Activation of Apc Reverted Colorectal Cancer Cells Back to Normal Tissue

Lukas Dow, PhD

Lukas Dow, PhD

Reactivation of the tumor suppressor geneadenomatous polyposis coli(Apc) reverted colorectal cancer cells back to normal intestinal tissue in mice, according to a recent preclinical study.^1,2These findings were published inCellon June 18, 2015, and suggest a novel mechanism for treating colorectal cancer through the Wnt pathway, which is central to proliferation, migration, and survival in various types of cells.

Colorectal cancer is the second leading cause of death in developed countries,³and “[current] treatment regimes for advanced colorectal cancer involve combination chemotherapies that are toxic and largely ineffective,” said Scott Lowe, senior study author from Memorial Sloan Kettering Cancer Center, in a press release. According to the researchers, modulating gene activity may provide a new avenue for more durable, less toxic cancer therapies.

Up to 90% of colorectal tumors contain a mutation inApc.⁴Mutations inApclead to excess activity of the Wnt signaling pathway, leading to uncontrolled cell proliferation in the colon. However, completely blocking Wnt signaling would be “severely toxic” to normal intestinal cells, according to Lowe.

Lead author Lukas Dow, PhD, of Weill Cornell Medical College stated in an interview withTargeted Oncologythat the goal ofApcreactivation in the current study was to “dampen,” not eliminate, the activity of the Wnt pathway so that the tumor cells behaved similarly to normal intestinal cells.

“We were looking for ways to re-engage this natural tumor suppressor mechanism,” said Dow.

Restoring function to mutated genes has been challenging because the resulting excess gene activity can cause problems to normal cells. To circumvent this difficulty, Dow and his colleagues used a mouse model of colorectal cancer in whichApcwas directly and reversibly suppressed using a doxycycline-regulated small hairpin (sh)RNA.

Apcsuppression in the mice activated the Wnt pathway and led to development of adenomas in the colon and small intestine. Reactivation of Apc normalized Wnt activity, halted proliferation of tumor cells, and restored normal function in the intestinal cells after 4 days. The adenomas regressed and reintegrated into normal tissue within 2 weeks, a response that was sustained 6 months later.

Although the results from Dow and his colleagues suggest a relatively durable response, he notes that the shorter overall lifespan of the mouse must be accounted for when predicting long-term response in humans. Furthermore, tumor cells often develop resistance to initially effective therapies over time, and this acquired resistance is a common problem with current methods of cancer treatment.

“We don’t know the types of resistance mechanisms that may arise from [modulating the Wnt pathway], said Dow. “We intend to predict that [in future research]. We need to understand what types of [mechanisms] might allow for resistance of these tumors if we were to target the Wnt pathway with a therapy,” said Dow.

Although the researchers induced selectiveApcmutations in the mice, mutations inApcthat lead to colorectal cancer vary in humans. The mutations in humans tend to cluster around a similar region within the gene, but Dow stated that even slight variations in humanApcmutations could potentially affect the rate of tumor progression and response to therapy. According to Dow, understanding this relationship will be important for developing effective therapies targetingApcand the Wnt pathway.

“In human colorectal cancer, there are lots of different types of mutations that can occur in the gene,” said Dow. “For technical reasons, researchers haven’t been able to recreate these mutations in mouse models [in the past], and that’s something we’re actively doing right now.”

New methods published in the past few years allow creation of mice that express specific types of gene mutations that occur in human cancer. According to Dow, these methods can be used to inspect the different types ofApcmutations, and ultimately their “functional consequence.”

Apcmutations are relatively unique to colorectal tumors. Nevertheless, Dow indicated disruption of the downstream Wnt pathway can occur in multiple tumor types, including lung, breast, and liver cancer, but through mutations in different modulators of the pathway. He stated that understanding why certain mutations tend to develop in particular tumor types may help develop specific therapies that regulate the Wnt pathway.

Furthermore, understanding how tumor growth and progression is regulated in the 10% of colorectal tumors that do not haveApcmutations could provide information for development of individualized therapies.

“Up to 90% of human colon cancers have mutations inApc, but that means that 10% don’t,” said Dow. “There are many ways for a cell to become a tumor [cell] without mutations inApc. We think they are almost all dependent on the Wnt pathway, but we have not tried to modulate the pathway much [in the clinical setting].”

References

1. Dow LE, O’Rourke KP, Simon J, et al. Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer.Cell. 2015;161(7):1539-1552.
2. Weill Cornell press release.http://meyercancer.weill.cornell.edu/news/2015-06-18/single-gene-turns-colorectal-cancer-cells-back-normal-tissue-mice. Accessed June 24, 2015.
3. Jemal A, Bray F, Center MM, et al. Global cancer statistics.CA Cancer J. Clin. 2011; 61: 69-90.
4. Brannon AR, Vakiani E, Sylvester BE, et al. Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions.Genome Biol. 2014;15:454.