Linking Stem Cells to Thyroid Cancer

Recent progress in tumor cell biology and genetics provides increasing evidence that a specific subpopulation of tumor cells plays a crucial role in tumor initiation, invasive growth, and metastasis in several malignancies (for review, see Ref. 1). These cells, designated cancer stem cells (CSCs) or tumor-initiating cells, have the ability of asymmetric cell division, i.e. they generate a self-copy (selfrenewal) and give rise to progenitor cells that progressively differentiate into multiple lineages of the heterogeneous tumor cell mass (2). When transplanted into immunodeficient, i.e. NOD/SCID, mice, CSCs regenerate a phenocopy of the cancer of origin. Indeed, CSCs have been detected in several solid tumors, in leukemia, and in cancer cell lines (2). CSCs may arise through acquisition of mutations or epigenetic changes from adult stem cells or their committed progenitor cells. Adult stem cells, which are capable of self-renewal and differentiation throughout the organism’s lifetime, are characterized by their pluripotency and undifferentiated state. The CSC model (hierarchy model) argues that the striking morphological and functional heterogeneity, which is a hallmark of most tumors, is sustained by a biologically distinct subpopulation of CSCs (3). However, not all malignancies follow the CSC model of heterogeneity. Thus, an alternative model has been put forward to explain this heterogeneity. The stochastic model for tumor initiation predicts that a tumor is primarily biologically homogenous and acquires heterogeneity by randomly occurring secondary events that alter proliferation, differentiation, and survival of individual cells. All tumor cells are equally sensitive to intrinsic (e.g. levels of transcription factors, signaling pathways) or extrinsic factors (e.g. host factors, microenvironment, immune response) that affect single cells and thus may generate heterogeneity (4). Support for the CSC concept of carcinogenesis comes from findings that several signaling pathways that are known to regulate adult stem cells are altered in malignancies, including the canonical Wnt pathway, Hedgehog, and Notch signaling pathways (5–7). Furthermore, there are close relationships between gene expression pattern in embryonic stem cells and some malignancies (1).