The Niche

Cancer stem cells cultures generated by outgrowths

Hi everyone, We’ve got this Cell Stem Cell article slated to go up as a story in a couple Thursdays, but the press release is really making the rounds. So here’s the reported story by Asher Mullard.

The origins of cancer stem cells have long been elusive and controversial. While some researchers think that they are stem cells gone awry, others suspect that cancer stem cells arise from differentiated cells that have been reprogrammed. In support of the reprogramming theory, a tissue-culture study suggests that mutant mouse embryonic fibroblast (MEF) cells that lack retinoblastoma proteins are reprogrammed when they are cultured in suspension, and come to resemble cancer stem cells.

The retinoblastoma 1 (RB1) pathway is crucial for detecting cell-cell contact and regulating cell cycle arrest. Consequently, whereas cultured MEFs normally grow in a monolayer, MEFs lacking RB1 grow into mounds of cells that eventually detach and form colonies of free-floating ‘spheres’. The RB1 pathway is also frequently lost in cancers. These and other observations set Douglas Dean of Brown Cancer Center in Louisville, USA, and his colleagues wondering whether spheres had a role in reprogramming differentiated cells into cancer stem cells.

Reporting in Cell Stem Cell, Dean and his colleagues show that when RB1–/– cells are forced to grow in spheres for 2 weeks, a new cellular morphology emerges1. Moreover, some cells from 2 week old spheres, but not from younger spheres or from the original monolayer, persistently express embryonic stem cell genes, including Oct4 and Nanog as well as cancer stem cell markers. “It’s like a switch has been flipped,” says Dean. Thus, he argues that spheres might enable reprogramming of cancer stem cells. “There may be a technique down the road for producing an inducible pluripotent stem cell from a fibroblast using this technique,” he adds excitedly.

But Thea Tlsty, a pathologist at University of California San Francisco, is not convinced for two reasons. In the 2 weeks it took for the new morphology and characteristics to arise, the culture setup might have selected stem-cell-like cells that were already present in the population, rather than enabled de novo reprogramming. And although Dean took precautions to minimize this possibility, he acknowledges it has not yet been definitively ruled out.

And Tlsty is also uncertain about the claim that cells from aged spheres even have the characteristics of cancer stem cells. When Dean transplanted sphere-reared cells into mice, he observed tumour formation, supporting the notion that these cells have cancer stem cell capabilities. Yet this evidence isn’t conclusive, explains Tlsty. “A cancer stem cell phenotype is usually accompanied by an invasive phenotype, and while I saw a growth in vivo, I did not see an examination of invasive phenotypes.”

“To clear up my confusion, I would want them to start with single differentiated somatic cell,” says Tlsty. “And I would want to see some evidence of invasion potential.”

Dean readily notes another limitation of his study. “This is a cell culture based set of studies,” he says. “What we’re doing is trying to put forward a hypothesis that we and others can test in real tumours.”

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Liu, Y. et al. Mouse fibroblasts lacking RB1 function form spheres and undergo reprogramming to a cancer stem cell phenotype. Cell Stem Cell 4, 336–347 (2009).


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