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#1由 sufang 在 五, 05/29/2015 – 13:49 發表。
2015/05/15 新方向2015/05/15 新方向 -> metabolism |
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#2由 sufang 在 一, 05/18/2015 – 09:57 發表。
2015/05/08 email 紀錄Re: 口腔癌整合型計劃主題討論outline (by 珍)_2015.05.08
Ya-Wen Chen <980727@nhri.org.tw> Attachments May 13
For your references.
Best, Ya-Wen  Janelle Kuo <cckuo@nhri.org.tw> May 13
謝謝小雯 Su-Fang Lin <sflin1@gmail.com>
May 14 (4 days ago) Reply to Ya-Wen, Janelle, 李岳倫, David, Shih 謝謝雅雯提供的figure! Accordingly, I listed all the genes involved in one-carbon metabolism as follows, except “ALDH2” which I found in this reference.
AHCY
ALDH1L1 ALDH2 AMT ATIC BHMT DHFR DNMT1 DNMT3A DNMT3B FOLH1 FTCD GART KIAA0828 MAT1A MAT2B MTFMT MTHFD1 MTHFD1L MTHFD2 MTHFR MTHFS MTR MTRR SHMT1 SHMT2 TCNII TYMS 長長的、有點醜, 不過希望將子Johnson只要copy/paste就可以放在excel檔使用
Best,
Su-Fang **************************
口腔癌整合型計劃主題_2015.05.14 Janelle Kuo <cckuo@nhri.org.tw> May 14 to 李岳倫, 陳雅雯, David, 林素芳, Shih Dear all Ya-Wen Chen <980727@nhri.org.tw> May 14
我可以理解, 沒關係啦. |
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#3由 sufang 在 一, 05/18/2015 – 09:43 發表。
2015/05/07 開會紀錄口腔癌整合型計劃主題討論outline (by 珍)_2015.05.07 to Alan Yueh-Luen., Ya-Wen, David, 林素芳, Shih, 林佩瑩 Dear all ———- Ya-Wen Chen Dear all —————— 謝謝珍奈兒! 抱歉 每次都因趕車要先離席.. 還有, 杯子我取回了 謝謝雅雯!! SF ————————— 謝謝靜娟： 同時很抱歉應為要趕短程交通車，提早離席!! 靜娟的整理非常詳細，我個人對於 MTHFD2 相關的部分很有興趣 (其次是recurrence的部分)，因為 MTHFD2 可以連結一個完整的”代謝”路徑，又跟hypermethylation及臨床outcomes有關，我這邊就有可以切入的點，相關的訊息，下次再跟大家報告!! 興國 ——————— Janelle Kuo Dear all —————- Ya-Wen Chen MTHDFD1?又是如何? ————- Dear 小雯
—————- Ya-Wen Chen —————— MTHFD1 也是up的阿 ******************* Dear all: ******************* Janelle Kuo <cckuo@nhri.org.tw> Reply Dear all ***************** |
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#4由 sufang 在 一, 01/12/2015 – 16:21 發表。
Small containers, important cargoSmall containers, important cargo
M. Teresa Villanueva
Nature Reviews Cancer 14, 764–765 (2014) doi:10.1038/nrc3864
Published online 24 November 2014
The role of exosomes as mediators between cancer cells and the microenvironment has gained increasing attention. Two studies have provided further information on the part these small vesicles play in tumour progression and resistance to therapy.
Lara Crow / NPG
Boelens et al. were interested in how stromal communication with cancer cells can influence treatment response. The authors had previously characterized a gene signature for radiation resistance that included many interferon-stimulated genes (ISGs), termed the interferon-related DNA damage resistance signature (IRDS). As ISGs can be regulated by the microenvironment, the authors examined ISG expression in xenografts derived from the metastatic breast cancer cell line MDA-MB-231 alone or co-injected with fibroblasts. Tumours containing both cancer cells and fibroblasts showed high expression of several IRDS genes, including STAT1, and maintained proliferation after radiation treatment, whereas tumours from breast cancer cells alone had lower IRDS expression and regressed after radiation treatment. The authors also identified two groups of breast cancer cells: IRDS responders (IRDS-Rs) — in which interaction with fibroblasts induced IRDS genes and conferred protection against radiation (mediated by STAT1) — and IRDS non-responders (IRDS-NRs), in which interaction with fibroblasts failed to induce IRDS or protect against radiation.
