The cancer stem cell: Cell type or cell state?

Stemness. Cancer is often viewed as a caricature of normal developmental processes, but the extent to which it depends upon mechanisms central to embryonic multilineage differentiation, or adult stem cell mediated regeneration remains unknown. In embryogenesis, experiments from nuclear-somatic cell transfer to the creation of induced pluripotent stem cells (1) are consistent with the concept that stemness is a cell state and not a cell type. Behind the concept of cell type is the acquisition of specialized and fixed functionality based on a unidirectional differentiation paradigm. On the other hand, cell states, such as entry into cell cycle, are conditional and reversible. The fact that a definitive stem cell gene expression signature has remained elusive has received much attention and elicited a variety of explanations, including the hypothesis that stemness results from the arrest of a linear process of differentiation (2). Oct4, Sox2 and Nanog, three of four genes capable of inducing pluripotency in differentiated human cells, are consistently coexpressed in pluripotent stem cells. According to a theory proposed by Casanova, each factor promotes a given fate by repressing the alternative: Oct4 suppresses neural ectodermal differentiation and promotes mesendodermal differentiation, while Sox2 inhibits mesendodermal differentiation and promotes neural ectodermal differentiation. When coexpressed, they repress all germ-layer differentiation and, in so doing, promote the stem cell phenotype (3). Thus embryonic stem cells retain their stemness not because all differentiation pathways are open, but because they are closed. The classical tissue maintenance/regeneration scheme, drawn from hematopoiesis, is a unidirectional paradigm in which resting self-replicating adult tissue stem cells are rarely called into cycle, giving rise to progenitor cells of high proliferative capacity, or a cascade of amplifying cells as in the erythroid series. The progeny of these lineage-committed progenitors differentiate into mature functional cell types with limited (monocytes, lymphocytes) or no (erythrocytes, polymorphonuclear leukocytes, platelets) proliferative capacity. Increasingly, examples have been noted in which mature functional cells appear to be conditionally differentiated: hepatocytes, airway cells and pancreatic islet cells appear to dedifferentiate to a transit-amplifying progenitor state under conditions that summon tissue repair, suggesting that, in these tissues as well, the capacity to self-renew and differentiate is a state rather than a discrete cell type (4). The widespread use of the term stem cell to describe both the pluripotent cell responsible for embryogenesis, and the somatic cells responsible for tissue maintenance and repair has generated confusion in the literature, especially when applied to cells outside these two paradigms. Nevertheless, both usages refer to cells capable of self-renewal and differentiation. Further, maintenance of the stem cell phenotype is highly dependent on signals provided by surrounding cells. In embryogenesis, plasticity is a hallmark. In adult tissue stem cells, the capacity to give rise to multiple lineages is more restricted. In most instances cells described as stem cells are more resistant to toxic insults than their progeny. This is accomplished through a variety of mechanisms including phase I metabolism, conjugation and transport. Differentiation, dysdifferentiation, transdifferentiation and dedifferentiation in cancer. The modern interpretation of the cancer stem cell hypothesis is drawn largely from analogies of clonogenic tumor cells to normal stem cells, both embryonic and adult, and is supported by phenotypic (surface marker), functional (metabolic enzymes and transporters), and clonogenic (self-renewal and tumorigenicity) data. The concept that stemness results from loss of differentiation signaling may be applied to cancer, both in its initiation and in its progression. Cancer is a disease of genetic alteration and epigenetic dysregulation, potentially explaining well-known cases of transdifferentiation (B cell blast crisis in chronic myeloid leukemia) and dysdifferentiation, the partial expression of a differentiation program or the promiscuous expression of lineage incompatible proteins. The epithelial to mesenchymal transition in epithelial cancers, a normal process in embryonic development, can be viewed as transdifferentiation, but also dedifferentiation as it is accompanied by the expression of CD44 and CD90, proteins associated with both epithelial and mesenchymal adult tissue stem cells. Dedifferentiation, in the sense of reacquisition of stem-like properties by a tumor cell with a mature phenotype, has been speculative (5), because it can only be definitively distinguished from clonal selection at the