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#1由 sufang 在 六, 11/01/2014 – 14:24 發表。
王陸海院士: Glucocorticoids mediated induction of miRNA-708王陸海院士: Glucocorticoids mediated induction of miRNA-708 to suppress ovarian cancer cell invasion and metastasis through targeting Rap18
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#2由 sufang 在 六, 11/01/2014 – 14:22 發表。
侯明峰教授: The role of adipocytokines in breast cancer侯明峰教授: Kaohsiung Municipal Ta-Tung Hospital/Kaohsiung Medical University (高雄市立大同醫院/高雄醫學大學)
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#3由 sufang 在 六, 11/01/2014 – 14:17 發表。
葉祥勝博士: Pre-competitive collaborations to promote cancer葉祥勝博士: Dr. Xiang S. Ye, Senior Director of Cancer Research in China/Asia, Lilly China Research and Development Center, PRC
Pre-competitive collaborations to promote cancer reasearch and drug development in asia
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#4由 sufang 在 六, 11/01/2014 – 11:07 發表。
麥德華教授 Future anti-cancer targets: put the cart before the horses麥德華教授: Dr. Tak Wah Mak, Dept Medical Biophysics, U of Toronto, Canda
ImmuneScience (1996). Regulation of T cell receptor signaling by tyrosine phosphatase SYP association with CTLA-4.
Immuno Rev (1996). CTLA-4, a negative regulator of T-lymphocyte activation.
-CTLA4, PD-1 etc are immune checkpoints, which lead to landmark paper of NEJM 2010 Improved survival with ipilimumab in patients with metastatic melanoma.
Science (2012). iRhom2 regulation of TACE controls TNF-mediated protection against Listeria and responses to LPS.
AneuploidyTTK and PLK4
Cancer Cell (2014) Functional characterization of CFI-400945, a Polo-like kinase 4 inhibitor, as a potential anticancer agent.
-PLK4 centriole duplication CFI-400945
-CFI-400945 in a breast caner PDX
TTK spindle assembly checkpoint Bioorg Med Chem. (2014) Discovery of inhibitors of the mitotic kinase TTK based on N-(3-(3-sulfamoylphenyl)-1H-indazol-5-yl)-acetamides and carboxamides.
MetabolismRedox Inducers and scavengers of ROS (fire and water)
Oncogenes inudce a lot of ROS Scagengers: Glutathione NADPH, NRF2 De novo GSH synthesis –Cell Death Differ (2013). Functional significance of glutamate-cysteine ligase modifier for erythrocyte survival in vitro and in vivo.
–GCLM reuired for mammary development (Cancer Cell inpress)
Are tumors addicted to oncogenes or metabolism?
(A) DJ-1=PARK7 (in Parkison Disease) PNAS (2006). DJ-1, a cancer- and Parkinson’s disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2.
(B) CPT1C (in collaboration with AVEO): Genes Dev (2011). Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Redox is crucial to tumor cell survival!!
Nat Rev Cancer (2011) Regulation of cancer cell metabolism.
Multiple molecular mechanisms, both intrinsic and extrinsic, converge to alter core cellular metabolism and provide support for the three basic needs of dividing cells:
(1) rapid ATP generation to maintain energy status (more ATP);
(2) increased biosynthesis of macromolecules (more building blocks);
(3) tightened maintenance of appropriate cellular redox status (more redox).
Three pathways (PPP, IDHs and ME1) for NAPDH and one pathway (glutaminolysis) for GSH.
 Figure 4 | Mechanisms of redox control and their alterations in cancer. The production of two of the most abundant antioxidants, reduced nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), has been shown to be modulated in cancers. Pyruvate kinase isoform M2 (PKM2), which is overexpressed in many cancer cells, can divert metabolic precursors away from glycolysis and into the pentose phosphate pathway (PPP) to produce NADPH. NADP-dependent isocitrate dehydrogenase 1 (IDH1), IDH2 and malic enzyme 1 (ME1) also contribute to NADPH production. MYC increases glutamine uptake and glutaminolysis, driving the de novo synthesis of GSH. Additionally, MYC contributes to NADPH production by promoting the expression of PKM2. Together, NADPH and GSH control increased levels of reactive oxygen species (ROS) driven by increased cancer cell proliferation. αKG, α-ketoglutarate; G6P, glucose-6-phosphate.
Cancer Discovery (2013). Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities. Nat Rev Drug Discov 2013: Modulation of oxidative stress as an anticancer strategy.  Figure 1. The production of reactive oxygen species (ROS) can be induced by hypoxia, metabolic defects, endoplasmic reticulum (ER) stress and oncogenes. Conversely, ROS are eliminated by the activation of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), the production of glutathione and NADPH, the activity of tumour suppressors (such as breast cancer susceptibility 1 (BRCA1), p53, phosphatase and tensin homolog (PTEN) and ataxia telangiectasia mutated (ATM)) and the action of dietary antioxidants.
