When flies and mice develop cancer

Methylation of Cancer-Stem-Cell-Associated Wnt Target Genes Predicts Poor Prognosis in Colorectal Cancer Patients

Are transplantable stem cells required for adult hematopoiesis?

Bone Marrow–Derived Hepatic Oval Cells Differentiate Into Hepatocytes in 2-Acetylaminofluorene/Partial Hepatectomy–Induced Liver Regeneration

Adult stem cells retain some capacity for self-renewal, although it is limited in comparison with embryonic stem cells, and are more restricted in their differentiation capacity. Adult stem cells are also commonly referred to as tissue specific stem cells. Some adult stem cells are still able to give rise to several specialized cell types (multipotent stem cells), whereas others are limited to a single specialized cell type (unipotent stem cells). Progenitor cells, the progeny of adult stem cells, differ from stem cells in that the potential for long-term self-renewal is lost. Scientifically, progenitor cells are more differentiated than stem cells. Primary stem cell progeny progenitor cells, usually known as multipotent adult progenitor cells, have full lineage-specific potential, whereas next-generation progenitors (oligopotent progenitors) are more lineage-restricted. This adult stem cell and progenitor cell hierarchy system exists to preserve a homeostatic repair and maintenance of the body, replenishing specialized cells and sustaining the routine cellular turnover in regenerative organs. Furthermore, the properties of these cells make them good candidates for targeted drug/gene delivery to specific organs; for example, mesenchymal stem cells (MSCs) have recently been shown to preferentially home to the lung. Adult stem and progenitor cells may be either circulating or resident in a particular tissue/organ system, including the lung and pulmonary vasculature. This chapter briefly describes the adult stem and progenitor cells currently identified in the pulmonary vasculature and introduces methodological approaches to successfully identify stem and progenitor cells.

The human colorectal epithelium is maintained by multipotent stem cells that give rise to absorptive, mucous, and endocrine lineages. Recent evidence suggests that human colorectal cancers are likewise maintained by a minority population of so-called cancer stem cells. We have previously established a human colorectal cancer cell line with multipotent characteristics (HRA-19) and developed a serum-free medium that induces endocrine, mucous and absorptive lineage commitment by HRA-19 cells in vitro. In this study, we investigate the role of the β1 integrin family of cell surface extracellular matrix receptors in multilineage differentiation by these multipotent human colorectal cancer cells. We show that endocrine and mucous lineage commitment is blocked in the presence of function-blocking antibodies to β1 integrin. Function-blocking antibodies to α2 integrin also blocked both HRA-19 endocrine lineage commitment and enterocytic differentiation by Caco-2 human colon cancer cells; both effects being abrogated by the MEK inhibitor, PD98059, suggesting a role for ERK signaling in α2-mediated regulation of colorectal cancer cell differentiation. To further explore the role of α2 integrin in multilineage differentiation, we established multipotent cells expressing high levels of wild-type α2 integrin or a non-signaling chimeric α2 integrin. Overexpression of wild-type α2 integrin in HRA-19 cells significantly enhanced endocrine and mucous lineage commitment, while cells expressing the non-signaling chimeric α2 integrin had negligible ability for either endocrine or mucous lineage commitment. This study indicates that the collagen receptor α2β1 integrin is a regulator of cell fate in human multipotent colorectal cancer cells.

Pluripotent cells have the potential to differentiate into all of the cell types of an animal. This unique cell state is governed by an interconnected network of transcription factors. Among these, Oct4 plays an essential role both in the development of pluripotent cells in the embryo and in the self-renewal of its in vitro counterpart, embryonic stem (ES) cells. Furthermore, Oct4 is one of the four Yamanaka factors and its overexpression alone can generate induced pluripotent stem (iPS) cells. Recent reports underscore Oct4 as an essential regulator of opposing cell state transitions, such as pluripotency establishment and differentiation into embryonic germ lineages. Here we discuss these recent studies and the potential mechanisms underlying these contrasting functions of Oct4.

141st ENMC International Workshop Inaugural Meeting of the EURO-Laminopathies Project Nuclear Envelope-linked Rare Human Diseases: From Molecular Pathophysiology towards Clinical Applications 10–12 March 2006, Naarden, The Netherlands

SY05-01: Genetic and non-genetic mechanisms contribute to long-term clonal growth dynamics and therapy resistance.

Quiescence regulators for hematopoietic stem cell

Safety and Efficacy of CMX001 as Salvage Therapy for Severe Adenovirus Infections in Immunocompromised Patients

Immunotherapy Exposes Cancer Stem Cell Resistance and a New Synthetic Lethality

Embryonic stem cells are pluripotent and capable of unlimited self-renewal. Elucidation of the underlying molecular mechanism may contribute to the advancement of cell-based regenerative medicine. In the present work, we performed a large scale analysis of the phosphoproteome in mouse embryonic stem (mES) cells. Using multiplex strategies, we detected 4581 proteins and 3970 high confidence distinct phosphosites in 1642 phosphoproteins. Notably, 22 prominent phosphorylated stem cell marker proteins with 39 novel phosphosites were identified for the first time by mass spectrometry, including phosphorylation sites in NANOG (Ser-65) and RE1 silencing transcription factor (Ser-950 and Thr-953). Quantitative profiles of NANOG peptides obtained during the differentiation of mES cells revealed that the abundance of phosphopeptides and non-phosphopeptides decreased with different trends. To our knowledge, this study presents the largest global characterization of phosphorylation in mES cells. Compared with a study of ultimately differentiated tissue cells, a bioinformatics analysis of the phosphorylation data set revealed a consistent phosphorylation motif in human and mouse ES cells. Moreover, investigations into phosphorylation conservation suggested that phosphoproteins were more conserved in the undifferentiated ES cell state than in the ultimately differentiated tissue cell state. However, the opposite conclusion was drawn from this conservation comparison with phosphosites. Overall, this work provides an overview of phosphorylation in mES cells and is a valuable resource for the future understanding of basic biology in mES cells.

Cancer stem cells (CSCs) are rare tumor cells that exhibit stem cell properties such as self-renewal capacity and pluripotency. In recent years, cancer stem cells have been recognized as key tumor-initiating cells that are therapyresistant and highly tumorogenic and therefore may play a pivotal role in cancer recurrence following chemotherapy. While chemotherapy is often capable of inducing cell death in tumors and reducing the tumor bulk, remaining cells can re-grow and many cancer patients experience recurrence and ultimately death. Herein, we discuss the mechanisms of chemoresistance identified in CSCs and methods of treating chemoresistant cancers driven by CSCs. These mechanisms include: aberrant ABC transporter expression/activity, aldehyde dehydrogenase (ALDH) activity, B-cell lymphoma-2 (BCL2) related chemoresistance, enhanced DNA damage response, activation of pro-survival signaling pathways and epigenetic deregulations. Developmental pathways, such as the Wnt/β-catenin pathway, direct the differentiation of normal stem cells promoting: proliferation, genomic instability and DNA damage tolerance in CSCs. The Notch/- secretase/Jagged and BMP signaling pathways are important regulators of differentiation. These signaling pathways represent novel attractive targets for drug discovery. CSCs can be forced to differentiate, lose their properties and become more sensitive to chemotherapy. Growing evidence emphasizes the interplay between metabolic disturbances, epigenomic changes and cancer. Epigenetic-based mechanisms are reversible and the possibility of "resetting" the abnormal cancer epigenome by applying pharmacological compounds provides a new and attractive approach. A number of compounds targeting epigenetic enzymes were screened for their ability to induce differentiation or to make CSCs more sensitive to therapy. Despite controversies surrounding the CSC hypothesis, there is substantial evidence for their role in cancer and a number of drugs intended to specifically target CSCs have entered clinical trials. Understanding how tumor-initiating cells escape chemotherapy will help to develop more specific and personalized approaches to treating cancer that may improve clinical outcomes for cancer patients. Keywords: ABC transporters, ALDH, cancer stem cells, DNA damage response, differentiation therapy, epigenetics, resistance to therapy.

Epithelial and Mesenchymal Contribution to the Niche: A Safeguard for Intestinal Stem Cell Homeostasis

Stem cell gene transfer—efficacy and safety in large animal studies