Stem Cells: The Real Culprits in Cancer? [Preview]

A dark side of stem cells--their potential to turn malignant--is at the root of a handful of cancers and may be the cause of many more. Eliminating the disease could depend on tracking down and destroying these elusive killer cells
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THE HUMAN BODY is a highly compartmentalized system made up of discrete organs and tissues, each performing a function essential to maintaining life. Individual cells that make up these tissues are often short-lived, however. The skin covering your body today is not really the same skin that you had a month ago, because its surface cells have all since sloughed off and been replaced. The lining of the gut turns over every couple of weeks, and the life span of the platelets that help to clot blood is about 10 days.

The mechanism that maintains a constant population of working cells in such tissues is consistent throughout the body and, indeed, is highly conserved among all complex species. It centers on small pools of long-lived stem cells that serve as factories for replenishing supplies of functional cells. This manufacturing process follows tightly regulated and organized steps wherein each generation of a stem cell's offspring becomes increasingly specialized.

This system is perhaps best exemplified by the hematopoietic family of blood and immune cells. All the functional cells found in the blood and lymph arise from a single common parent known as the hematopoietic stem cell (HSC), which resides in bone marrow. The HSC pool represents less than 0.01 percent of bone marrow cells in adults, yet each of these rare cells gives rise to a larger, intermediately differentiated population of progenitor cells. Those in turn divide and differentiate further through several stages into mature cells responsible for specific tasks, ranging from defending against infection to carrying oxygen to tissues [see box on opposite page]. By the time a cell reaches that final functional stage, it has lost all ability to proliferate or to alter its destiny and is said to be terminally differentiated.

The stem cells themselves meanwhile remain undifferentiated, a state they maintain through their unique capacity for self-renewal: to begin producing new tissues, a stem cell divides in two, but only one of the resulting daughter cells might proceed down a path toward increasing specificity. The other daughter may instead retain the stem cell identity. Numbers in the overall stem cell pool can thus remain constant, whereas the proliferation of intermediate progenitors allows populations of specific hematopoietic cell types to expand rapidly in response to changing needs.

The capacity of stem cells to re-create themselves through self-renewal is their most important defining property. It gives them alone the potential for unlimited life span and future proliferation. In contrast, progenitors have some ability to renew themselves during proliferation, but they are restricted by an internal counting mechanism to a finite number of cell divisions. With increasing differentiation, the ability of the progenitors' offspring to multiply declines steadily.

The practical significance of these distinctions can be observed when hematopoietic stem cells or their descendants are transplanted. After the bone marrow of a mouse is irradiated to destroy the native hematopoietic system, progenitor cells delivered into the marrow environment can proliferate and restore hematopoiesis temporarily, but after four to eight weeks those cells will die out. A single transplanted hematopoietic stem cell, on the other hand, can restore the entire blood system for the lifetime of the animal.

The hematopoietic system's organization has been well understood for more than 30 years, but similar cellular hierarchies have recently been identified in other human tissues, including brain, breast, prostate, large and small intestines, and skin. Principles of regulated stem cell behavior are also shared across these tissues, including specific mechanisms for controlling stem cell numbers and for directing decisions about the fates of individual cells. Several genes and the cascades of events triggered by their activity—known as genetic pathways—play key roles in dictating stem cells' fate and function, for example. Among these are signaling pathways headed by the Bmi-1, Notch, Sonic hedgehog and Wnt genes. Yet most of these genes were first identified not by scientists studying stem cells but by cancer researchers, because their pathways are also involved in the development of malignancies.

Many such similarities between stem cells and cancer cells have been noted. The classical definition of malignancy itself includes cancer cells' apparent capacity to survive and multiply indefinitely, their ability to invade neighboring tissues and to migrate (metastasize) to distant sites in the body. In effect, the usual constraints that tightly control cellular proliferation and identity seem to have been lifted from cancer cells.

Normal stem cells' power to self-renew already exempts them from the rules limiting life span and proliferation for most cells. Stem cells' ability to differentiate into a broad range of cell types allows them to form all the different elements of an organ or tissue system. A hallmark of tumors, too, is the heterogeneity of cell types they contain, as though the tumor were a very disorderly version of a whole organ. Hematopoietic stem cells have been shown to migrate to distant parts of the body in response to injury signals, as have cancer cells.

In healthy stem cells, strict genetic regulation keeps their potential for unlimited growth and diversification in check. Remove those control mechanisms, and the result would be something that sounds very much like malignancy. These commonalities, along with growing experimental evidence, suggest that failures in stem cell regulation are how many cancers get started, how they perpetuate themselves, and possibly how malignancies can spread.

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