Stem Cells and Cancer: Two Faces of EveKey Properties of Tissue Stem CellsDid Stem Cells Evolve as a Protection against Cancer?The Crucial Role of the Stem Cell NicheStem Cell Regulation and CancerCancer in Stem Cell and Progenitor Cell LineagesReferencesLeading EdgeEssayCell 124, March 24, 2006 ©2006 Elsevier Inc. 1111The need for cells to proliferate over the life span of an organism may place individuals at risk in the numbers game that underlies cancer. Adult stem cell lineages may have evolved to lower this risk by minimizing the chance of cells escaping the mechanisms that restrict their expansion. There is emerging evidence that some blood cell cancers and solid tumors may contain a cancer cell hierarchy reminiscent of the nor-mal tissue in which the malignan-cies first arose, with a cancer stem cell producing progeny with lim-ited replication potential (Al-Hajj et al., 2003; Lapidot et al., 1994; Singh et al., 2004). For example, in tumors of the breast and brain, a minority population of cancer stem cells have the ability to self-renew, whereas the majority of cancer cells have limited or no ability to proliferate. This suggests that can-cer stem cells may drive the growth and spread of the tumor. The pres-ence of a stem cell population in a tumor has implications for the diagnosis and treatment of can-cer, as it is these cancer stem cells that must be targeted to achieve a cure. Failure to eliminate these self-renewing cells sets the stage for the regrowth of a tumor follow-ing cessation of chemotherapy. The ability to prospectively iden-tify cancer stem cells will allow the investigation of key molecules and pathways that could be targeted to eliminate these malignant cells. Key steps in the progression to cancer may involve failure of nor-mal developmental mechanisms evolved by long-lived multicellu-lar organisms to meet the needs for renewing short-lived cell types such as those of the skin, gut, and blood. Cancers often arise in tissues such as skin, gut, and blood where constant proliferation is required to ensure a continued supply of newly differentiated cells. Replacement of the mature cells in these tissues is accomplished by a highly orches-trated process in which a relatively small population of self-renewing adult stem cells gives rise to prolif-erating progenitor cells (sometimes called transit-amplifying cells) that undergo limited rounds of mitotic division and then terminally differen-tiate, losing their ability to proliferate further (see Figure 1A). In this hier-archical system, only the stem cells are long-lived. Indeed, although progenitor cells have some ability to replicate, their life span as prolifer-ating cells is short, often measured in days or weeks.Key Properties of Tissue Stem CellsThe remarkable longevity of tissue stem cells relies on their unique abil-ity to undergo self-renewing mitotic divisions in which one or both prog-eny retain the stem cell identity and the capacity to replicate almost indefinitely. The daughters of stem cell divisions also have the option to follow a differentiation pathway. The balance between self-renewal and differentiation must be strictly regulated to maintain the stem cell pool and to generate the required supply of fully differentiated cells needed for tissues to carry out their many tasks.Stem cells in adult tissues must produce large numbers of differ-entiated progeny. These transit-amplifying progenitor cells may undergo a limited series of mitotic cycles, sometimes referred to as transit-amplifying cell divisions, before entering a postmitotic fully differentiated state (see Figure 1A). In this way, the activity of a rela-tively small number of stem cells can be amplified to produce large numbers of differentiated progeny. For example, in the male germline or the bone marrow (both of which contain well-studied stem cell pop-ulations), a relatively small number of germline or hematopoietic stem cells produce billions of sperm or mature blood cells over the life of the individual.Did Stem Cells Evolve as a Protection against Cancer?The evolution of single-cell organ-isms into multicellular animals with their specialized cell types and complex organ systems neces-sitated development of strict con-trols to keep cellular proliferation in check. If any cells in the tissue community shake loose from these constraints on proliferation, then the resulting tumor can kill the individ-Stem Cells and Cancer: Two Faces of EveMichael F. Clarke1,* and Margaret Fuller21Stanford Institute for Stem Cell Biology and Regenerative Medicine 2Departments of Developmental Biology and GeneticsStanford University School of Medicine, Stanford, CA 94305, USA*Contact: [email protected] 10.1016/j.cell.2006.03.011Recent evidence suggests that a subset of cancer cells within some tumors, the so-called cancer stem cells, may drive the growth and metastasis of these tumors. Understanding the pathways that regulate proliferation, self-renewal, survival, and differentiation of malig-nant and normal stem cells may shed light on mechanisms that lead to cancer and suggest better modes of treatment.1112 Cell 124, March 24, 2006 ©2006 Elsevier Inc.ual organism. Long-lived multicel-lular organisms have evolved many fail-safe mechanisms to protect them against developing cancer. As a result, progression to cancer requires that a number of mutations accumulate in the same cell lineage in order to collectively circumvent these protective mechanisms. For example, progression to cancer may involve loss of normal growth controls leading to the formation of polyps, or the inactivation of the fail-safe mechanisms that com-pel abnormal cells to die or that prevent cells from migrating into surrounding tissues (Fearon and Vogelstein, 1990). However, even the requirement for a single cell to accumulate several mutations before it becomes cancerous may not be sufficient to prevent long-lived organisms from dying of can-cer at a relatively young age. Avoid-ing cancer is essentially a numbers game. For example, trillions of cells are formed in the human body