槐生拜尔孔菌Vanderbylia robiniophila (Murrill) B.K. Cui & Y.C. Dai,俗称：槐耳,在我国主要分布于辽宁、河北、山东、北京、河南、陕西等地,主要以刺槐为寄主（戴玉成 2012）,是我国民间重要的药用真菌之一（Wu et al. 2019）,隶属于担子菌门Basidiomycetes、伞菌纲Agaricomycetes、多孔菌目Polyporales、多孔菌科Polyporaceae。该种最初由 （1907）归为栓菌属Trametes,后由（Ryvarden 1983）转移到多年卧孔菌属Perenniporia,而（Cui et al.2019）最近的研究将其归为Vanderbylia属。槐耳最早出现于公元659年李绩等著的《唐本草》中,在明代医药学家李时珍的《本草纲目》中也有记载,称为槐檽（戴玉成和李玉 2011）。现代药理研究表明,槐耳可以通过抑制肿瘤细胞的生长与增殖、诱导肿瘤细胞凋亡、抑制血管新生、抑制肿瘤细胞侵袭与转移、调节多种癌基因与抑癌基因的表达、提高机体免疫力、逆转肿瘤细胞的耐药性等多种途径发挥抗肿瘤作用（Song et al. 2015;Zhao & Liu 2018;Li et al. 2020）。其单味药物及提取物作为癌症辅助治疗药物于1997年在我国获批上市,商品名为“金克”,用于原发性肝癌的治疗（张洪梅等 2017;陈霞飞等 2018）。2018年,由陈孝平院士主导的一项涉及39个中心和1 044名患者的多中心、随机临床试验表明槐耳颗粒能使肝癌术后复发率降低33%,证实了槐耳颗粒作为一种肝癌术后辅助治疗药物的有效性（Chen et al. 2018）。本文对槐耳的化学成分、生物活性及其抗肿瘤作用机制等方面进行了概括总结,为后续的相关研究提供参考。
1 槐耳的化学成分及其生物活性
1.1 多糖类成分
近年来,随着槐耳良好的抗癌疗效与极低的毒副作用得到临床的广泛认可,对槐耳化学成分的报道也日益增多,目前的研究普遍认为多糖蛋白为槐耳的主要活性物质,其组成包括41.53%多糖、12.93%氨基酸和8.72%水分（王建忠和程若川 2003;杨爱琳等 2015）。从人工培养的槐耳子实体中提取出的粗多糖可以通过增加巨噬细胞的吞噬作用和NO的产生,促进淋巴细胞的增殖和自然杀伤细胞的活性来增强肉瘤S180实体瘤小鼠的免疫应答,从而发挥肿瘤抑制作用（Jia et al. 2009）。从槐耳子实体中分离得到的粗多糖可以通过靶向三阴性乳腺癌（TNBC）中的乳腺癌干细胞（BCSC）,使微球体形成减少,干细胞相关基因表达下调,醛脱氢酶阳性细胞比例降低,并可以在体内抑制异种移植肿瘤的形成。而进一步的机制研究表明该粗多糖显著降低了雌激素受体α-36（ERα-36）的表达,并减弱了ERα-36介导的ERα-36highTNBC细胞中AKT/β-catenin信号的激活（Hu et al. 2019）。而粗多糖（SP1）可以在0-800μg/mL的浓度范围内显著抑制SMMC-7721细胞的体外增殖和毛细血管形成,还可以抑制SMCC-7721荷瘤小鼠的肝癌肿瘤生长和向肺的转移性结节。其机制研究表明,SP1可以下调(HIF)-lalpha、VEGF、MMP2、Bcl-2、N-cadherin、STAT3及MTDH的表达水平,并在肿瘤组织中上调Bax和NE-cadherin的表达,可在晚期阶段抑制肝癌患者的肿瘤生长和转移（Zou et al. 2015）。
