Moraga Biotech Blog http://moragabiotech.com/nucleus/ en-us Nucleus CMS v3.23 © Weblog http://backend.userland.com/rss http://moragabiotech.com/nucleus//nucleus/nucleus2.gif Moraga Biotech Blog http://moragabiotech.com/nucleus/ Telomerase-Immortalized Human Mammary Stem/Progenitor Cells with Ability to Self-Renew and Differentiate http://moragabiotech.com/nucleus/index.php?itemid=987 de novo, or reprogamming of more differentiated cell type (e.g. progenitors), scientists from the University of Nebraska Medical Center, X. Zhao et al., published in the July 26th online edition of PNAS their study results on immortalizing human mammary epithelial cells (hMECs) with human telomerase reverse transcriptase (hTERT) and assaying in vitro their stem cell characteristics. Three subpopulations of cells were isolated and characterized. One subpopulation coexpressed basal cell markers (K15, K14, and vimentin) and another expressed luminal cell markers (E-cadherin, K8, K18, or K19). The third subpopulation expressed stem/progenitor markes (CD49f, CD29, CD44, and p63). Clonal derivatives of the progenitors were either K5+/K19- or K5+/K19+ of which both types had the ability to self-renew and differentiate. Microarray analysis revealed that these progenitors expressed components of stem cell-associated signaling pathways such as Notch, Wnt, Hedgehog and LIF. The authors concluded that these immortalized hMECs could be used as a cell source "to explore unresolved questions related to stem/progenitor origin of breast cancer."]]> Stem Cells and Cancer http://moragabiotech.com/nucleus/index.php?itemid=987 Fri, 6 Aug 2010 08:44:00 -0700 Wilms Tumor Chromatin Profiles Stem Cell Properties http://moragabiotech.com/nucleus/index.php?itemid=976 Cell Stem Cell, A. P. Aiden et al. from Harvard University reported their study results on identifying transcriptional and epigenetic mechanisms which give rise to Wilms tumor formation. With a comparison of genome-wide chromatin profiling of cells derived from Wilms tumors, embryonic stem cells (ESCs), and normal kidney, the investigators found that large active chromatin domains normally regulating gene expression in ESCs were also expressed in Wilms cells. These genes were associated with kidney development as well as maintaining the adult renal stem cell compartment. Interestingly, the Wilms cells expressing the embryonic-like chromatin regulators maintain stem cells in the kidney compartment by silencing p16. The experimental data revealed that these "bivalent promoters" in Wilms tumor correlated to silencing genes during early stages of differentiation in kidney progenitors. The authors concluded from their experimental results which they suggest that "Wilms cells share a transcriptional and epigenetic landscape with normal renal stem cells, which is inherently susceptible to transformation and my represent a cell of origin for this disease" (i.e. cancer stem cells).
]]> Stem Cells and Cancer http://moragabiotech.com/nucleus/index.php?itemid=976 Fri, 25 Jun 2010 21:18:00 -0700 Cripto-1: A Tumorigenic Marker for Human Embryonal Carcinoma Cells http://moragabiotech.com/nucleus/index.php?itemid=971 Stem Cells, K. Watanabe et al. from the National Institute of Health (Bethesda, MD), published their study results on the expression of Cripto-1 (CR-1) and cancer stem cells. The investigators noted that CR-1 is a GP1-linked glycoprotein which is expressed during early embryogenesis and in human embryonal carcinoma (EC) cells. With FACS analysis, the researchers found two subpopulations of EC expressing either CR-1High or CR-1Low from EC cell lines (NTERA2/D1). The subpopulation expressing CR-1High was more tumorigenic, formed spheres in vitro, and tumors in xenografts. The CR-1High cells were also shown to be pluripotent in which they expressed pluripotent transcription factors Oct4, Sox2, and Nanog. The study results also revealed that CR-1 expression in the EC cell lines was regulated by Smad2/3 via the autocrine feedback loop during upregulation of the transcription factors Oct4/Nanog. The authors concluded that "CR-1 expression is enriched in an undifferentiated, tumorigenic subpopulation and is regulated by key regulators of pluripotent stem cells."]]