Scimex: Anti-cancer strategies generally involve killing off tumour cells, but according to new findings from US and Dutch scientists, simply reactivating a gene could coax these cells to turn back into normal tissue. The researchers found that restoring normal levels of a tumor suppressor gene in mice stopped tumour growth and re-established normal intestinal function within only 4 days. Remarkably, the tumours were eliminated within 2 weeks and signs of cancer were prevented months later.
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 June 18th 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," says senior study author
Scott Lowe of the Memorial Sloan Kettering Cancer Center.
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.
"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 of Weill Cornell Medical College. 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.
this challenge, Lowe and his 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
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.
Apc reactivation is unlikely to be relevant to other types of cancer,
the general experimental approach could have broad implications. "The
concept of identifying tumor-specific driving mutations is a major focus
of many laboratories around the world," 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."
For their own
part, Lowe and his team 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.
"It is currently
impractical to directly restore Apc function in patients with colorectal
cancer, and past evidence suggests that completely blocking Wnt
signaling would likely be severely toxic to normal intestinal cells,"
Lowe says. "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."