为了进一步研究槐耳多糖成分与活性的关系,很多研究者对提取工艺进行了优化,（Liu et al.2014）用冷碱法、热碱法、常规法和高温-超高压法分别提取和纯化槐耳多糖,结果表明采用高温-超高压梯度乙醇沉淀法提取,经脱蛋白处理后的多糖含量最高（41.32%）,其抗氧化活性也最高（54.73%）。（Wang et al.2014）分离得到纯度为(85.3±1.3)%的多糖,其单糖组成为岩藻糖、阿拉伯糖、木糖、甘露糖、半乳糖和葡萄糖,摩尔百分比分别为5.82%、13.11%、16.88%、15.85%、11.40%和36.94%。同时发现该多糖在体外对ABTS、超氧阴离子和羟基自由基具有明显的抗氧化潜力。而一种纯度为93.2%的槐耳粗多糖可以显著抑制HMC SMMC-7721荷瘤小鼠的肿瘤生长和向肺的转移,且对正常细胞没有毒性。通过免疫组织化学对肿瘤的分析表明,这种粗多糖可以抑制PCNA表达,增加TUNEL阳性细胞的数量,并降低微血管密度（MVD）。此外,还可以降低肿瘤组织中(HIF)-1alpha、VEGF、AUF-1和AEG-1的蛋白表达（Li et al. 2015）。
随着研究的深入,（Sun et al.2013）首次从槐耳的子实体中分离出一个分子量为2.5×104Da的中性水溶性多糖（W-NTRP）,主要由半乳糖（Gal）、阿拉伯糖（Ara）和葡萄糖（Glc）,以相对摩尔比为4.2:2.5:0.7组成。体外抗肿瘤和免疫调节活性实验结果表明,其对3种人胆管癌细胞系（QBC939、Sk-ChA-1和MZChA-1）表现出显著的抑制作用,IC50值分别为47.8、75.9和43.7g/mL,但对正常细胞L-929无毒。进一步的研究表明,W-NTRP可以通过上调可诱导的NO合酶（iNOS）来显著刺激巨噬细胞产生一氧化氮（NO）。这些结果表明,该多糖类化合物可作为治疗胆管癌的潜在抗肿瘤药物。
此外,槐耳子实体中还发现了另外一种平均分子量约为8.7×104Da的均多糖（TRP）,由葡萄糖、半乳糖和阿拉伯糖组成,摩尔比为4.2:1.10:1.06,该多糖的骨架为1,3,6-和1,4-连接的吡喃葡萄糖基,在1,3,6-连接的吡喃葡萄糖基上以（1→3）键连接呋喃阿拉伯糖基和吡喃半乳糖基为端基糖片段。TRP经口服给药后可以通过诱导细胞凋亡来显著抑制BALB/c裸鼠中U-2OS肿瘤的生长,并使肿瘤组织中TUNEL阳性细胞数量增加,Bax/Bcl-2比率升高,caspase-9、caspase-3和裂解的PARP表达升高,caspase-8保持不变,降低MTDH的过度表达,从而抑制了人骨肉瘤癌细胞的增殖（Zhao et al. 2015a,2015b）。
槐耳菌质的水提物是槐耳颗粒的原料药,含有大量的多糖蛋白,从中鉴定了一种分子量约为5.59×104Da的蛋白聚糖（TPG-1）,其总碳水化合物和蛋白质组成分别为43.9%和41.2%。TPG-1可以通过激活TLR4-NF-kB/MAPK信号通路,增强机体免疫作用,从而发挥抗肿瘤活性（Yang et al. 2019）。
1.2 甾体类和生物碱类成分
图1
2 槐耳提取物的抗肿瘤作用机制研究
槐耳入药已有1 400余年历史,目前在临床上,槐耳及其原料药材槐耳菌质作为中药国家一类新药,主要用于多种癌症的补充治疗。现代药理学研究表明,槐耳可以抑制多种恶性肿瘤细胞的增殖、侵袭和转移,诱导细胞发生凋亡,同时增强患者的机体免疫力,在乳腺癌、肺癌、胃癌、肝癌等恶性肿瘤的治疗中具有重要作用。
