In April, The Scientist asked, Are Cancer Stem Cells Ready for Prime Time? The controversial hypothesis posits that cells with stem-cell-like characteristics—such as the ability to self-renew and give rise to more tumor cells—contribute to cancer’s ability to evade traditional therapies. But despite previous investigations, which found subsets of tumor cells with the ability to grow in immunocompromised mice, not everyone is convinced that endogenous tumor development is stimulated by cells with self-renewal capacity.

Now, using genetic labeling techniques, three new studies trace cell lineages in new tumors to provide strong evidence for the existence of cancer stem cells. Published today (August 1) in Nature and Science, the technically elegant studies “provide support for the cancer stem cell model” across three different types of solid tumors—skin, intestinal, and brain—said Max Wicha, an oncologist at the University of Michigan who helped develop the cancer stem cell hypothesis and in...

The cancer stem cell hypothesis states that cells in tumors display a similar “hierarchy” to normal tissues that are renewed by stem cells, like the skin or intestinal epithelium, explained Sunit Das, a neurobiologist at the University of Toronto who did not participate in the research. Stem cells self-renew slowly, spending long periods in a quiescent non-dividing state, and produce a variety of faster-growing cell types. Because radiation and chemotherapy therapies target fast-growing cells, slow-growing cancer stem cells are thought to survive treatment, only to later repopulate the tumor.

Previous studies examining the existence and function of cancer stem cells used transplantation models, said Cédric Blanpain at the Université Libre de Bruxelles, who led one of the two Nature studies. “In the past, researchers would isolate different tumor cell populations and transplant them into immunocompromised mice,” Blanpain explained. “They found that some tumor fractions grow better than others. They called them cancer stem cells, thinking the cells were feeding pure tumor growth.

But critics argued that rather than demonstrating the existence of cancer stem cells, this just showed selection of cells capable of growing in the new environment. Luis Parada, whose group at University of Texas Southwestern Medical Center published the second Nature paper, noted that these criticisms are especially valid for solid tumors, which need a great deal of manipulation before any subsets of cells can be transplanted. “The question we wanted to address was, Is it possible to probe the existence of cancer stem cells in a natural setting, where the cancer arose naturally and spontaneously without manipulation?”

To identify and track cancer stem cells directly, all three groups used genetics. Blanpain’s group engineered mice so skin tumor cells would express a fluorescent protein after administration of the carcinogen tamoxifen and tracked the growth dynamics of the glowing tumor cells. Shortly after being exposed to the carcinogen, the mice developed non-malignant papillomas on their skin, in which Blanpain and his colleagues identified two major cell types: a progenitor population with a limited ability to differentiate and a surprisingly short life span, and stem-cell-like cells, which were long-lived and could self-renew or divide to produce new progenitors.

It’s generally accepted that cancer cells acquire excessive proliferative abilities, so Blanpain expected “the progenitor cells to be immortal,” he said. “But only the cancer stem cells survived long term,” highlighting their importance for supporting tumor growth.

Work by a group in The Netherlands provided similar evidence in intestinal cancer, published in Science. This team used a combination of genetic mutations that promoted colon cancer development from intestinal stem cells, and again marked the tumor cells with fluorescence. Tracing the lineage of the marked cells, the researchers showed that the many different cell types of a tumor were all derived from the cancer stem cells, said co-first author Hugo Snippert at University Medical Center Utrecht. “We saw that the cancer stem cells were producing new cells so fast they were taking over the tumor.”

The third study, published in Nature by Parada’s group, examined the brain cancer glioblastoma, and provided evidence for another facet of the cancer stem cell hypothesis—that cells with stem-cell-like properties promote cancer recurrence after treatment. Once again, the researchers used fluorescent markers in mice to show that after chemotherapy, stem-cell-like cells drove regrowth of the tumor. Engineering this population of cells to be sensitive to the anti-viral drug ganciclovir, the scientists were able to selectively kill the cancer stem cells in the tumor. Doing so slowed the progression of pre-cancerous lesions and prevented malignancies from infiltrating surrounding normal brain tissue. Combining ganciclovir with chemotherapy significantly prolonged the mice’s lives.

Knocking out the stem cells didn’t cure the glioblastomas, suggesting that other cancer cells also possess a limited ability to divide and differentiate, but the tumors that did recur were much less aggressive, said Alonzo Ross, a cancer biologist at University of Massachusetts Medical School, who was not involved in the studies. Reproducing a similar result in humans would be “a huge step forward,” he said, given that average survival of glioblastoma patients is about 14 months, and even after surgery, radiation, and chemotherapy, tumors invariably recur within 5 to 6 months.

Parada’s group is screening cultured glioblastoma cancer stem cells for sensitivity to drugs that don’t kill normal stem cells. It may also be possible, Das postulated, to make cancer stem cells more vulnerable to standard therapies by using drugs that push cancer stem cells to differentiate.

But regardless of the strategy, the slow-growing cancer cells need to be targeted to prevent chemotherapy resistance and tumor recurrence. “[That] message is indisputable,” said Dean Tang, a pathologist who studies cancer stem cells at MD Anderson Cancer Center in Texas, and did not participate in the research. “But how do you target quiescence? That is the big question facing the field.”

G. Driessens, et al., “Defining the mode of tumour growth by clonal analysis,” Nature, doi: 10.1038/nature11344, 2012.

A. G. Schepers, et al., “Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas,” Science, doi: 10.1126/science.1224676, 2012.

J. Chen, et al., “A restricted cell population propagates glioblastoma growth after chemotherapy,” Nature, doi: 10.1038/nature11287, 2012.

Editor's Note (August 1, 2012): This story has been updated to include Max Wicha's co-founding of the company OncoMed Pharmaceuticals.

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