Cancer stem cells and impaired apoptosis.
ABSTRACT For more than 100 years scientists have fervently sought the fundamental origins of tumorigenesis, with the ultimate hope of discovering a cure. Indeed, these efforts have led to a significant understanding that multiple genetic and molecular aberrations, such as increased proliferation and the inhibition of apoptosis, contribute to the canonical characteristics of cancer. Despite these advances in our knowledge, a more thorough understanding, such as the precise cells, which are the targets of neoplastic transformation, especially in solid tumors, is currently lacking. An emerging hypothesis in the field is that cancer arises and is sustained from a rare subpopulation of tumor cells with characteristics that are highly similar to stem cells, such as the ability to self-renew and differentiate. In addition, more recent studies indicate that stem cell self-renewal pathways that are active primarily during embryonic development and adult tissue repair may be aberrantly activated in various cancers. This chapter introduces the cancer stem cell hypothesis; explores evidence for the presence of cancer stem cells, particularly in leukemia; and discusses various classical stem cell self-renewal pathways in relation to cancer. Investigating the role of cancer stem cells in the context of the major characteristics of cancer, especially impaired apoptosis, offers great promise for the design of superior tumor-selective and apoptosis-inducing therapies.
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ABSTRACT: Formaldehyde is an economically important chemical, to which more than 2 million U.S. workers are occupationally exposed. Substantially more people are exposed to formaldehyde environmentally, as it is generated by automobile engines, is a component of tobacco smoke and is released from household products, including furniture, particleboard, plywood, and carpeting. The International Agency for Research on Cancer (IARC) recently classified formaldehyde as a human carcinogen that causes nasopharyngeal cancer and also concluded that there is "strong but not sufficient evidence for a causal association between leukemia and occupational exposure to formaldehyde". Here, we review the epidemiological studies published to date on formaldehyde-exposed workers and professionals in relation to lymphohematopoietic malignances. In a new meta-analysis of these studies, focusing on occupations known to have high formaldehyde exposure, we show that summary relative risks (RRs) were elevated in 15 studies of leukemia (RR=1.54; confidence interval (CI), 1.18-2.00) with the highest relative risks seen in the six studies of myeloid leukemia (RR=1.90; 95% CI, 1.31-2.76). The biological plausibility of this observed association is discussed and potential mechanisms proposed. We hypothesize that formaldehyde may act on bone marrow directly or, alternatively, may cause leukemia by damaging the hematopoietic stem or early progenitor cells that are located in the circulating blood or nasal passages, which then travel to the bone marrow and become leukemic stem cells. To test these hypotheses, we recommend that future studies apply biomarkers validated for other chemical leukemogens to the study of formaldehyde.Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 08/2008; 681(2-3):150-68. · 2.85 Impact Factor
Article: A simple mathematical model based on the cancer stem cell hypothesis suggests kinetic commonalities in solid tumor growth.[show abstract] [hide abstract]
ABSTRACT: The Cancer Stem Cell (CSC) hypothesis has gained credibility within the cancer research community. According to this hypothesis, a small subpopulation of cells within cancerous tissues exhibits stem-cell-like characteristics and is responsible for the maintenance and proliferation of cancer. We present a simple compartmental pseudo-chemical mathematical model for tumor growth, based on the CSC hypothesis, and derived using a "chemical reaction" approach. We defined three cell subpopulations: CSCs, transit progenitor cells, and differentiated cells. Each event related to cell division, differentiation, or death is then modeled as a chemical reaction. The resulting set of ordinary differential equations was numerically integrated to describe the time evolution of each cell subpopulation and the overall tumor growth. The parameter space was explored to identify combinations of parameter values that produce biologically feasible and consistent scenarios. Certain kinetic relationships apparently must be satisfied to sustain solid tumor growth and to maintain an approximate constant fraction of CSCs in the tumor lower than 0.01 (as experimentally observed): (a) the rate of symmetrical and asymmetrical CSC renewal must be in the same order of magnitude; (b) the intrinsic rate of renewal and differentiation of progenitor cells must be half an order of magnitude higher than the corresponding intrinsic rates for cancer stem cells; (c) the rates of apoptosis of the CSC, transit amplifying progenitor (P) cells, and terminally differentiated (D) cells must be progressively higher by approximately one order of magnitude. Simulation results were consistent with reports that have suggested that encouraging CSC differentiation could be an effective therapeutic strategy for fighting cancer in addition to selective killing or inhibition of symmetric division of CSCs.PLoS ONE 01/2012; 7(2):e26233. · 4.09 Impact Factor