Through computational analysis, the pattern recognition receptor RIG-I was identified as the mediator of fibroblast-induced upregulation of STAT1 and IRDS genes. Indeed, knocking down RIG-I in IRDS-Rs inhibited IRDS gene induction and radiation protection in cancer cells after co-culture with fibroblasts. Conditioned media from IRDS-Rs cultured with fibroblasts upregulated IRDS genes in breast cancer cells, suggesting the presence of a secreted factor that is capable of activating RIG-I in these cells. The authors found that this paracrine induction of IRDS genes was triggered by an increase in the number of exosomes after co-culture, which were transferred from stromal cells to breast cancer cells. Further experiments showed that these exosomes contained 5′-triphosphate RNA that can activate RIG-I signalling in breast cancer cells.
Breast cancer cells separated from fibroblasts by a transwell filter that allowed exosome transfer retained IRDS induction but lost resistance to radiation, suggesting that RIG-I mediates radiation resistance in a juxtacrine way. A computational analysis of the interactome between IRDS-Rs and fibroblasts revealed that expression of NOTCH3 was increased in IRDS-Rs, and its membrane-bound ligand JAG1 was induced in fibroblasts. The authors found that STAT1 (which mediates fibroblast-induced expression of IRDS genes in cancer cells) was required for the transcription of NOTCH3 and NOTCH target genes. Inhibition of the NOTCH pathway with a γ-secretase inhibitor after radiotherapy reversed the protection conferred by fibroblasts and eliminated xenograft tumours in 30% of mice.
So, stromal exosomes transfer 5′-triphosphate RNA to mediate activation of RIG-I signalling in breast cancer cells, which then — through STAT1 — cooperates with NOTCH3 to expand radiation-resistant cells.
Melo et al. investigated the contribution of microRNAs (miRNAs) contained in exosomes to tumour progression. The authors analysed exosomes secreted by breast cancer cell lines (such as MDA-MB-231) and by non-tumorigenic human mammary epithelial cells (MCF10A cells), and observed that six miRNAs, all of which have been widely implicated in cancer progression, were increased in cancer exosomes. Incubating purified exosomes for different periods of time showed an enrichment of miRNAs over time, suggesting active miRNA biogenesis in exosomes. Further analysis revealed the presence of pre-miRNA, as well as the required proteins to process them (the key components of the RISC-loading complex). Incubation of MCF10A cells with MDA-MB-231-derived exosomes induced oncogenic transcriptome changes in MCF10A cells, and MCF10A cells exposed to cancer exosomes could then form tumours when implanted into nude mice. Moreover, exosomes isolated from the serum of patients with breast cancer also induced MCF10A cell tumorigenesis, whereas exosomes from healthy donors did not.
“exosomes can alter the transcriptomes of target cells to promote therapeutic resistance, as well as tumour initiation and progression”
These two papers describe how exosomes can alter the transcriptomes of target cells to promote therapeutic resistance, as well as tumour initiation and progression, opening new possibilities for developing exosome-based biomarkers and therapies.
References
Boelens, M. C. et al. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell 159, 499–513 (2014)
CASArticle
Melo, S. A. et al. Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 26, 707–721 (2014)
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#5由 sufang 在 六, 01/10/2015 – 10:41 發表。
Extracellular vesicles as carriers of microRNA, proteins and lipInt J Cancer. 2015 Jan 5. doi: 10.1002/ijc.29417. [Epub ahead of print] Extracellular vesicles as carriers of microRNA, proteins and lipids in tumor microenvironment.
