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The theory of cancer stem cells states that a subset of cancer cells within a tumor has the ability to self-renew and differentiate. Only those cells within a tumor that have these two properties are called cancer stem cells. This concept was first demonstrated in the study of leukemia where only cells with specific surface antigen profiles were able to cause leukemia when engrafted into immunodeficient mice. In recent years solid tumors were studied utilizing similar techniques in mice. Human tumors where evidence of cancer stem cells has been published include tumors of the breast, brain, pancreas, head and neck, and colon. If this difference in tumorigenicity of cancer cells also occurs in patients, then the ability to enrich for cancer stem cells lays an important groundwork for future studies where mechanisms involved in cancer stem cells can now be investigated. [Copyright &y& Elsevier]

Recent studies have begun to elucidate the mechanisms controlling hematopoietic stem cell (HSC) self-renewal. Self-renewal requires the integration of survival signals and proliferation controls with the maintenance of an undifferentiated state. This demands a complex crosstalk between extrinsic signals from the microenvironment and the cell-intrinsic regulators of self-renewal. The Polycomb protein Bmi1 is absolutely required for the maintenance of both adult HSCs and neural stem cells. Evidence from studies in murine and human embryonic stem cells indicates that Polycomb group proteins play a dynamic role in concert with master transcriptional regulators in actively maintaining an undifferentiated state, suggesting that this mechanism applies to multiple types of stem cell. Recently, various new players that regulate HSC maintenance (e.g. Mcl1, Tel/Etv6, Gfi1, Pten and Stat5) have been identified. In order to better understand HSC self-renewal, we need to understand how these pathways are coordinated. [Copyright &y& Elsevier]

Recent evidence suggests that a subset of cancer cells within some tumors, the so-called cancer stem cells, may drive the growth and metastasis of these tumors. Understanding the pathways that regulate proliferation, self-renewal, survival, and differentiation of malignant and normal stem cells may shed light on mechanisms that lead to cancer and suggest better modes of treatment. [Copyright &y& Elsevier]

Solid tumors arise in organs that contain stem cell populations. The tumors in these tissues consist of heterogeneous populations of cancer cells that differ markedly in their ability to proliferate and form new tumors. In both breast cancers and central nervous system tumors, cancer cells differ in their ability to form tumors. While the majority of the cancer cells have a limited ability to divide, a population of cancer stem cells that has the exclusive ability to extensively proliferate and form new tumors can be identified based on marker expression. Growing evidence suggests that pathways that regulate the self-renewal of normal stem cells are deregulated in cancer stem cells resulting in the continuous expansion of self-renewing cancer cells and tumor formation. This suggests that agents that target the defective self-renewal pathways in cancer cells might lead to improved outcomes in the treatment of these diseases.Oncogene (2004) 23, 7274-7282. doi:10.1038/sj.onc.1207947 [ABSTRACT FROM AUTHOR]

The authors focus on new insights on tumor radioresistance. The authors reflect on the findings by a medical study that cells from breast cancer cell lines radioresistant compared with the remainder of breast cancer cells. These cells, termed as cancer stem cells (CSCs), are driven and maintained by a subpopulation of cells that have a capacity to self-renew. The authors suggest that the studies showed that radioresistance may be a general property of CSCs.

This article focuses on brain cancer. Brain cancers are among the most devastating tumours in humans and are often rapidly fatal despite aggressive treatments. These tumours typically contain varied populations of cells that differ in the specific proteins or markers displayed on the cell surface. Insights into how tissues are maintained provide hints as to why only a minority of the cancer cells drives tumour formation. Most cancers arise in tissues, such as the bone marrow, gut and breast, that are composed of a cellular hierarchy in which a small population of stem cells gives rise to progenitor cells that regenerate mature tissue cells.

Alzheimer's disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. Therefore, we set out to identify a potential earlier targetable phenotype. Utilizing a mouse model of AD and human fetal cells harboring mutant amyloid precursor protein, we show cell intrinsic neural precursor cell (NPC) dysfunction precedes widespread inflammation and amyloid plaque pathology, making it the earliest defect in the evolution of the disease. We demonstrate that reversing impaired NPC self-renewal via genetic reduction of USP16, a histone modifier and critical physiological antagonist of the Polycomb Repressor Complex 1, can prevent downstream cognitive defects and decrease astrogliosis in vivo. Reduction of USP16 led to decreased expression of senescence gene Cdkn2a and mitigated aberrant regulation of the Bone Morphogenetic Signaling (BMP) pathway, a previously unknown function of USP16. Thus, we reveal USP16 as a novel target in an AD model that can both ameliorate the NPC defect and rescue memory and learning through its regulation of both Cdkn2a and BMP signaling. [ABSTRACT FROM AUTHOR]

Stem cells generate the differentiated cell types within many organs throughout the lifespan of an organism and are thus ultimately responsible for the longevity of multicellular organisms. Therefore, senescence of stem cells must be prevented. Bmi1 is required for the maintenance of adult stem cells in some tissues partly because it represses genes that induce cellular senescence and cell death. [ABSTRACT FROM AUTHOR]

Discusses evidences that stem cell biology could provide insights into cancer biology. Similarities in the mechanisms that regulate self-renewal of normal stem cells and cancer cells; Possibility that tumor cells developed from normal stem cells.

