Cancer Stem Cells: Mouse studies lead to paradigm shift in cancer research

For the past 15 years one of the most intriguing ideas in cancer research has been that the growth and spread of most – if not all – cancers is driven by cancer stem cells. The hypothesis is that only a tiny proportion of cancer cells, cancer stem cells, have the stem cell-like ability to proliferate indefinitely to produce cells that can differentiate into other cancer cell types. It suggests that the reason why cancer often returns after apparently being eradicated is that while the therapy (surgery/radiation/chemotherapy) may remove the differentiated cancer cells it fails to remove all the cancer stem cells, whose subsequent proliferation results in the cancer’s return.

Multicolored intestine tissue in genetically modified mice allows scientists to track which cells give rise to tumors.
Credit: A. G. Schepers et al., Science (2012) DOI: 10.1126/science.1224676

Today 3 teams of scientists have announced important results that provide the strongest evidence to date that cancer stem cells are indeed at the heart of cancer proliferation.

The first evidence that only a small minority of cancer cells may have the ability to proliferate indefinitely came from a study of leukemia cells in 1997, when Dr Dominique Bonnet and Dr John Dick, then both working at the University of Toronto, observed that when they injected a variety of acute myeloid leukemia (AML) cell populations obtained from human biopsy into immunodeficient mice and analyzed which cells gave rise to leukemia cells in the mice, and found that regardless of the characteristics of injected AML cells the cells that initiated the leukemic cell populations in the mice always expressed the cell surface marker CD34 and lacked the cell surface marker CD38, a key characteristic of stem cells.

Since then similar observations have been made for a wide variety of cancer types, and scientists have discovered important new facts about cancer stem cells, for example in 2009 we discussed how scientists at Stanford University had used genetic modification of bone marrow stem cells to show that leukemia stem cells were very similar to embryonic stem cells.  However, these studies all involved the transplantation of cancer cells into mice, and there has always been some concern that the manipulation of these cells during their isolation from humans and sorting into specific populations before injection into mice may have affected their behavior.

Today, three independent studies of mouse models of brain, skin and intestinal tumours, led respectively by Dr Luis Parada at the University of Texas Southwestern Medical Center, Dr Benjamin Simmons of the Gurdon Institute and Dr Cédric Blanpain of the Free University of Brussels, and Dr Hans Clevers of the Hubrecht Institute, and published in the prestigious scientific journals Nature and Science,  provide the first evidence that cancer stem cells do arise during tumour formation in intact organs, and drive tumour formation.

What these studies all share is that they were able to do this because rather than injecting cancer cells into the mice they used genetically modified mice in which cancer develops spontaneously. Using additional genetic modification to label certain types of cells they were able to track the different cell types involved in the growth and spread of cancer, and even assess the differing effects of standard cancer therapies and therapies that included drugs that specifically target cancer stem cells.

There is an excellent discussion of the three projects and their implications for cancer research in Nature News, and Science Now also offers a informative prespective on the work.  From its very first paragraphthe Nature News article highlights how these studies provide crucial information that could not be obtained through other methods:

Cancer researchers can sequence tumour cells’ genomes, scan them for strange gene activity, profile their contents for telltale proteins and study their growth in laboratory dishes. What they have not been able to do is track errant cells doing what is more relevant to patients: forming tumours. Now three groups studying tumours in mice have done exactly that. Their results support the ideas that a small subset of cells drives tumour growth and that curing cancer may require those cells to be eliminated.”

Commenting in an article in the LA Times, Dr. Owen Witte of the UCLA Broad Stem Cell Center was clear about what these results mean for cancer research.

People can stop arguing…Now they can say, ‘OK, the cells are here. We now need to know how to treat them.’ ”

And “how to treat them” will not be an easy problem to solve, perhaps drugs that target the cancer stem cells or prevent their development may be the answer, but as the Nature News, Science Now and LA Times articles stress we don’t yet know enough about the origins of cancer stem cells to be sure which approach will work.

What is true is that thanks to advanced animal research methods a huge gap in our knowledge of how cancer develops and spreads – a gap that we only recently realised existed – has been filled. As research accelerates to turn this new knowledge into effective cancer therapies we can be certain of one thing; animal research will continue to provide key insights that turn hypothesis into cures.

Paul Browne

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