposed to stressed conditions such as inflammation are more likely to develop cancer," said Xu. "We have learned that indeed stress can help tumor development and it does so by activating the JNK stress signaling process. Now we know this, we can consider targeting it with therapeutics."


'/>"/>

Contact: Jennifer Michalowski
michalow@hhmi.org
301-215-8576
Howard Hughes Medical Institute
Source:Eurekalert

Related biology news :

1. Study of huge numbers of genetic mutations point to oxidative stress as underlying cause
2. Species diversity helps ASU researchers refine analyses of human gene mutations
3. DNA mutations linked to diabetes
4. Further gene mutations linked to autism risk
5. Rapid approach to identify influenza A virus mutations and drug resistance developed
6. Penn biologists discover how silent mutations influence protein production
7. Researchers discover gene mutations that cause childhood brain cancer
8. Heavy metal link to mutations, low growth and fertility among crustaceans in Sydney Harbor tributary
9. Large reservoir of mitochondrial DNA mutations identified in humans
10. How hidden mutations contribute to HIV drug resistance
11. Smothered genes combine with mutations to yield poor outcome in cancer patients
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:5/16/2016)... YORK , May 16, 2016   EyeLock ... solutions, today announced the opening of an IoT Center ... to strengthen and expand the development of embedded iris ... an unprecedented level of convenience and security with unmatched ... authenticate one,s identity aside from DNA. EyeLock,s platform uses ...
(Date:5/3/2016)... 3, 2016  Neurotechnology, a provider of high-precision ... Automated Biometric Identification System (ABIS) , a complete ... MegaMatcher ABIS can process multiple complex biometric transactions ... of fingerprint, face or iris biometrics. It leverages ... and MegaMatcher Accelerator , which have been ...
(Date:4/26/2016)... BANGALORE, India and LONDON ... Infosys Finacle, part of EdgeVerve Systems, a ... ), and Onegini today announced a partnership to ... banking solutions.      (Logo: http://photos.prnewswire.com/prnh/20151104/283829LOGO ... banks to provide their customers enhanced security to ...
Breaking Biology News(10 mins):
(Date:6/23/2016)... Durham, NC (PRWEB) , ... June 23, 2016 , ... ... Odense University Hospital in Denmark detail how a patient who developed lymphedema after being ... (fat) tissue. The results could change the paradigm for dealing with this debilitating, frequent ...
(Date:6/23/2016)... BEACH, Calif. , June 23, 2016  Blueprint ... new biological discoveries to the medical community, has closed ... co-founder Matthew Nunez . "We have ... us with the capital we need to meet our ... will essentially provide us the runway to complete validation ...
(Date:6/23/2016)... 23, 2016 On Wednesday, June 22, ... down 0.22%; the Dow Jones Industrial Average edged 0.27% lower ... 2,085.45, down 0.17%. Stock-Callers.com has initiated coverage on the following ... Therapeutics (NASDAQ: NKTR ), Aralez Pharmaceuticals Inc. (NASDAQ: ... BIND ). Learn more about these stocks by accessing ...
(Date:6/23/2016)... WI (PRWEB) , ... June 23, 2016 , ... ... focused on quality, regulatory and technical consulting, provides a free webinar ... presented on July 13, 2016 at 12pm CT at no charge. , Incomplete ...
Breaking Biology Technology: