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\"In proving the existence of stem cells, Ernest Armstrong McCulloch and James Edgar Till formed the most important partnership in Canadian medical research since Frederick Banting and Charles Best, the discoverers of insulin. Together, Till and McCulloch instructed, influenced, and inspired successive generations of researchers who have used their findings to make huge advances against disease. Thousands of people who would have died from leukemia and immunological disorders now owe their lives to therapies supported by their seminal discoveries\"-- Dust jacket flap.

We isolated seven new iridoid glucosides (valerianairidoids I–VII; 1–3, 6, 7, 9, and 12) and six known compounds from the methanol extract of the dried rhizomes and roots of Valeriana fauriei. Chemical and spectroscopic data were used to elucidate the chemical structures of the seven new iridoid glucosides, and their absolute configurations were determined by comparing their electronic circular dichroism (ECD) spectra with those determined experimentally. Aglycones 1a, 6a, and 9a, which were obtained by enzymatic hydrolysis of the isolated iridoid glucosides, exhibited anti-proliferative activities against cancer stem cells (CSCs) established by a sphere-formation assay using human breast cancer (MDA-MB-231) and human astrocytoma (U-251MG) cells. Interestingly, these iridoids selectively showed anti-proliferative activities against CSCs from MDA-MB-231 cells. These results suggest that the iridoids obtained in this study may have potency as a breast cancer treatment and as preventive agent via exterminating CSCs.

Cancer stem cell (CSC) biology and tumor immunology have shaped our understanding of tumorigenesis. However, we still do not fully understand why tumors can be contained but not eliminated by the immune system and whether rare CSCs are required for tumor propagation. Long latency or recurrence periods have been described for most tumors. Conceptually, this requires a subset of malignant cells which is capable of initiating tumors, but is neither eliminated by immune cells nor able to grow straight into overt tumors. These criteria would be fulfilled by CSCs. Stem cells are pluripotent, immune-privileged, and long-living, but depend on specialized niches. Thus, latent tumors may be maintained by a niche-constrained reservoir of long-living CSCs that are exempt from immunosurveillance while niche-independent and more immunogenic daughter cells are constantly eliminated. The small subpopulation of CSCs is often held responsible for tumor initiation, metastasis, and recurrence. Experimentally, this hypothesis was supported by the observation that only this subset can propagate tumors in non-obese diabetic/scid mice, which lack T and B cells. Yet, the concept was challenged when an unexpectedly large proportion of melanoma cells were found to be capable of seeding complex tumors in mice which further lack NK cells. Moreover, the link between stem cell-like properties and tumorigenicity was not sustained in these highly immunodeficient animals. In humans, however, tumor-propagating cells must also escape from immune-mediated destruction. The ability to persist and to initiate neoplastic growth in the presence of immunosurveillance - which would be lost in a maximally immunodeficient animal model - could hence be a decisive criterion for CSCs. Consequently, integrating scientific insight from stem cell biology and tumor immunology to build a new concept of \"CSC immunology\" may help to reconcile the outlined contradictions and to improve our understanding of tumorigenesis.

Prominin-1 (CD133) is a cholesterol-binding membrane glycoprotein selectively associated with highly curved and prominent membrane structures. It is widely recognized as an antigenic marker of stem cells and cancer stem cells and is frequently used to isolate them from biological and clinical samples. Recent progress in understanding various aspects of CD133 biology in different cell types has revealed the involvement of CD133 in the architecture and dynamics of plasma membrane protrusions, such as microvilli and cilia, including the release of extracellular vesicles, as well as in various signaling pathways, which may be regulated in part by posttranslational modifications of CD133 and its interactions with a variety of proteins and lipids. Hence, CD133 appears to be a master regulator of cell signaling as its engagement in PI3K/Akt, Src-FAK, Wnt/β-catenin, TGF-β/Smad and MAPK/ERK pathways may explain its broad action in many cellular processes, including cell proliferation, differentiation, and migration or intercellular communication. Here, we summarize early studies on CD133, as they are essential to grasp its novel features, and describe recent evidence demonstrating that this unique molecule is involved in membrane dynamics and molecular signaling that affects various facets of tissue homeostasis and cancer development. We hope this review will provide an informative resource for future efforts to elucidate the details of CD133’s molecular function in health and disease.

Principles of Stem Cell Biology and Cancer: Future Applications and Therapeutics Tarik Regad, The John van Geest Cancer Research Centre, Nottingham Trent University, UK, Thomas J. Sayers, Centre for Cancer Research, National Cancer Institute, Frederick, USA and Robert Rees The John van Geest Cancer Research Centre, Nottingham Trent University, UK The field of cancer stem cells is expanding rapidly, with many groups focusing on isolating and identifying cancer stem cell populations. Although some progress has been made developing efficient cancer therapies, targeting cancer stem cells remains one of the important challenges facing the growing stem cell research community. Principles of Stem Cell Biology and Cancer brings together original contributions from international experts in the field to present the very latest information linking stem cell biology and cancer. Divided into two parts, the book begins with a detailed introduction to stem cell biology with a focus on the characterization of these cells, progress that has been made in their identification, as well as future therapeutic applications of stem cells. The second part focuses on cancer stem cells and their role in cancer development, progression and chemo-resistance. This section of the book includes an overview of recent progress concerning therapies targeting cancer stem cells. Features: An authoritative introduction to the link between stem cell biology and cancer. Includes contributions from leading international experts in the field. Well-illustrated with full colour figures throughout. This book will prove an invaluable resource for basic and applied researchers and clinicians working on the development of new cancer treatments and therapies, providing a timely publication of high quality reviews outlining the current progress and exciting future possibilities for stem cell research.

Tumor heterogeneity represents an ongoing challenge in the field of cancer therapy. Heterogeneity is evident between cancers from different patients (inter-tumor heterogeneity) and within a single tumor (intra-tumor heterogeneity). The latter includes phenotypic diversity such as cell surface markers, (epi)genetic abnormality, growth rate, apoptosis and other hallmarks of cancer that eventually drive disease progression and treatment failure. Cancer stem cells (CSCs) have been put forward to be one of the determining factors that contribute to intra-tumor heterogeneity. However, recent findings have shown that the stem-like state in a given tumor cell is a plastic quality. A corollary to this view is that stemness traits can be acquired via (epi)genetic modification and/or interaction with the tumor microenvironment (TME). Here we discuss factors contributing to this CSC heterogeneity and the potential implications for cancer therapy.

Glioblastoma multiforme (GBM) is one of the most aggressive types of brain tumor and is highly resistant to therapy. The median survival time for patients with GBM is 15 months. GBM resistance to treatment is associated with cancer stem cells (CSCs). CD133 membrane glycoprotein is the best-known marker of GBM CSCs. The Wnt signaling pathway plays an important role in the proliferation of all stem cells. To the best of our knowledge, the present study was the first to examine the expression levels of proteins associated with the Wnt signaling pathway in СD133+ CSCs of human GBM. Furthermore, potential targets that may regulate СD133+ CSCs in human GBM were investigated. The human GBM U-87MG cell line was cultured in neurobasal medium supplemented with B27, fibroblast growth factor, epidermal growth factor and no serum. Immunohistochemical characteristics of glioma spheres were investigated based on the expression of key markers of CSCs. CD133+ cells were extracted from glioma spheres by cell sorting and then lysed. High-performance liquid chromatography-mass spectrometry was used for proteome analysis. Lysates of CD133− cells in GBM were used for comparison. The present study was the first to describe the conceptual proteome differences between GBM and CD133+ CSCs of the common pool. Major differences were identified in the glycolysis/gluconeogenesis, focal adhesion, tight junction and Wnt signaling pathways. This study aimed to analyze the crucial role that proteins of the Wnt signaling pathway play in stem cell proliferation. The identified proteins were analyzed for their association with the Wnt signaling pathway using the international open databases PubMed, Protein Analysis Through Evolutionary Relationships, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and Search Tool for the Retrieval of Interacting Genes/Proteins. An increased expression of 12 proteins associated with the Wnt signaling pathway were identified in GBM CD133+ CSCs, which included catenin β-1, disheveled associated activator of morphogenesis 1, RAC family small GTPase 2 and RAS homolog gene family member A, a number of which are also associated with adherens junctions. The Wnt signaling pathway is not upregulated in CSCs; however, the high expression levels of adenomatous polyposis coli, β-catenin, C-terminal binding protein (CtBP) and RuvB-like AAA ATPase 1 (RUVBL1 or Pontin52) proteins suggest the possibility of alternative activation of specific genes in the nuclei of these cells. Calcyclin-binding protein, casein kinase II α, casein kinase II β, CtBP1, CtBP2, CUL1 and RUVBL1 proteins may be used as targets for the pharmaceutical regulation of CSCs in complex GBM treatment.

Signaling pathways involving signal transducer and activator of transcription 3 (STAT3) play key roles in the aggressiveness of pancreatic ductal adenocarcinoma (PDAC), including their tumorigenesis, invasion, and metastasis. Cancer stem cells (CSCs) have been correlated with PDAC aggressiveness, and activation of STAT3 is involved in the regulation of CSC properties. Here, we investigated the involvement of interleukin-6 (IL-6) or the leukemia inhibitory factor (LIF)/glycoprotein 130 (gp130)/STAT3 pathway and their role in pancreatic CSCs. In PDAC CSC-like cells formed by culturing on a low attachment plate, autocrine/paracrine IL-6 or LIF contributes to gp130/STAT3 pathway activation. Using a gp130 inhibitor, we determined that the gp130/STAT3 pathway contributes to the maintenance of stemness features, the expression of membrane-type 1 matrix metalloproteinase (MT1-MMP), and the invasion of PDAC CSC-like cells. The gp130/STAT3 pathway also modulates the transforming growth factor (TGF)-β1/Smad pathway required for epithelial-mesenchymal transition induction through regulation of TGFβ-RII expression in PDAC CSC-like cells. Furthermore, chromatin immunoprecipitation assays revealed that p-STAT3 can access the active promoter region of H19 to influence this metastasis-related long non-coding RNA and contribute to its transcription in PDAC CSC-like cells. Therefore, the autocrine/paracrine IL-6 or LIF/gp130/STAT3 pathway in PDAC CSC-like cells may eventually facilitate invasion and metastasis, two hallmarks of malignancy. We propose that inhibition of the gp130/STAT3 pathway provides a promising strategy for targeting CSCs for the treatment of PDAC.

Liver cancer is an often fatal malignant tumor with a high recurrence rate and chemoresistance. The major malignant phenotypes of cancer, including recurrence, metastasis, and chemoresistance, are related to the presence of cancer stem cells (CSCs). In the past few decades, CSCs have been identified and characterized in many tumors including liver cancer. Accumulated evidence has revealed many aspects of the biological behavior of liver CSCs and the mechanism of their regulation. Based on these findings, a number of studies have investigated eradication of liver CSCs. This review focuses on the recent advances in our understanding of the biology of liver CSCs and the development of strategies for their treatment.