Penfornis P1, Vallabhaneni K, Whitt J, Pochampally R. Author information Abstract In recent years the knowledge about the control of tumor microenvironment has increased and emerged as an important player in tumorigenesis. The role of normal stromal cells in the tumor initiation and progression has brought our vision in to the forefront of cell-to-cell communication. In this review, we focus on the mechanism of communication between stromal and tumor cells, which is based on the exchange of extracellular vesicles. We describe several, ever-growing, pieces of evidence that extracellular vesicles transfer messages through their miRNA, lipid, protein and nucleic acid contents. A better understanding of this sophisticated method of communication between normal cancer cells may lead to developing novel approaches for personalized diagnostics and therapeutics. This article is protected by copyright. All rights reserved. © 2015 UICC. PMID: 25559768 |
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#6由 sufang 在 六, 01/10/2015 – 10:28 發表。
陽明大學-臺北榮總腫瘤免疫研究團隊重要突破：頭頸癌腫瘤微環境解密陽明大學–臺北榮總腫瘤免疫研究團隊重要突破：頭頸癌腫瘤微環境解密 由 sufang 在 三, 12/31/2014 – 12:54 發表 Oral Cancer oral cancer news 103年12月10日楊慕華教授記者會【陽明大學-臺北榮總腫瘤免疫研究團隊重要突破：頭頸癌腫瘤微環境解密】 傳統的癌症治療通常是以癌細胞做為治療的首要標的，例如化學治療是根據癌細胞快速增殖的特性，以化學藥物抑制癌細胞的增生；大部分的標靶治療，是針對癌細胞表現的特殊分子進行阻斷治療。但惡性腫瘤的組成，是包括種子(癌細胞)與土壤(宿主細胞)兩大部分，亦即除了癌細胞外，尚需許多其他種類的細胞共同形成腫瘤，這些細胞包括宿主的免疫細胞，血管內皮細胞，纖維母細胞等等，此即腫瘤生物學中重要的“種子與土壤”理論。因此，腫瘤細胞能躲過患者免疫系統監控持續生長，甚至重塑腫瘤微環境，使宿主細胞由“敵人”變為有利於腫瘤細胞的“戰友”，是腫瘤惡化的關鍵。近年癌症醫學快速進展，腫瘤免疫學已成為最熱門的研究課題，許多治療也因應而生。但是腫瘤轉移時，這些惡性度更高的“變形”癌細胞，如何反客為主，改造腫瘤微環境，仍多有未知。但最近，陽明大學-臺北榮總的腫瘤免疫團隊，有了新的突破性的發現！ 由陽明大學臨床醫學研究所楊慕華教授領導的癌症研究團隊，在與免疫學專家-陽明大學微生物免疫學研究所陳念榮副教授，以及頭頸癌專家-臺北榮總耳鼻喉頭頸部戴世光教授合作下，發現了頭頸癌惡化時，會分泌各種細胞激素，誘使宿主巨噬細胞聚集至腫瘤處，並“改造”這些免疫細胞成為癌症的幫兇，加速腫瘤的惡化與轉移。這項重要發現，已於今年十月十三日在癌症醫學界具領導地位的頂尖期刊“癌細胞”(Cancer Cell)發表。 楊教授的團隊過去在頭頸癌轉移研究有相當豐富的經驗，先前的系列研究已發現轉移調控蛋白Snail在誘發癌症幹細胞生成，增加細胞侵犯性扮演關鍵性角色。本研究楊教授團隊基於過去研究成果，進一步探討Snail如何重塑腫瘤微環境。研究團隊發現，當腫瘤處於一種輕微發炎狀態時，腫瘤壞死因子(tumor necrosis factor a；TNFa)可促進Snail的乙醯化(acetylation)，而這個訊號乃是誘發腫瘤微環境重塑的關鍵。乙醯化的Snail具有誘發各式細胞激素的能力，進一步吸引宿主巨噬細胞(macrophages)於腫瘤處聚集。巨噬細胞原本是具有吞噬外來病原的免疫細胞，但腫瘤處聚集的巨噬細胞，經癌細胞的影響後，反而促進腫瘤之血管新生與惡化。楊教授進一步與陳念榮副教授合作，使用TNFa基因剔除鼠進行動物實驗，發現腫瘤分泌的TNFa是操控這個惡性循環的元凶。研究團隊也分析頭頸癌的病患標本，發現乙醯化Snail確實與腫瘤組織中巨噬細胞的數量有關：腫瘤細胞中表現較多的乙醯化Snail，通常伴隨較大量的巨噬細胞聚集，而此類病患的預後也較差。圖一顯示小鼠實驗結果：在TNFa基因剔除鼠植入表現Snail之癌細胞，若抑制癌細胞中之TNFa表現，腫瘤轉移與巨噬細胞聚集均會減少。圖二為頭頸癌組織標本，case 1為有較高乙醯化Snail表現之病例，腫瘤處也聚集較多之巨噬細胞；case 2則是乙醯化Snail低表現之個案，腫瘤處巨噬細胞也較少。 圖一在TNFa基因剔除鼠植入表現Snail之癌細胞(LLC1-Snail)或是表現Snail但抑制TNFa之癌細胞(LLC1-Snail-shTNFa)。上圖為小鼠肺部，箭頭指出處為轉移腫瘤；下突為植入腫瘤組織切片，紅色染色處為巨噬細胞。 圖二頭頸癌病患腫瘤組織中乙醯化Snail(左圖箭頭標示處之紅點)與巨噬細胞(右圖棕染色處)。 本研究最具意義的是發現了腫瘤惡化過程中，癌細胞透過TNFa誘發Snail乙醯化為腫瘤微環境重塑之關鍵，未來若能針對此訊號做為阻斷標的，將對晚期癌症治療產生重要影響。本研究特色是跨領域臨床與基礎醫學合作：楊慕華教授是癌症生物學的專家，也同時是腫瘤專科醫師，多年來專注於腫瘤轉移的分子生物學研究；陳念榮副教授是免疫學專家，對於巨噬細胞有相當深入的研究；臺北榮總戴世光教授為頭頸外科醫師，是頭頸癌治療的專家。論文第一作者許信賢博士是陽明大學臨床醫學研究所的博士後研究員，長期在楊教授指導下進行癌症轉移研究，著手進行本研究已有三年半之久。其餘團隊成員均為楊教授實驗室成員，包括研究助理王曉蓉小姐，博士生周俊宏先生，博士生謝佳欣小姐，以及研究助理邱柏憲先生。 本研究完全於台灣進行，整個研究都在陽明大學及臺北榮總內完成。楊教授的研究團隊，近年在癌症研究上有豐碩的研究成果，除本論文外，團隊已於四年內三度在頂尖細胞生物學期刊Nature Cell Biology發表研究成果，且均為於本土進行的腫瘤轉移之系列研究，使本團隊成為癌症轉移研究之國際一流團隊。楊教授本身為醫師科學家，同時肩負科學研究與臨床癌症醫療的任務，所有基礎與臨床醫學訓練均在陽明大學與台北榮總完成。楊教授近年的研究成果，顯示純本土訓練培養的研究團隊，已達國際一流水準，尤其是在國人重要疾病頭頸癌研究上居於領先地位，對本土醫師科學家以及生物醫學研究者，具有相當大之意義。
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#7由 sufang 在 四, 11/20/2014 – 12:58 發表。