2.1 乳腺癌
乳腺癌是全世界女性中最常见的恶性肿瘤,每年诊断病例超过130万例,死亡45万人（Cancer Genome Atlas 2012;DeSantis et al. 2019;Liang et al. 2020）。在过去的几年中,乳腺癌的治疗已取得了实质性进展,但相关的并发症和副作用却严重影响患者的生活质量（Greenlee et al. 2017;Harbeck & Gnant 2017）。随着RNA测序和基因芯片技术的发展,高通量数据为药物作用机制的研究提供了重要线索。采用转录组芯片HTA 2.0分析槐耳水提物对ER阴性的乳腺癌细胞MDA-MB-231的多靶点作用（Kong et al. 2015）,GO分析结果表明,槐耳可能会影响乳腺癌肿瘤发生和发展的多个关键步骤,包括转录、凋亡、细胞周期阻滞、免疫反应、DNA复制和细胞增殖。此外,通过KEGG分析表明,槐耳给药后各种关键的信号网络发生了变化,包括MAPK信号通路、NF-κB信号通路、细胞凋亡、细胞周期、DNA复制和代谢途径。
以上结果在很多文献中也得到了验证,有研究表明槐耳清膏可以诱导人乳腺癌细胞MCF-7和MDA-MB-231凋亡,降低其细胞存活率,并且呈现时间和剂量依赖性。进一步的机制研究发现,槐耳清膏可以通过激活p53将MCF-7细胞周期阻滞在G0⁄G1期,而在p53突变的MDA-MB-231细胞中没有观察到这一现象。在线粒体途径中,Bcl-2家族成员承担着在不同情况下调节细胞凋亡的责任,包括抗凋亡的Bcl-2蛋白和促凋亡的Bax蛋白（Hengartner 2000）。槐耳可以通过线粒体途径,下调Bcl-2、上调Bax,从而诱导ER阳性和ER阴性乳腺癌细胞凋亡,可以作为乳腺癌的有效补充剂辅助癌症治疗（Zhang et al. 2010）。
免疫系统可以通过细胞、抗体和细胞因子的相互作用网络识别和消除早期恶性细胞。越来越多的证据表明,肿瘤细胞微环境的变化具有免疫抑制作用,可以通过多种机制帮助癌细胞逃避免疫监视,是肿瘤生长和转移的重要因素（Parkin & Cohen 2001;Baumeister et al. 2016）。肿瘤微环境中的巨噬细胞大多是M2极化的,可以促进肿瘤发生,也被定义为肿瘤相关巨噬细胞（TAM）（Qian & Pollard 2010）。采用RAW264.7鼠巨噬细胞系对槐耳提取物调节TAM的作用进行评价,结果表明槐耳提取物可以剂量依赖性的方式抑制巨噬细胞向肿瘤微环境的浸润,调节巨噬细胞的极化,降低M2极化并增加RAW264.7细胞的吞噬作用。此外,还发现槐耳可以抑制巨噬细胞诱导的血管生成并降低MMP2、MMP9和VEGF的表达水平,揭示了槐耳提取物通过靶向TAMs抑制血管生成的抗肿瘤作用机制（Li et al. 2016）。该课题组随后的一项研究结果表明,槐耳提取物在乳腺癌患者和鼠乳腺癌模型中均具有免疫调节功能,并能改变血清IL-7、MCP-1和MIP-1β的水平,抑制癌细胞的转移,这提示槐耳提取物诱导的乳腺癌患者全身细胞因子谱和促炎/抗炎细胞因子的平衡可提供一种新的治疗策略（Zhang et al. 2018）。
趋化因子是一类特定的小分子蛋白质,在白细胞的募集和激活、癌症的进展和转移以及宿主免疫反应的调节中发挥着重要作用（Yang et al. 2013）。槐耳水提物能够促进DARC的表达并降低其配体CCL-2、CXCL-8、IL-8、MMP-2和CXCL-1的表达。通过比较来自同一患者的DARC在原发性和转移性乳腺癌组织中的状态发现,乳腺癌原发灶和转移灶之间的DARC表达水平具有显著差异,而原发灶和转移灶之间ER、PR和HER2的表达差异不明显（Chen et al. 2018）。
内分泌疗法是早期乳腺癌患者的主要疗法之一,他莫昔芬和氟维司群是乳腺癌患者内分泌治疗的主要药物,然而,肿瘤细胞的耐药性经常引起患者治疗失败和复发（Poggio et al. 2016）。槐耳提取物对他莫昔芬耐药细胞（M7-TR）和氟维司群耐药细胞（M7-FR）均有抑制增殖的作用。流式细胞术和免疫印迹实验结果表明,槐耳提取物可以诱导两种细胞的G0/G1期阻滞,并通过下调miR-203显著增加共济失调毛细血管扩张突变蛋白（ATM）的表达来抑制M7-TR和M7-FR细胞的增殖。此外,槐耳提取物在异种移植小鼠模型中也具有抑制体内肿瘤生长的作用（Gao et al. 2017）。
多药耐药（MDR）是限制癌症治疗效果并影响患者预后的主要原因之一（Lage & Dietel 2002;Miller et al. 2019）,紫杉醇是用于转移性乳腺癌的一线化疗药物（Willson et al. 2019）,可通过结合β-微管蛋白来促进微管蛋白聚合,将细胞周期阻滞在G2/M期并诱导细胞死亡（Bharadwaj & Yu 2004）。槐耳可以将细胞周期阻滞于G0/G1期,能够与紫杉醇产生协同作用从而抑制人乳腺癌细胞MCF-7和MDA-MB-231增殖并诱导其发生凋亡。进一步的实验结果表明,槐耳提取物能够降低p65和c-Met表达并增加IκBα表达,而紫杉醇增加p65表达并降低IκBα和c-Met表达（Yang et al. 2017）。此外,在另一项研究中也发现了协同效应,槐耳联合紫杉醇可能通过PI3K/Akt信号通路抑制BT474和MDA-MB- 231乳腺癌异种移植肿瘤中的葡萄糖摄取,从而抑制肿瘤的生长（Chen et al. 2018）。
2.2 肺癌
肺癌是全球最常见的癌症,占所有癌症病例的11.6%,这类癌症也是导致癌症死亡的主要原因,占癌症死亡总人数的18.4%（Freddie et al. 2018）。2015年我国新发肺癌病例约为78.7万例,发病率为57.26/10万,因肺癌死亡人数约为63.1万例,死亡率为45.87/10万,严重威胁人们的健康和生命（郑荣寿等 2019）。研究发现在槐耳处理后的肺癌A549细胞中存在66个差异表达的miRNA,其中miR-26b-5p上调,瞬时转染miR-26b-5p能抑制细胞增殖并促进细胞的凋亡,而用miR-26b-5p抑制剂转染槐耳处理后的A549细胞可逆转槐耳的抗肿瘤作用。进一步的研究表明EZH2是miR-26b-5p的直接靶基因,miR-26b-5p介导的EZH2、β-catenin和Bcl-2表达降低可能是槐耳使肺癌细胞增殖减少和凋亡增加的关键调控机制（Wu et al. 2014）。
