Editors' ChoiceCancer

Ovarian Stem Cells Find Their Niche

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Science Translational Medicine  20 Mar 2013:
Vol. 5, Issue 177, pp. 177ec47
DOI: 10.1126/scitranslmed.3006108

Ovarian cancer is the fifth leading cause of cancer deaths in women, diagnosed in more than 22,000 women each year in the United States alone. Epithelial ovarian cancer comprises >80% of cases. Studies have suggested that epithelial ovarian cancer arises from the ovaries, fallopian tubes, or uterus, yet the cell of origin has remained notoriously controversial and elusive. Flesken-Nikitin and colleagues have reignited the debate by arguing that a select population of stem cells contributes to the disease.

The authors identified a population of cells in mice that are prone to developing high-grade serous ovarian cancer—one of the most aggressive forms of the disease. These cells were located in an anatomical region on the ovarian surface called the hilum, which is an entry and an exit point for nerves and blood vessels. Flesken-Nikitin et al. found that stem cell markers such as ALDH1 and LGR5 were enriched in the hilum and that hilum cells exhibited stem cell behaviors, such as colony formation, long-term label retention, regenerative potential, and susceptibility to transformation. Using lineage-tracing techniques, they showed that LGR5+ hilum progenitors could regenerate the entire ovarian surface epithelium after ovulation. As compared with a mixture of other cell types in the ovary, hilum cells were exceptionally sensitive to transformation by loss of Rb1 and Trp53, two critical tumor suppressor genes that are often disrupted in aggressive ovarian cancer.

Given that these studies were performed by using mouse ovaries, the challenge now will be to determine whether a similar cell population resides in humans. Indeed, although the hilum-derived stem cell population gave rise to metastatic ovarian cancer upon loss of Rb1 and Trp53, other ovarian cell types may be vulnerable to transformation in response to disruption of other oncogenic/tumor suppressor pathways or alterations in the microenvironment. Ultimately, these findings support the notion that certain stem cell populations may be poised in anatomical niches that are primed to respond to injury. The identification of this population of stem cells—and the molecular markers to isolate them—has opened the door for future studies to examine their specific roles in human regeneration and tumorigenesis.

A. Flesken-Nikitin et al., Ovarian surface epithelium at the junction area contains a cancer-prone stem cell niche. Nature 495, 241–245 (2013). [Full Text]

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