Gene silencing triggered a cancer-like response (left); reactivation restored normal cell division (right). Picture credit: Kevin P. O'Rourke
The tumor suppressor gene known as adenomatous polyposis coli (APC) is thought to have been affected by inactivating mutations in "the vast majority" of colorectal tumors, the researchers publishing in the journal Cell say.
They found that restoring normal levels of the human colorectal cancer gene in mice stopped tumor growth and re-established normal intestinal function within just 4 days.
According to information from the CDC, colorectal cancer is the second-leading cause of cancer-related death in the US, with 135,260 people receiving the diagnosis in 2011.
The authors of the study say: "APC mutant colorectal cancer cells account for more than 600,000 deaths annually worldwide."
While their scientific findings are early, the potential reach is illustrated by senior author Scott Lowe, PhD, of the Memorial Sloan Kettering Cancer Center in New York City, NY:
"Treatment regimes for advanced colorectal cancer involve combination chemotherapies that are toxic and largely ineffective, yet have remained the backbone of therapy over the last decade."
"Remarkably," say the researchers, tumors were eliminated within 2 weeks of the gene reactivation, and there were no signs of cancer a number of months later.
Proof of principle - that restoring the function of a single tumor suppressor gene can lead to tumor regression - is established by this laboratory work. It opens avenues for the development of effective cancer treatments.
Do the gene mutations maintain the cancer as well as initiate it?
Although the inactivating mutations were thought to initiate colorectal cancer, it was not clear whether APC inactivation also played a role in tumor maintenance, which is what the team set out to test.
"We wanted to know whether correcting the disruption of APC in established cancers would be enough to stop tumor growth and induce regression," says first author Lukas Dow, PhD, of Weill Cornell Medical College, also in NYC.
Lowe and his team needed to overcome an experimental challenge in answering this question. Excess gene activity can often be triggered by attempts to restore function to lost or mutated genes in cancer cells.
To overcome this effect on normal cells, the team used a genetic technique that would precisely and reversibly disrupt APC activity in a new mouse model of colorectal cancer.
Consistent with previous findings, APC suppression in the animals activated the WNT signaling pathway, which is known to control cell proliferation, migration and survival.
When APC was reactivated in the laboratory models:
- WNT signaling returned to normal levels
- Tumor cells stopped proliferating
- Intestinal cells recovered normal function.
Within 2 weeks, tumors regressed and disappeared, or reintegrated into normal tissue - and there were no signs of cancer within a 6-month follow-up.
The scientists also found their approach was effective in mice with malignant colorectal cancer tumors containing Kras and p53 mutations - these are found in about half of colorectal tumors in humans, they say.
Although APC reactivation is unlikely to be relevant to other types of cancer, the experimental technique may have broad implications.
"The concept of identifying tumor-specific driving mutations is a major focus of many laboratories around the world," Dr. Dow says. "If we can define which types of mutations and changes are the critical events driving tumor growth, we will be better equipped to identify the most appropriate treatments for individual cancers."
There is some work to do before the laboratory work finds clinical relevance.
"It is currently impractical to directly restore APC function in patients with colorectal cancer," Dr. Lowe says, "and past evidence suggests that completely blocking WNT signaling would likely be severely toxic to normal intestinal cells."
"However, our findings suggest that small molecules aimed at modulating, but not blocking, the WNT pathway might achieve similar effects to APC reactivation.
"Further work will be critical to determine whether WNT inhibition or similar approaches would provide long-term therapeutic value in the clinic."