PNAS (2014). Estrogen controls the survival of BRCA1-deficient cells via a PI3K-NRF2-regulated pathway.
–Can the regulation of the ROS levels explain BRCA1 carriers mainly only develop breast and ovarian cancers.
–Estrogen-controlled NRF2 activation in BRCA1-related tumorigenesis
–Basal-like breast cancers express lower levels of rearrangements
 (A) Model for NRF2 regulation in BRCA1-associated tumorigenesis. In breast tissue, estrogen induces NRF2 activation through the PI3K/AKT pathway in BRCA1-deficient cells and protects them from ROS-induced cell death. (B) Major estrogen sources in humans and mice. Red arrow indicates major tissue source of estrogen in premenopausal women. (C) Paracrine signaling in the mammary gland. In response to estrogen and progesterone, paracrine mediators promote the proliferation and differentiation of stem/progenitor cells, as well as ERα-/PR-negative luminal epithelial cells. |
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#5由 sufang 在 六, 11/01/2014 – 10:41 發表。
閻雲校長:Nanoparticles conjugated shRNA in cancer therapy閻雲校長: Dr. Yun Yen, Taipei Medical University Nanoparticles conjugated shRNA in cancer therapy
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#6由 sufang 在 六, 11/01/2014 – 10:38 發表。
洪明奇院士: Mechanism-driven target therapy洪明奇院士: Dr. Mien-Chie Hung, Dept Mol Cell Oncology, U of Texas M.D. Anderson Cancer Center, USA
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#7由 sufang 在 六, 11/01/2014 – 10:19 發表。
楊慕華教授: The two sided effect of snail in cancer metastasis楊慕華教授 (Dr. Muh-Hwa Yang): The two sided effect of snail in cancer metastasis
Nat Cell Biol. 2014 Mar;16(3):268-80. doi: 10.1038/ncb2910.
MicroRNA-146a directs the symmetric division of Snail-dominant colorectal cancer stem cells.
Hwang WL, Jiang JK, Yang SH, Huang TS, Lan HY, Teng HW, Yang CY, Tsai YP, Lin CH, Wang HW, Yang MH.
Abstract
Asymmetrical cell division (ACD) maintains the proper number of stem cells to ensure self-renewal. In cancer cells, the deregulation of ACD disrupts the homeostasis of the stem cell pool and promotes tumour growth. However, this mechanism is unclear. Here, we show a reduction of ACD in spheroid-derived colorectal cancer stem cells (CRCSCs) compared with differentiated cancer cells. The epithelial-mesenchymal transition (EMT) inducer Snail is responsible for the ACD-to-symmetrical cell division (SCD) switch in CRCSCs. Mechanistically, Snail induces the expression of microRNA-146a (miR-146a) through the β-catenin-TCF4 complex. miR-146a targets Numb to stabilize β-catenin, which forms a feedback circuit to maintain Wnt activity and directs SCD. Interference with the Snail-miR-146a–β-catenin loop by inhibiting the MEK or Wnt activity reduces the symmetrical division of CRCSCs and attenuates tumorigenicity. In colorectal cancer patients, the Snail(High)Numb(Low) profile is correlated with cetuximab resistance and a poorer prognosis. This study elucidates a unique mechanism of EMT-induced CRCSC expansion.
Comment in [Nat Cell Biol. 2014] PMID:24561623
 Figure 1: Cell division modes used by cancer stem cells and their regulation in colorectal cancer. (a) Colorectal cancer stem cells (CRCSCs) undergo symmetric self-renewing divisions giving rise to two self-renewing daughter cells (red). The red curved arrows indicate self-renewal. (b) CRCSCs also undergo asymmetric self-sustaining divisions by localizing cell fate determinants with opposite functions (red and blue crescents) to opposite poles, thereby generating one self-renewing (red) and one differentiating (blue) daughter cell. (c) Symmetric differentiating divisions can also be induced in non-CSC colorectal cancer cells (blue); for example, by the presence of miR-34a (ref. 12). (d) Model of integrated regulation of cell division mode, tumour progression and metastasis. Left: miRNA-regulated Wnt and Notch signalling promotes symmetric self-renewing cell divisions of intestinal stem cells at the bottom of intestinal crypts. In non-neoplastic stem cells and CRCSCs from early tumour stages, Snail expression is low or absent, whereas Numb expression is high, leading to proteasomal degradation of β-catenin (β-cat) and attenuation of Wnt signalling. As a result, intestinal stem cells and early-stage CRCSCs divide asymmetrically. Right: Hwang et al.3 propose a positive feedback mechanism in late tumorigenesis, whereby the Snail-dependent action of nuclear β-catenin (β-catn) and TCF4 induces miR-146a expression and the subsequent downregulation of Numb. This relieves the Numb-mediated degradation of β-catenin and enhances Wnt signalling, thereby increasing symmetric divisions and maintaining the self-renewing CRCSC phenotype. The Snail–β-cat–miR-146a axis promotes tumour growth and metastasis, in part independently of the epithelial-to-mesenchymal transition (EMT).