Preconditioning the ECM for fibrosisNature Reviews Molecular Cell Biology | Research Highlight Published online 12 November 2014
Remodelling of the extracellular matrix (ECM) by myofibroblasts is crucial for wound repair, but if dysregulated can result in pathological fibrosis. Hinz and colleagues describe how pre-organization of the ECM by myofibroblasts can prime for increased fibrosis by regulating the activation of the pro-fibrotic cytokine transforming growth factor-β (TGFβ).
Latent TGFβ is secreted bound to latency-associated peptide (LAP), which binds to the ECM protein latent TGFβ-binding protein 1 (LTBP1). Integrin-dependent binding of contracting myofibroblasts to LAP induces a conformational change in LAP that releases active TGFβ from the ECM. Therefore, the short-term contractile state of the wound determines the activity of TGFβ. New work now shows that this process is augmented by longer-term changes to the organization of the ECM.
“differences in ECM structure might affect contraction-induced TGFβ1 activation”
In a rat model of wound healing, restraining the wound edges mechanically resulted in accelerated expression of ECM proteins such as fibronectin and LTBP1, and increased fibril organization of the ECM, which correlated with increased TGFβ1 signalling. This increased ECM organization was the result of increased strain exerted by myofibroblasts. High-contractile human dermal myofibroblasts (DMFs) had increased expression of ECM proteins compared with low-contractile human dermal fibroblasts (DFs), and there was greater organization of LTBP1 and fibronectin in the DMF ECM than in the DF ECM. Moreover, cell contraction resulted in threefold higher levels of active TGFβ1 in human DMF cultures compared with human DF cultures. This indicates that differences in ECM structure might affect contraction-induced TGFβ1 activation.
In support of this, when decellularized ECM from human DMFs and from human DFs was reseeded with human DMFs, DMF contraction-induced activation of TGFβ1 was twofold greater from DMF-remodelled ECM than from DF-remodelled ECM, despite similar total levels of TGFβ1. This correlated with the extent of ECM organization, which was significantly higher in DMF cultures than in DF cultures. The authors confirmed that pre-organization of the ECM affects TGFβ1 activation using Fak−/− mouse embryonic fibroblasts, which have a disorganized ECM with a low fibril density and are defective for TGFβ activation.
Increasing the pre-strain of the ECM using a mechanical strain device — to rapidly simulate long-term ECM straining by myofibroblasts — correlated with increased levels of TGFβ1 activation by human DMF contraction. Furthermore, at high levels of ECM pre-strain, TGFβ could be activated in the absence of human DMFs, and the strain threshold for this was lower for DMF ECM than for DF ECM, which is in keeping with the greater level of organization of the DMF ECM.
The results suggest that mechanical pre-straining of the ECM determines the efficacy of TGFβ activation, which sets a mechanical threshold for the pro-fibrotic activity of myofibroblasts. Manipulating this threshold could have important implications for normal versus fibrotic tissue repair.