> Stem Cells and Cancer http://moragabiotech.com/nucleus/index.php?itemid=971 Mon, 21 Jun 2010 14:01:23 -0700 A Subpopulation of CD26+ Cancer Stem Cells with Metastatic Capacity in Human Colorectal Cancer http://moragabiotech.com/nucleus/index.php?itemid=972 Cell Stem Cell, R. Pang et al. from The University of Hong Kong, identified in their published study results a subpopulation of CD26+ from primary and mestastatic colorectal tumors with cancer-initiating properties of cancer stem cells (CSCs). The investigators reported that these tumorigenic CSCs had the ability to self-renew and were CD133+. Additionally, the experimental data revealed that co-expression CD133 and CD44 surface markers enhanced tumorigenicity when the CSCs were serially passaged in a xenograft mouse model. However, in comparing differential expression of markers in metastatic colorectal cancers and primary tumors, cells expressing CD26 were found in both primary colorectal tumors and liver metastasis. The researchers also demonstrated that CD26+ cells had the capacity to form liver metastases when injected into the cerum of mice; irrespective of whether they CD133 or CD44. On the other hand, CD26- cells were not able to form liver metastasis regardless of CD133 or CD44 expression. Subcutaneous coinjection of CD26+ cells and normal human intestinal fibroblasts significantly enhanced liver metastasis in SCID mice. CD26+ CSCs showed enhanced chemoresistance. The authors concluded from their experimental observations that they "have uncovered a critical role of CSCs in the mestatic progression of cancer" which allows one to "predict metastasis based on analysis of CSC subsets in the primary tumor."]]> Stem Cells and Cancer http://moragabiotech.com/nucleus/index.php?itemid=972 Fri, 18 Jun 2010 14:01:00 -0700 Synovial Sarcoma is a Stem Cell Malignancy http://moragabiotech.com/nucleus/index.php?itemid=964 Stem Cells, N. Naka et al. from the Osaka Medical Center for Cancer and Cardiovascular Diseases (Japan) reported their experimental findings which suggested that synovial sarcoma (SS) may originate from dysregulated stem cells. The investigators noted that SS is a malignant tumor characterized by chromosomal translocation (X & 11) resulting in SS18-SSX fusion gene protein product. SS human cell lines were shown to form sarcospheres and tumors in serial xenografts as well as the ability to self-renew. Both the SS cell lines and15 primary human tumor specimens were found to express the pluripotent proteins, Oct3/4, Nanog, and Sox2. Moreover, the researchers were able to differentiate the SS cells into mesenchymal lineages such as osteocytes and chondrocytes. Silencing of SS18-SSX abrogated the ability to form sarcospheres in the SS cells in suspension and the cells formed an adherent monolayer in cell culture experiments. Cells derived from the monolayer cultures were able to differentiate into osteocytes, chondrocytes, adipocytes and macrophages. The authors concluded that their data suggest "that a human multipotent mesenchymal stem cell can serve as a cell of origin for SS and SS is a stem cell malignancy resulting from dysregulation of self-renewal and differentiation capacities driven by the SS18-SSX fusion protein."]]> Stem Cells and Cancer http://moragabiotech.com/nucleus/index.php?itemid=964 Wed, 9 Jun 2010 13:40:00 -0700 Wnt Activity Defines Colon Cancer Stem Cells and Regulated by the Microenvironment http://moragabiotech.com/nucleus/index.php?itemid=955 Nature Cell Biology, L. Vermeulen et al. from the University of Amsterdam (Netherlands) reported their study results correlating the level of Wnt signaling in tumors and colon cancer stem cells. With a Wnt reporter construct, the investigators observed that high activity of Wnt signaling was observed in tumor cells located close to stromal myofibroblasts. The data suggested that "Wnt activity and cancer stemness may be regulated by extrinsic cues. The researchers found that myofibroblast-secreted factors (e.g. hepatocyte growth factor) activated β-catenin transcription and cancer stem cell (CSC) clonogenicity. Interestingly, the study results also revealed that myofibroblast-secreted factors could also induce CSCs (activation of a quiescent population of CSCs?) in adenocarcinomas populated with differentiated tumor cells both in vitro and in vivo. The authors concluded from their observtions that "stemness of colon cancer cells is in part orchestrated by the microenvironment and is a much more dynamic quality than previously expected that can be defined by high Wnt activity."