Cancer Cell. 2014 Oct 13;26(4):534-48. doi: 10.1016/j.ccell.2014.09.002.
Acetylation of snail modulates the cytokinome of cancer cells to enhance the recruitment of macrophages.
Hsu DS1, Wang HJ1, Tai SK2, Chou CH1, Hsieh CH3, Chiu PH1, Chen NJ4, Yang MH5.
Abstract
Snail is primarily known as a transcriptional repressor that induces epithelial-mesenchymal transition by suppressing adherent proteins. Emerging evidence suggests that Snail can act as an activator; however, the mechanism and biological significance are unclear. Here, we found that CREB-binding protein (CBP) is the critical factor in Snail-mediated target gene transactivation. CBP interacts with Snail and acetylates Snail at lysine 146 and lysine 187, which prevents the repressor complex formation. We further identified several Snail-activated targets, including TNF-α, which is also the upstream signal for Snail acetylation, and CCL2 and CCL5, which promote the recruitment of tumor-associated macrophages. Here, we present our results on the mechanism by which Snail induces target gene transactivation to remodel the tumor microenvironment. PMID: 25314079 SignificanceThe understanding of Snail as an activator is relatively limited, compared with the knowledge of Snail as a repressor. Here, we identify the mechanism that guides the activity of Snail through the acetylation of Snail. The “yin and yang” effect of Snail is, therefore, elucidated; “repressor Snail” inhibits adherent protein expression to promote the disaggregation and migration of epithelial cancer cells, whereas “activator Snail” induces mesenchymal proteins to complete EMT and cytokine expression to remodel the tumor microenvironment. The paracrine effect of cells undergoing EMT has been highlighted, explaining the pivotal role of these stem-like cancer cells in host-cancer interplay.
 Figure 8. Clinical Significance of Snail Acetylation in Head and Neck Cancer Patients. (A) PLA for detecting acetylated Snail (left) and IHC for analyzing CD68+ (middle) or CD163+ (right) macrophages in head and neck cancer patients. The arrows indicate the representative PLA-positive signals. Case 1 is a representative case with increased acetylated Snail and CD68+/CD163+ macrophages. Case 2 is a representative case with low acetylated Snail and macrophage recruitments. Scale bars: for PLA photo, 20 μm; for CD68/CD163 IHC, 200 μm. (B) The box plot for showing the percentage of PLA-positive cells in CD68low versus CD68high (upper panel) and CD163low versus CD163high (lower panel) head and neck cancer samples (n = 15). The p value was shown in each panel. The box plots represent sample maximum (upper end of whisker), upper quartile (top of box), median (band in the box), lower quartile (bottom of box), and sample minimum (lower end of whisker). (C) Representative results of immunohistochemistry using the antibody against acetylated Snail lysine 187 or a macrophage marker CD163 in head and neck cancer samples. Case 1, a representative case of increased acetylated Snail in cancer cells and tumor-associated macrophages. Case 2, a representative case of low level of acetylated Snail in cancer cells and few macrophages. Scale bars, 200 μm. (D) A Kaplan-Meier analysis of the progression-free survival in 82 head and neck cancer patients. The p value is shown in the panel.
Acetylation of Snail in Head and neck cancer !! acetylation of snail –> transcriptinal activator! Tumor Microenvironment in HNSCC (Cancer Cell Oct-2014) http://eln.nhri.org.tw/lims/?q=node/1836 按我 |
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#8由 sufang 在 六, 11/01/2014 – 10:13 發表。
安康教授: From nutrient deficiency to mitochondria dysfunction安康教授: Dr. David K. Ann, Dept Metabolic Diseases Beckman Research Institute, City of Hope, USA
From nutrient deficiency to mitochondria dysfunction: a translational study of targeting arginine auxotrophic cancers
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#9由 sufang 在 六, 11/01/2014 – 10:08 發表。
馮新華教授: How cancer cells escape from TGF-b control?3. 馮新華教授 (Xin-Hua Feng, Life Sciences Institute, Zhejiang University, PRC)
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#10由 sufang 在 六, 11/01/2014 – 10:01 發表。
陳慶士所長: Fighting an organized crime network in pancreatic cancer陳慶士所長: Fighting an organized crime network in pancreatic cancer: tumor and its microenvironment
#1由 sufang 在 六, 11/01/2014 – 09:57 發表。
Dr. Alex Chang 張元吉教授Dr. Alex Chang 張元吉教授 (Johns Hopkins Singapore International Medical Centre, Singapore) Combination targeted therapy in advanced lung cancer
 Mechanisms of EGFR inhibitor resistance and therapeutic strategies.
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