EMT是将上皮细胞转化为运动性间充质细胞的过程,它可以增强细胞转移和侵袭的能力,并参与肿瘤转移的过程（Tsai & Yang 2013;Jolly et al. 2017）。有研究表明槐耳能够以剂量和时间依赖性方式抑制A549和NCI-H1650细胞的增殖、迁移和侵袭,诱导细胞凋亡及S期细胞周期阻滞。免疫印迹实验结果表明,槐耳能够抑制MTDH的表达,增加Bax/Bcl-2的比率,促进Cleaved Caspase-3表达,提高Caspase-3的活性,从而促进细胞凋亡,抑制细胞增殖。此外,槐耳还可以通过降低EMT相关蛋白的表达水平来抑制肺癌细胞的转移和侵袭,同时抑制了JAK2/STAT3和MAPK信号通路的表达。小鼠皮下移植肿瘤试验表明,槐耳不仅可以抑制皮下肿瘤的生长,而且不影响小鼠体重的增长,说明其在体内外均能显著抑制肿瘤的增殖和转移,具有安全治疗肺癌的潜力（Chen et al. 2018）。
2.3 胃癌
胃癌在全世界癌症相关死亡率中居第二位,其中我国的病例最多,占全世界所有病例的42%（Torre et al. 2015;Chen et al. 2016）。槐耳的正丁醇提取物可以抑制HGC27、MGC803和AGS人胃癌细胞的增殖、诱导其发生细胞周期阻滞、减少细胞侵袭和转移的能力。在槐耳正丁醇提取物处理的MGC803和HGC27细胞中,c-Myc的表达水平降低,受c-Myc调节的Bmi1的表达水平也相应减少,而Bmi1的过表达逆转了槐耳正丁醇提取物对胃癌细胞的作用,这表明c-Myc-Bmi1信号通路可能是槐耳发挥抗肿瘤作用的信号通路（Wang et al. 2019）。对槐耳提取物抑制胃癌细胞转移的作用机制研究表明,槐耳可以通过上调上皮标记物E-钙黏着蛋白的表达、下调间充质标记物N-钙黏着蛋白和波形蛋白的表达,部分逆转上皮-间质转化。此外,与对照组相比,经槐耳处理的细胞Twist表达水平更低,而过度表达Twist可以部分消除槐耳的抗转移活性,并且发现Twist的表达升高与晚期TNM分期,淋巴结转移率高以及胃癌患者无病生存期降低有关,以上发现说明槐耳在抗胃癌复发的治疗中具有良好的应用前景（Xu et al. 2017）。
2.4 肝癌
我国是全球肝癌发病率最高和死亡人数最多的国家,大多数肝癌患者确诊时已为晚期,治疗手段有限,预后较差,亟需开发更多潜在的治疗肝癌的先导化合物（Raza & Sood 2014;Chen et al. 2016）。槐耳可以显著抑制人肝癌细胞SKHEP-1的增殖,诱导其发生凋亡,并能够抑制SKHEP-1细胞的转移能力,药理机制研究表明,槐耳作用后可以使SKHEP-1细胞中Lamin B1的表达水平下调,NOV的表达水平上调,从而发挥抗肝癌作用（Hu et al. 2016）。
2.5 前列腺癌
前列腺癌是男性中最常见的恶性肿瘤之一,其发病率已占我国男性泌尿系统肿瘤之首（Trewartha & Carter 2013）。槐耳提取物可以抑制人前列腺癌PC3细胞的增殖和转移能力,使细胞发生明显的S期阻滞,并且能够下调N-cadherin和TCF8/ZEB1的表达水平、上调E-cadherin的蛋白表达水平,表明槐耳清膏能够促进PC3细胞MET的发生,同时还发现MAPK信号通路中的关键蛋白JNK和ERK的磷酸化水平明显下降（杨爱琳等 2016）。此外,在随后的研究中发现Lamin B1的下调与槐耳抑制PC3细胞增殖和转移有关,并且发现槐耳可以诱导PC3细胞发生自噬。这项研究为槐耳在前列腺癌中的临床应用提供了新的理论基础（Yang et al. 2018）。
2.6 急性淋巴细胞白血病
