A molecular switch that includes Notch, Numb, and miR-34a might prevent tumor growth during intestinal inflammation. The switch stimulates intestinal stem cells to divide asymmetrically, preventing them from proliferating excessively.
Inflammation promotes colorectal cancer, but it may also trip a molecular switch that hinders tumor growth by stimulating stem cells to divide asymmetrically, a recent study reported (Cell Stem Cell 2016;18:189–202).
Many types of normal stem cells divide asymmetrically, typically producing another stem cell and a cell that goes on to differentiate; normal intestinal and colon stem cells divide symmetrically. Cancer stem cells can divide symmetrically or asymmetrically, and “the consensus is that asymmetric division limits or suppresses cancer,” says Xiling Shen, PhD, of Duke University in Durham, NC, because it caps the number of cancer stem cells.
Shen and his colleagues investigated what controls intestinal stem cells' mode of division, focusing on the developmental genes Numb and Notch and the tumor suppressor miR-34a. Notch stimulates cell division and promotes colon cancer, whereas Numb and miR-34a cause cells to differentiate and develop normally.
To the team's surprise, they found that in addition to directly inhibiting Notch, miR-34a inhibits Numb—which is also an inhibitor of Notch. This counterintuitive result made sense, however, because the researchers determined that Numb, Notch, and miR-34a interact to form an incoherent feed-forward loop, a control circuit that behaves like a switch, directing cells to one of two fates. Flipping the switch in one direction produces high levels of Notch and causes symmetric division and retention of stemness. Flipping the switch in the opposite direction results in low Notch levels, leading to asymmetric division and spurring differentiation.
When the scientists examined intestinal samples from genetically modified mice that lack miR-34a, they found no differences in the number of intestinal stem cells, suggesting that the switch is not necessary under normal conditions.
However, they found that the switch does play a role during inflammation. Adding the inflammation-promoting molecule TNFα to cultured intestinal stem cells increased the rate of asymmetric division from 4.6% to 19%. To determine whether that increase also occurs in vivo, the team stimulated intestinal inflammation in mice that do or do not express miR-34a. The frequency of asymmetric divisions among intestinal stem cells rose from 2% to 13% in normal mice, but this increase didn't occur in miR-34a–deficient mice.
Given that inflammation may be a cause of colorectal cancer, the authors suggest that the shift to asymmetric division may be a safeguard against too much stem-cell self-renewal after inflammation-induced damage—and possibly under oncogenic stress—and thus may serve as a tumor-suppressive mechanism. Indeed, when Shen and colleagues compared healthy and cancerous intestinal tissue from patients with colorectal tumors, they found that asymmetric division was more common in the tumor samples.
Although the switch can curb division, it may not be successful in preventing tumors. If they form, they eventually eliminate miR-34a, restoring symmetric division and accelerating cellular proliferation, says Shen. “That unleashes the badness.”
The symmetric division of normal intestinal stem cells has been “a paradox,” says Sharon Pine, PhD, of Rutgers University in New Brunswick, NJ, who wasn't connected to the study. “This work adds a new element to the equation—inflammation” and suggests that asymmetric division “is a mechanism to curb expansion of the stem cells during injury and repair.”
The work also offers an explanation for how miR-34a controls tumor growth, adds Tannishtha Reya, PhD, of the University of California, San Diego. “This study suggests that miR-34a could act as a tumor suppressor in part by regulating asymmetric division.” –Mitch Leslie
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- ©2016 American Association for Cancer Research.