Colorectal cancer is the second leading cause of cancer-related death in developed countries, accounting for nearly 700,000 deaths worldwide every year. Anti-cancer therapies generally involve killing off tumor cells. In a major development of cancer treatment, now the cancer cells can be turned back into normal tissue simply by reactivating a single gene, revealed a new study.
Researchers have now found that restoring normal levels of a human colorectal cancer gene in mice stopped tumor growth and re-established normal intestinal function within only four days. Remarkably, the tumors were eliminated within two weeks, and signs of cancer were prevented months later. The study findings suggest future avenues for developing effective cancer treatments.
Senior study author Scott Lowe from Memorial Sloan Kettering Cancer Centre, New York, said, "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 the cancer has already developed.
The research team 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 clinical patients.
Consistent with previous findings, Apc suppression in the mice activated the Wnt signalling pathway, which is known to control cell proliferation, migration, and survival. When Apc was reactivated, Wnt signalling returned to normal levels, tumor cells stopped proliferating, and intestinal cells recovered their normal function. The tumors regressed and disappeared or reintegrated into normal tissue within two 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 50% of colorectal tumors in humans.
Lowe said, "It is currently impractical to directly restore Apc function in patients with colorectal cancer, and past evidence suggests that completely blocking Wnt signalling 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."
The study is published in the Cell.