In a new study, cancer biologists show that restoring the protein p53's function in mice with early lung cancer has no effect in tumor development but restoring p53 function later may prevent more advanced tumors from spreading throughout the body.
Cancer researchers have known since the 1980s that p53 plays a critical role in protecting cells from becoming cancerous and P53 is defective in about half of all human cancers; when it functions correctly, it appears to suppress tumor formation by preventing cells with cancer-promoting mutations from reproducing. Knowing p53's critical role in controlling cancer, researchers have been trying to develop drugs that restore the protein's function, in hopes of reestablishing the ability to suppress tumor growth. One such drug is now in clinical trials.
P53 is known to control the cell cycle, which regulates cell division. In particular, the protein stops a cell from dividing when its DNA is damaged. P53 then activates DNA repair systems, and if the damage proves irreparable, it instructs the cell to commit suicide.
Without p53, cells can continue dividing even after acquiring hazardous mutations. Eventually, after a cell accumulates enough mutations, it becomes cancerous. Cancer biologists believe that sustained inactivation of p53 and other tumor suppressors is necessary for cancers to become advanced.
The findings of this new study suggest that drugs that restore p53 function could help prevent aggressive lung cancers from metastasizing, though they might spare benign tumor cells that could later turn aggressive. "Even if you clear the malignant cells, you're still left with benign cells harboring the p53 mutation," says David Feldser, lead author of the paper and a postdoctoral fellow at the David H. Koch Institute for Integrative Cancer Research at MIT.
However, such drugs are still worth pursuing because they could prolong the life of the patient, says Feldser, who works in the lab of Koch Institute Director Tyler Jacks, senior author of the paper.
In the new study, the researchers studied mice that are genetically engineered to develop lung tumors shortly after birth. Those mice also have an inactive form of the p53 gene, but the gene includes a genetic "switch" that allows the researchers to turn it back on after tumors develop.
At first, the researchers turned on p53 in mice that were four weeks old and had developed tumors known as adenomas, which are benign. To their surprise, restoring p53 had no effect on the tumors.
Next they turned on p53 in another group of tumor-prone mice, but they waited until the mice were 10 weeks old. At this point, their tumors had progressed to adenocarcinomas, a malignant type of cancer. In these mice, turning on p53 cleared the malignant cells, but left behind cells that had not become malignant.
This suggests that the p53 signaling pathway is recruited only when there is a lot of activity from other cancer genes. In benign tumors, there is not enough activity to engage the p53 system, so restoring it has no effect on those tumors. In the malignant tumor cells, reactivated p53 eliminates cells with too much activity in a signaling pathway involving mitogen-activated protein kinase (MAPK), which is often overactive in cancer cells, leading to uncontrolled growth.
The researchers are now looking for drugs that reactivate mutant forms of p53, and also plan to study whether tumors that have metastasized would be vulnerable to p53 restoration.
The research was funded by the Howard Hughes Medical Institute.
Citation: David M. Feldser, Kamena K. Kostova, Monte M. Winslow, Sarah E. Taylor, Chris Cashman, Charles A. Whittaker, Francisco J. Sanchez-Rivera, Rebecca Resnick, Roderick Bronson, Michael T. Hemann, et al., 'Stage-specific sensitivity to p53 restoration during lung cancer progression', Nature 468, 572-575 (24 November 2010) doi:10.1038/nature09535
- PHYSICAL SCIENCES
- EARTH SCIENCES
- LIFE SCIENCES
- SOCIAL SCIENCES
Subscribe to the newsletter
Stay in touch with the scientific world!
Know Science And Want To Write?
- Sexual Fantasies: Threesomes Are Normal, Golden Showers Not So Much
- Ghost Light From Dead Galaxies - A Hubble Halloween
- Mediterranean Diet Linked To Better Kidney Health
- Greenpeace Says Its GMOs Are Better Than Science's GMOs, Still Hates Golden Rice
- Game Theory: When Are Groups Social? Or Insufferable?
- US Wildlife Bans On GMOs And Neonics Lack Transparency And Scientific Rationale
- Coulrophobia: Are Clowns Scary? Ha Ha Aaaargh
- "Twelve years in a major urban public school system, and I couldn't once bring myself to eat a school..."
- "Hardly a day goes by without some creative new take on the eternal Evil White Man meme. Without..."
- "There would be no controversy if it were all balloons and ponies stories like that. But I hope..."
- "Let's talk about this disaster: I lost a course at the university where I work and became ineligible..."
- "Partisan nastiness doesn't advance dialogue. We are all in this together. You asked for solutions..."
- Battle of Britain: NGOs and scientists clash over proposal to loosen EU GMO restrictions
- Genetically modified clean energy from bacteria
- Designer babies: You can screen for cystic fibrosis but intelligence is a ways off
- Science as profane: What superstition of 1752 and 2014 share in common
- What’s so “natural” about “natural crop breeding”?
- Worried you have cancer? Take a Google pill!
- Report examines health care challenges for pregnant women enrolled in covered California
- NYU research: Majority of high school seniors favor more liberal marijuana policies
- ESA Frontiers November preview
- Sexual fantasies: Are you normal?
- Synthetic lethality offers a new approach to kill tumor cells, explains Moffitt researcher