References Klingberg, F. et al. Prestress in the extracellular matrix sensitizes latent TGF-β1 for activation. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201402006 (2014)
J Cell Biol. 2014 Oct 27;207(2):283-97. doi: 10.1083/jcb.201402006. Epub 2014 Oct 20.
pdf:4270
PMID: 25332161
Klingberg F1, Chow ML1, Koehler A1, Boo S1, Buscemi L2, Quinn TM3, Costell M4, Alman BA5, Genot E6, Hinz B7.
Author information
Abstract
Integrin-mediated force application induces a conformational change in latent TGF-β1 that leads to the release of the active form of the growth factor from the extracellular matrix (ECM). Mechanical activation of TGF-β1 is currently understood as an acute process that depends on the contractile force of cells. However, we show that ECM remodeling, preceding the activation step, mechanically primes latent TGF-β1 akin to loading a mechanical spring. Cell-based assays and unique strain devices were used to produce a cell-derived ECM of controlled organization and prestrain. Mechanically conditioned ECM served as a substrate to measure the efficacy of TGF-β1 activation after cell contraction or direct force application using magnetic microbeads. The release of active TGF-β1 was always higher from prestrained ECM as compared with unorganized and/or relaxed ECM. The finding that ECM prestrain regulates the bioavailability of TGF-β1 is important to understand the context of diseases that involve excessive ECM remodeling, such as fibrosis or cancer.
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#8由 sufang 在 四, 10/09/2014 – 16:38 發表。
The polyphenol EGCG and luteolin inhibits TGFb induced myoblastPLoS One. 2014 Oct 1;9(10):e109208. doi: 10.1371/journal.pone.0109208. eCollection 2014. The presence of reactive stroma, predominantly composed of myofibroblasts, is directly associated with and drives prostate cancer progression. We have previously shown that (-)-Epigallocatechin-3-gallate (EGCG), in the form of Polyphenon E, significantly decreases serum levels of HGF and VEGF in prostate cancer patients. Given that HGF and VEGF are secreted from surrounding tumor myofibroblasts, these observations suggested that EGCG may inhibit prostate cancer-associated myofibroblast differentiation. Herein, we demonstrate that micromolar combinations of EGCG and a second polyphenol, luteolin, synergistically inhibit TGF-β-induced myofibroblast phenotypes in prostate fibroblast cell lines, as observed primarily by potentiation of fibronectin expression. Functionally, EGCG and luteolin inhibited TGF-β-induced extracellular matrix contraction, an enhancer of tumor cell invasion. EGCG and luteolin inhibited downstream TGF-β-induced signaling, including activation of ERK and AKT, respectively, but mechanistically, only ERK appeared to be necessary for TGF-β-induced fibronectin expression. Furthermore, neither EGCG nor luteolin affected Smad signaling or nuclear translocation. Rho signaling was found to be necessary for TGF-β-induced fibronectin expression and EGCG and luteolin each reduced RhoA activation. Finally, EGCG and luteolin were shown to reverse TGF-β-induced fibronectin expression, implicating that these natural compounds may be useful not only in preventing but also in treating already activated myofibroblasts and the diseases they cause, including cancer. The ability of EGCG and luteolin to synergistically target myofibroblasts suggests that combined clinical use of these compounds could prevent or reverse cancer progression through targeting the tumor microenvironment, in addition to the tumor itself. PMID: 25272043 |
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#9由 sufang 在 四, 10/09/2014 – 16:33 發表。
ECM stiffness paves the way for tumor cellsIn the mammary gland, the stiffness of extracellular matrix (ECM) collagen is thought to influence tumor progression and clinical outcome. A new mechanism orchestrated by a microRNA circuit is shown to mediate the physical effects of the microenvironment on tumor cell progression. The findings may explain how increased breast matrix stiffness is associated with poor survival and could help identify women with aggressive breast cancer (pages 360–367).
Increased ECM stiffness promotes β1 integrin clustering, transcriptionally activates MYC and induces the polycistronic miR-17-92 cluster. This results in the upregulation of a particular miRNA, miR-18a, which, in turn, reduces expression of PTEN and HOXA9. Low PTEN increases signaling through the phosphoinositide 3-kinase (PIP3)–AKT pathway, promoting invasion and metastasis. Increased ECM-generated mechanical force can therefore regulate the expression of PTEN, HOXA9 and also BRCA1 via a miR-18a–dependent signaling network. FAK, focal adhesion kinase; IP3, inositol triphosphate. |
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#10由 sufang 在 四, 10/09/2014 – 10:00 發表。
Fwd: 萊富蕙敏~~TO:劉柯俊老師劉 柯俊 開始轉寄郵件： > 寄件人: “Wang, Laetitia” <Laetitia.Wang@thermofisher.com>
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