β-Catenin is a central effector of Wnt signaling in embryonic and stem cell development and in tumorigenesis. Here, through a mass spectrometric analysis of a β-catenin protein complex, we identified 12 proteins as putative β-catenin interactors. We show that one of them, 14-3-3ζ, enhances β-catenin-dependent transcription by maintaining a high level of β-catenin protein in the cytoplasm. More importantly, 14-3-3ζ facilitates activation of β-catenin by the survival kinase Akt and colocalizes with activated Akt in intestinal stem cells. We propose that Akt phosphorylates β-catenin, which results in 14-3-3ζ binding and stabilization of β-catenin, and these interactions may be involved in stem cell development.
Cancer cells are heterogeneous and, it has been proposed, fall into at least two classes: the tumor-initiating cancer stem cells (CSC) and the more differentiated tumor cells. The transmembrane protein CD133 has been widely used to isolate putative CSC populations in several cancer types, but its validity as a CSC marker and hence its clinical ramifications remain controversial. Here, we conducted transcriptomic profiling of sorted CD133 + and CD133 − cells from human glioblastoma multiforme (GBM) and, by subtractive analysis, established a CD133 gene expression signature composed of 214 differentially expressed genes. Extensive computational comparisons with a compendium of published gene expression profiles reveal that the CD133 gene signature transcriptionally resembles human ES cells and in vitro cultured GBM stem cells, and this signature successfully distinguishes GBM from lower-grade gliomas. More importantly, the CD133 gene signature identifies an aggressive subtype of GBM seen in younger patients with shorter survival who bear excessive genomic mutations as surveyed through the Cancer Genome Atlas Network GBM mutation spectrum. Furthermore, the CD133 gene signature distinguishes higher-grade breast and bladder cancers from their lower-grade counterparts. Our systematic analysis provides molecular and genetic support for the stem cell-like nature of CD133 + cells and an objective means for evaluating cancer aggressiveness.
Background The effect of neoadjuvant chemotherapy (NACT) on topographical distribution patterns of lymph node metastasis in cervical cancer was unknown. Methods Patients with FIGO stage IB1-IIB who underwent radical surgery with or without NACT were enrolled (3527 patients). A matched-case comparison design was used to compare the effects of NACT on lymph node metastasis. Results We analyzed groups of 167 and 140 patients who were diagnosed with lymph node metastasis in the matched primary surgery group and NACT group, respectively, and no significant difference was observed (p = 0.081). The incidence of lymph node metastasis was significantly decreased in the NACT-responsive group compared to the non-responsive group (18.4% vs. 38.6%, P<0.001). The metastatic rates for every lymph node group also declined in the NACT-responsive group except for the deep inguinal and the para-aortic lymph node groups. Clinical response, deep stromal, parametrial and lymph vascular invasions were independent risk factors for lymph node metastasis in the NACT group. Furthermore, deep stromal invasion and lymph vascular invasion, but not the response to NACT, were independently associated with upper LNM. The number of lymph nodes involved, response to NACT, tumor histology and a positive vaginal margin were independent prognostic factors affecting DFS or OS rates in node-positive patients treated with NACT plus radical surgery. Conclusion The frequency and topographic distribution of LNM are not modified by NACT, and clinical non-responders showed more involved LNs. A systemic and extensive lymphadenectomy should be performed in patients treated with NACT plus surgery regardless of the response to NACT.
SOSTDC1 for germinal center regulation T follicular helper (T FH ) cells are CD4 + T cells that facilitate B cell antibody production and B cell memory responses in the germinal centers (GCs) of lymphoid organs. These activities are in turn restrained by T follicular regulatory (T FR ) cells, a population of T cells with unclear origins. Wu et al. now demonstrate that a subpopulation of T FH cells and fibroblastic reticular cells both produce sclerostin domain-containing protein 1 (SOSTDC1), which drives T FR cell generation by inhibiting Wnt–β-catenin signaling. In mice lacking the gene Sostdc1 , T FR cell numbers were substantially decreased and GC responses were enhanced. These insights into T FR cell biology and GC regulation may have important implications for autoantibody-mediated diseases and the future development of vaccines and therapies for autoimmune disease. Science , this issue p. 984
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.
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