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Stem Cells

Stem Cells

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Published by Arun Malhotra

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Published by: Arun Malhotra on Jan 06, 2011
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11/04/2013

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Origin of Cancer Stem Cells: The Role of Self-Renewal and Differentiation

A paper by , Xiong-Zhi Wu

progenitor cells. maintenance. Self-renewal allows stem cells to persist during the lifetime of the organism.Cancer stem cells may be caused by transforming mutations occurring in stem cells. and regeneration after stress or injury. . and cancer cells. Self-renewal and differentiation potential are features of stem cells. mature cells. and differentiation potential allows stem cells to provide the progenitors and mature cells for tissue genesis. The genetic program controlling selfrenewal and differentiation is a key issue in origin of cancer stem cells.

the origin of cancer stem cells remains elusive.  This article focuses on current scientific controversies related to the establishment of the cancer stem cells in particular. how self-renewal and differentiation block might contribute to the evolution of cancer. could differentiate to mature cells. such as cancers of the hematopoietic system. which have the feature of differentiation and lose the activity of self-renewal  The roles for cancer stem cells have been demonstrated for some cancers. and liver.  Cancer stem cells could self-renew and produce cancer cells instead of normal cells. breast. the products of stem cells losing the activity of self-renewal. Differentiation is usually considered to be a one-way process of specialization as cells develop the functions of their ultimate fate and lose their immature characteristics. pancreas. However.  Progenitor cells. prostate. These properties are exactly what cancer stem cells exhibit in initiating and maintaining malignant growth. . such as self-renewal. brain.

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Shh. Hedgehog. such as cyclin D1 and C-myc .Pathways in Self-Renewal.  For instance.  Role of Wnt. Differentiation. the Wnt signalling pathway is activated by the binding of Wnt to their receptors. leading to the release of -catenin from the degradation complex and facilitating its entry into the nucleus. and Carcinogenesis  Many pathways that are classically associated with cancer may also regulate stem cell self-renewal and differentiation. where it regulates target gene transcription that modifies stem cell self-renewal or differentiation. and Notch signalling pathways in regulating stem cell self-renewal have shed new light on carcinogenesis  Similar signalling pathways may regulate self-renewal in normal and transformed stem cells.

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Deleting the Pten tumour suppressor gene in leukaemia-initiating cells leads to myeloproliferative disease. there are mechanistic differences in some cancers.  Pten deletion also promotes hematopoietic stem cell proliferation. it leads to hematopoietic stem cell depletion by inhibiting self-renewal. the mechanistic differences of self-renewal between normal stem cells and cancer stem cells can thus be targeted to deplete cancer stem cells without damaging normal stem cells. Rapamycin not only depletes leukaemia-initiating cells but also restores normal hematopoietic stem cell function.  Interestingly.  These effects are mostly mediated by mTOR as they are inhibited by rapamycin. Although similar signalling pathways may regulate self-renewal in normal stem cells and cancer stem cells. . However.

. As bipotential liver stem cells. oval cells are behind some hepatocellular carcinomas. oval cells have the bipotential for differentiating into hepatocyte and bile cells. Much research supports the notion that oval cells are the troublemakers behind some hepatocellular carcinomas. As bipotential liver stem cells.Cancers are caused by transforming mutations occurring in tissue-specific stem cells. oval cells have the bipotential for differentiating into hepatocyte and bile cells.

34 Leukemia stem cells possess an immunophenotype and global gene expression profile similar to that of normal granulocyte macrophage progenitor cells .The origin of human tumours has been recently debated as originating from stem or progenitor cells. There are two major nonexclusive hypotheses about the transformation:  the cells may dedifferentiate to tissue-specific stem cells  they may obtain the self-renewal activity by activating the self-renewal-associated genes. Progenitor cells. If cancer stem cells originate from progenitor cells. the transform cells must gain the selfrenewal activity. MOZ-TIF2 transduced progenitors have been serially replated in methylcellulose cultures and continuously propagated in liquid culture. which lose the activity of self renewal. which resulted in an acute myeloid leukemia in vivo that could be serially transplanted Leukemia stem cells are defined as transformed hematopoietic stem cells or committed progenitor cells that have amplified or acquired the stem cell capacity for self-renewal. are the link between tissue-specific stem cells and mature cells.

and a leukemia self-renewal associated signature is activated in the process.Transformed myeloid progenitors aberrantly express a small number of stem cell genes. Leukemia stem cells can thus be generated from committed progenitors without widespread reprogramming of gene expression. while still displaying the overall gene expression profile of myeloid progenitor cells. The transformed progenitors do not become stem cells but rather acquire stem cell like behavior. .

neural tumors. Transformed BMSCs could form many tumor types. and teratoma . including epithelial tumors. tumors of fibroblasts. supporting the hypothesis that some cancer stem cell originate from multipotential stem cell.In kidney allograft recipients. muscular tumors. bone marrow derived stem cells originating from a grafted kidney may migrate to the skin and undergo transformation into cancer Adult MSCs may be targets for malignant transformation and undergo spontaneous transformation after long-term in vitro culture. blood vessel endothelial tumors.

the transform cells must gain the differentiation feature of the special tissue. There are two major nonexclusive hypotheses about how transformed cells retain features of the special tissue:  differentiation.If cancer stem cells could originate from the multipotential stem cells.  fusing to tissue-specific stem cell/progenitor/mature cells .

concomitant with down regulation of 293T genes and differentiation indicators. and Oct4responsive genes. NANOG-. or from dedifferentiation of mature cells Taranger et al reported on the induction of dedifferentiation associated with genome-wide programming of gene expression in epithelial 293T cells treated with an extract of undifferentiated human NCCIT carcinoma cells. including OCT4-. such as A type lamins. SOX2-. .Mature cells are the final differentiation cells that lose the activity of self-renewal in most conditions. The transition from 293T to pluripotent cell phenotype involves a dynamic upregulation of genes encompass embryonic and stem cell markers. Two major nonexclusive hypotheses of the cellular origin of cancer are that malignancy arises from stem cells as a result of maturation arrest.

tissue-specific stem cells. the transform cells must gain the differentiation feature of the special tissue. mature cells. If cancer stem cells originate from the multipotential stem cells. Progenitor cells obtain the self-renewal activity by activating the self-renewal associated genes rather than dedifferentiating to tissue-specific stem cells.Conclusion Self-renewal and differentiation potential are features of stem cells. However. . the origin of the cancer stem cell remains elusive. such as MSCs. progenitor cells. The hypothesis is that cancer stem cells are caused by transforming mutations occurring in multipotential stem cells. Most cancer retains the feature of the primary tissue. Cancer stem cells could selfrenew and produce cancer cells instead of normal cells. and cancer cells.

partly because a single gene may exhibit distinct activities when expressed in different cell types. self-renewal and differentiation.Mature cells and cancer cells dedifferentiate into cancer stem cells by genetic and/or epigenetic events to gain self-renewal activity and lose some features of differentiation. a platform that can be provided by the research on cancer stem cells . Comprehending the cell-context dependent readout of any given gene requires an integrated knowledge of the complex cellular machinery. Cellular differentiation is usually considered to be a one-way process of specialization as the cells develop the functions of their ultimate fate and lose such immature characteristics as selfrenewal. The challenge is understanding the genetic programs controlling the stem cell state that is. Cracking the molecular codes that govern the stem cell state turns out to be a difficult task.

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