]]> Stem Cells and Cancer http://moragabiotech.com/nucleus/index.php?itemid=955 Thu, 27 May 2010 07:59:42 -0700 Integrin Alpha 6 Regulates Glioblastoma Stem Cells http://moragabiotech.com/nucleus/index.php?itemid=949 Cell Stem Cell, J. D. Lathia et al. from the Cleveland Clinic published their study results on identifying other markers that may have a role in the maintenance of cancer stem cells (CSCs). The investigators analyzed glioblastoma stem cells (GSCs) from primary tissue specimens of cancer patients. The CSC were enriched using CD133 (Prominin-1) marker. The study data revealed that cells from the perivascular regions of the primary tumor samples co-expressed integrin α6 in the GSC-enriched subpopulation of cells. Additionally, targeting integrin α6 inhibited GSC self-renewal, proliferation, and its tumor-initiating potential. The authors concluded that their study results "provide evidence that GSCs express high levels of integrin α6, which can serve not only as an enrichment marker but also as a promising antiglioblastoma therapy."]]> Stem Cells and Cancer http://moragabiotech.com/nucleus/index.php?itemid=949 Tue, 18 May 2010 08:28:02 -0700 PU.1-Mediated Upregulation of CSF1R is Crucial for Maintaining Leukemia Stem Cells http://moragabiotech.com/nucleus/index.php?itemid=935 reported in a letter in the April 25th online edition of Nature Medicine their findings identifying a subpopulation of cancer stem cells in mouse model for acute myeloid leukemia (AML). The investigators found that cells expressing high levels of the receptor for marcophage colony simulating factor (CSF1R) had potent leukemia-initiating activity. With a leukemia-associated monocytic leukemia zinc finger fusion protein (MOZ)-TIF2, the fusion protein interacts with the PU.1 promoter and subsequent induction in high CSF1R expression. The investigators also found that cells expressing high levels of CSF1R were subpopulation of cancer stem cells which were essential for maintaining AML. In transgenic mice expressing the drug inducible suicide gene controlled by the CSF-1R promoter, the researchers were able to cure the AML in the presence of the drug; which suggests ablation of the AML stem cells. Moreover, induction of AML was suppressed in CSF1R-deficient mice as well as in mice treated with inhibitors to CSF1R. The authors concluded from their observation that targeting PU.1-mediated upregulation of CSF1R expression might be a useful therapeutic approach."]]> Stem Cells and Cancer http://moragabiotech.com/nucleus/index.php?itemid=935 Wed, 28 Apr 2010 18:31:21 -0700 Natural Immunity to Pluripotency Antigen Oct4 in Humans http://moragabiotech.com/nucleus/index.php?itemid=929 published in the April 19th online edition of PNAS, K. M. Dhodapkar et al. from Yale University investigated natural immunity to the Oct4 transcription factor, whose expression is critical for pluripotency in human embryonic stem cells as well as induced pluripotent stem cells (iPSCs). In healthy human subjects, freshly isolated T cells were found to have specificity to Oct4 in over 80% of the healthy donors. The reactive Tcells were predominantly CD4+ T cells residing in the CD45RO+ T cell memory compartment. Proliferative T cell responses were induced when the cells had been exposed to dendritic cells which were pulsed with Oct4-derived peptides. Additionally, the researchers found that in cancer patients diagnosed with germ-cell tumors, such as testicular cancer, 35% of the patients had T cells with specificity to the Oct4 antigen. However, the investigators found that following chemotherapy of the germ-cell tumors, there was apparently an "induction of anti-Oct4 immunity in vivo in patients lacking such responses." The authors concluded that study results suggest that there is a "surprising lack of immune tolerance to this crticial pluripotency antigen in humans...and "harnessing natural immunity to this antigen may allow immune-based targeting of pluripotency-related pathways for prevention of cancers, including those in the setting of ES/IPS-based therapies."
]]> Stem Cells and Cancer http://moragabiotech.com/nucleus/index.php?itemid=929 Tue, 20 Apr 2010 10:53:00 -0700 Inhibition of Notch Signaling in Glioblastoma Targets Cancer Stem Cells via an Endolthelial Cell Intermediate http://moragabiotech.com/nucleus/index.php?itemid=927 Stem Cells, K. E. Hovinga et al. from Memorial Sloan-Kettering Cancer Center (New York) reported their experimental findings on anlayzing cancer stem cells derived from patients with glioblastoma multiforme (GBM). With a three-dimensional organotypic cultures derived from explants of GBM patients, the investigators found that Notch inhibition in the explants resulted in decreased proliferation of tumor cells concomitant with a decrease in endotlthelial cells. Additionally, selective elimination of the endolthelial cells with a specific cytotoxic reagent resulted in a decrease in self-renewing cancer stem cells. The researchers concluded that this particular observation suggests the endolthelial cells in the tumor have a critical role for cancer stem cell maintenance in GBM which is partly mediated by Notch signaling. With neurosphere derived from CD133+ cells, the researchers exposed both the neurospheres and explants to radiation and in combination with Notch signaling blockade. Radiation and Notch blockade resulted in a substantial decrease in self-renewal in tumor explants and in neurospheres, whereas radiation alone was less effective on the explant. The authors concluded that the "Notch signaling pathway plays a critical role in linking angiogenesis and cancer stem cells self-renewal and is thus a potential therapeutic target."
]]> Stem Cells and Cancer http://moragabiotech.com/nucleus/index.php?itemid=927 Fri, 16 Apr 2010 16:46:00 -0700
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