Anti-cancer strategies generally involve killing off tumor cells. However, cancer cells may instead be coaxed to turn back into normal tissue simply by reactivating a single gene, according to a study published in the journal Cell. Researchers found that restoring normal levels of a human colorectal cancer gene in mice stopped tumor growth and re-established normal intestinal function within only 4 days. Remarkably, tumors were eliminated within 2 weeks, and signs of cancer were prevented months later. The findings provide proof of principle that restoring the function of a single tumor suppressor gene can cause tumor regression and suggest future avenues for developing effective cancer treatments.
Colorectal cancer is the second leading cause of cancer-related death in developed countries, accounting for nearly 700,000 deaths worldwide each year. 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.
Up to 90% of colorectal tumors contain inactivating mutations in a tumor suppressor gene called adenomatous polyposis coli (Apc). Although these mutations are thought to initiate colorectal cancer, it has not been clear whether Apc inactivation also plays a role in tumor growth and survival once cancer has already developed.
The researchers wanted to know whether correcting the disruption of Apc in established cancers would be enough to stop tumor growth and induce regression. This question has been challenging to address experimentally because attempts to restore function to lost or mutated genes in cancer cells often trigger excess gene activity, causing other problems in normal cells.
To overcome this challenge, the researchers used a genetic technique to precisely and reversibly disrupt Apc activity in a novel mouse model of colorectal cancer. While the vast majority of existing animal models of colorectal cancer develop tumors primarily in the small intestine, the new animal model also developed tumors in the colon, similar to patients. 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, Wnt signaling returned to normal levels, tumor cells stopped proliferating, and intestinal cells recovered normal function. Tumors regressed and disappeared or reintegrated into normal tissue within 2 weeks, and there were no signs of cancer relapse over a 6-month follow-up period. Moreover, this approach was effective in treating mice with malignant colorectal cancer tumors containing Kras and p53 mutations, which are found in about half of colorectal tumors in humans.
The researchers will next examine the consequences of Apc reactivation in tumors that progress beyond local invasion to produce distant metastases. They will also continue to investigate why Apc is so effective at suppressing colon tumor growth, with the goal of one day mimicking this effect with drug treatments.
Based on material originally posted by Cell Press.