Summary: Human breast tumors contain a breast cancer stem cell (BCSC) population with properties reminiscent of normal stem cells. We found 37 microRNAs that were differentially expressed between human BCSCs and nontumorigenic cancer cells. Three clusters, miR-200c-141, miR-200b-200a-429, and miR-183-96-182 were downregulated in human BCSCs, normal human and murine mammary stem/progenitor cells, and embryonal carcinoma cells. Expression of BMI1, a known regulator of stem cell self-renewal, was modulated by miR-200c. miR-200c inhibited the clonal expansion of breast cancer cells and suppressed the growth of embryonal carcinoma cells in vitro. Most importantly, miR-200c strongly suppressed the ability of normal mammary stem cells to form mammary ducts and tumor formation driven by human BCSCs in vivo. The coordinated downregulation of three microRNA clusters and the similar functional regulation of clonal expansion by miR-200c provide a molecular link that connects BCSCs with normal stem cells. [ABSTRACT FROM AUTHOR]

We performed the first genome-wide expression analysis directly comparing the expression profile of highly enriched normal human hematopoietic stem cells (HSC) and leukemic stem cells (LSC) from patients with acute myeloid leukemia (AML). Comparing the expression signature of normal HSC to that of LSC, we identified 3,005 differentially expressed genes. Using 2 independent analyses, we identified multiple pathways that are aberrantly regulated in leukemic stem cells compared with normal HSC. Several pathways, including Wnt signaling, MAP Kinase signaling, and Adherens Junction, are well known for their role in cancer development and stem cell biology. Other pathways have not been previously implicated in the regulation of cancer stem cell functions, including Ribosome and T Cell Receptor Signaling pathway. This study demonstrates that combining global gene expression analysis with detailed annotated pathway resources applied to highly enriched normal and malignant stem cell populations, can yield an understanding of the critical pathways regulating cancer stem cells. [ABSTRACT FROM AUTHOR]

Most cancers comprise a heterogenous population of cells with marked differences in their proliferative potential as well as the ability to reconstitute the tumor upon transplantation. Cancer stem cells are a minor population of tumor cells that possess the stem cell property of self-renewal. In addition, dysregulation of stem cell self-renewal is a likely requirement for the development of cancer. This new model for cancer will have significant ramifications for the way we study and treat cancer. In addition, through targeting the cancer stem cell and its dysregulated self-renewal, our therapies for treating cancer are likely to improve. [Copyright &y& Elsevier]

Stem cells persist throughout life by self-renewing in numerous tissues including the central and peripheral nervous systems. This raises the issue of whether there is a conserved mechanism to effect self-renewing divisions. Deficiency in the polycomb family transcriptional repressor Bmi-1 leads to progressive postnatal growth retardation and neurological defects. Here we show that Bmi-1 is required for the self-renewal of stem cells in the peripheral and central nervous systems but not for their survival or differentiation. The reduced self-renewal of Bmi-1-deficient neural stem cells leads to their postnatal depletion. In the absence of Bmi-1, the cyclin-dependent kinase inhibitor gene p16Ink4a is upregulated in neural stem cells, reducing the rate of proliferation. p16Ink4a deficiency partially reverses the self-renewal defect in Bmi-1-/- neural stem cells. This conserved requirement for Bmi-1 to promote self-renewal and to repress p16Ink4a expression suggests that a common mechanism regulates the self-renewal and postnatal persistence of diverse types of stem cell. Restricted neural progenitors from the gut and forebrain proliferate normally in the absence of Bmi-1. Thus, Bmi-1 dependence distinguishes stem cell self-renewal from restricted progenitor proliferation in these tissues. [ABSTRACT FROM AUTHOR]

The main focus of this review is the role of mammary stem cells in normal breast development and carcinogenesis. We have developed a new in vitro culture system that permits, for the first time, the propagation of mammary stem and progenitor cells in an undifferentiated state, which should facilitate the elucidation of pathways that regulate normal mammary stem-cell self-renewal and differentiation. Furthermore, we propose a model in which transformation of stem cells, or early progenitor cells, results in carcinogenesis. A key event in this process is the deregulation of normal self-renewal in these cells. Transformed mammary stem or progenitor cells undergo aberrant differentiation processes that result in generation of the phenotypic heterogeneity found in human and rodent breast cancers. This phenotypic diversity is driven by a small subset of mammary tumour stem cells. We will discuss the important implications of this mammary tumour stem-cell model. [ABSTRACT FROM AUTHOR]

Details a study which developed an in vitro cultivation system that allows for propagation of human mammary epithelial cells. Interaction between stem and progenitor cells; Cellular composition of mammospheres; Transcriptional profile of mammosphere-derived cells.