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The cancer cell, stem cell connection
In 1875, the pathologist Julius Cohnheim suggested that stem cells misplaced during embryonic development give rise to tumors in adult life. Over the course of the next century, scientists increasingly recognized that cancer cells and normal stem cells share certain
properties, chief among these their seeming immortality.
Normal stem cells populate the tissues of the developing organism and maintain and regenerate tissues throughout life. They have two defining characteristics: they can divide nearly indefinitely to produce more copies of themselves – the immortality that scientists call self-renewal – and they can produce daughter cells that mature into various cell types.
Embryonic stem cells, which are perhaps the most versatile of stem cells, have made news headlines and sparked political controversy since they were first isolated from human embryos a decade ago. Because embryonic stem cells normally generate all of the diverse cell types in the organism, they are a tantalizing source of healthy cells for repairing diseased tissues. And while it might be possible in the future to direct their maturation for cell-based therapies, clinical “stem cell” applications may come first from killing their dark twins – the cancer stem cells that replenish and renew tumors.
“I believe there will be benefits on both sides, but I think we’ll know sooner if targeting cancer stem cells has a clinical impact than we’ll know how to direct stem cells to replace damaged tissues,” Wicha says.
Mark Magnuson, M.D., director of Vanderbilt’s Center for Stem Cell Biology, says that the two areas of stem cell research are cross-fertilizing and informing each other.
“Everything we’re learning about normal stem cells – what they are, how they grow, what genes confer ‘stemness’ – these are all interesting findings that are transforming our understanding of stem cells in general and that have relevance to both normal and cancer stem cells,” he says.
All cancer cells are not created equal
Although the idea that a small population of cancer cells has stem cell-like properties is more than a century old, the technologies for identifying these rare cells were only recently developed.
Using flow cytometry – a method for sorting living cell populations based on cell surface proteins – and a mouse model for growing human blood stem cells in mice, John Dick, Ph.D., and colleagues at the University of Toronto began to identify cancer stem cells in leukemia in the 1990s.
The investigators reported in a widely cited 1997 Nature Medicine paper that only a fraction of human leukemia cells could reproduce leukemia in a mouse. These cancer stem cells were selected based on certain cell surface proteins, and they represented less than one in 10,000 of the human leukemia cells. The leukemia that was produced in the mice shared the diversity
of cells present in the original leukemia, supporting the idea that
the cancer stem cells could both reproduce themselves and give rise to various mature cell types.
Evidence that solid tumors also contain cancer stem cells was first reported in 2003. Michael Clarke, M.D., Wicha, and colleagues at the University of Michigan used surface proteins to sort cells from human breast tumors. They showed that only one sub-population of cells was able to re-create the original tumor in mice. As few as 200
of these breast cancer stem cells, which represented between 1 percent and 10 percent of the original tumor, could form tumors, whereas 20,000 cells isolated from the same tumor but without the same cell surface characteristics did not form tumors.
Since then, cancer stem cells have been identified in a range of tumors including brain, colon, head and neck, prostate and pancreas.
“It appears that virtually all cancers have only a small component of cells that is capable of transferring the cancer in a mouse model; they’re likely the only cells that are really tumorigenic, that are driving the cancers,” Wicha says.
Cancer-in-waiting
Even though many types of tumors appear to have sub-populations of cells that can regenerate the tumor with all of its diverse cell types, the cancer stem cell hypothesis is still debatable.
“Currently, there’s no clear definition of what a cancer stem cell is,” says Susan Kasper, Ph.D., assistant professor of Urologic Surgery and Cancer Biology at Vanderbilt. “Cells identified as cancer stem cells appear to have a few cell surface markers in common, but one of the key challenges in the field is to define the characteristics of the cancer stem cell.”
Magnuson agrees. “The research related to cancer stem cells is all tumor-based. And the problem is you really don’t know what the stem cell in the tumor is,” he says.
Cancer stem cells might come from normal stem cells, when mutations dismantle the normally tight controls on their self-renewal properties. They might also come from mutations that restore the power of self-renewal to so-called progenitor cells, the offspring of stem cells that mature into certain cell types.
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