急性淋巴细胞白血病（ALL）是儿童中最常见的恶性肿瘤之一,约5%的ALL儿童为费城染色体阳性（Ph+）（Forghieri et al. 2015;Hunger & Mullighan 2015）。酪氨酸激酶抑制剂（TKIs）是Ph+ ALL的特异性药物,但Ik6与TKI耐药性和Ph+ ALL的不良预后密切相关（Rives et al. 2011）。而槐耳提取物和伊马替尼联合治疗对Ik6+ Ph+-ALL细胞系Sup-B15和BV173增殖的抑制作用更大,且可以增强诱导细胞凋亡的作用。药理机制研究表明,两种药物的组合在降低BCR-ABL的蛋白质和酶活性水平上也表现出明显作用,其分子机制可能涉及BCR-ABL相关途径,包括p-AKT、p-STAT5、p-mTOR和p-Lyn的失活。体内实验结果与体外一致,槐耳提取物和伊马替尼的组合抑制了异种移植肿瘤的生长和浸润。以上结果表明,槐耳提取物增强了伊马替尼在Ik6+ Ph+-ALL中的抗癌作用,为治疗难治性Ph+-ALL提供了潜在的临床应用（Qu et al. 2019）。
2.7 胰腺癌
胰腺癌被认为是最致命的癌症之一,根据美国癌症协会（ACS）估计为癌症致死的第4位病因,亟须探索新的治疗方法（Siegel et al. 2019）。槐耳提取物可以抑制胰腺癌细胞的增殖、迁移、侵袭和EMT,并且诱导其发生凋亡。此外,还观察到槐耳提取物抑制了β-catenin的表达。体内研究表明,槐耳提取物可能是通过抑制Wnt/β-catenin信号通路实现减缓胰腺癌肿瘤生长的作用（Zhou et al. 2020）。
2.8 系膜增生性肾小球肾炎和肾癌
系膜增生性肾小球肾炎（MsPGN）的特征是肾小球系膜细胞增殖和细胞外基质蛋白沉积,目前没有有效的药物来治疗MsPGN（Striker et al. 1989）。槐耳以时间和剂量依赖性方式抑制PDGF-BB诱导的大鼠系膜细胞增殖,并诱导G2细胞周期阻滞。与模型组相比,经槐耳处理后的系膜细胞中,细胞周期通路蛋白被下调,而Mxi-1被上调,表明其在治疗MsPGN中具有潜在的开发价值（Bai et al. 2017）。槐耳在肾癌的治疗中也具有潜在的应用价值,能够通过激活PI3K/AKT/ mTOR/p70S6K/4EBP1信号通路抑制肾癌细胞786-O的活力及侵袭和迁移能力,诱导细胞发生凋亡,部分逆转EMT,从而发挥抗肿瘤作用（Wei et al. 2018）。
2.9 结节性硬化症
结节性硬化症（TSC）是一种遗传性疾病,其特征是在包括大脑、眼睛、心脏、肾脏、皮肤和肺在内的多个器官系统中形成良性肿瘤（Crino et al. 2006）。槐耳水提物可以通过诱导S期阻滞抑制两种TSC细胞的增殖、诱导其发生凋亡。此外,槐耳还可以抑制TSC细胞发生侵袭和转移。进一步的机制研究发现,槐耳可以下调JAK2、p-JAK2、STAT3和p-STAT3的蛋白表达水平,抑制ERK和JNK的磷酸化,以剂量依赖性方式抑制JAK2/STAT3和MAPK信号通路,从而发挥抗肿瘤作用（Yang et al. 2016）。
3 结语
综上所述,槐耳对乳腺癌、肺癌、胃癌、肝癌、前列腺癌、胰腺癌、肾癌、急性淋巴细胞白血病及结节性硬化症均有一定的抗肿瘤作用,其作用靶点众多,涵盖了肿瘤发生发展的多个途径。在临床上槐耳对多种恶性肿瘤均有治疗效果,且毒性甚微,可以延缓肿瘤患者病情进展、提高患者生命质量、延长患者生存期,具有较好的应用前景。尽管研究人员发现了许多积极的实验结果,但对槐耳的研究仍然存在一些不足和缺陷。首先,与针对槐耳粗提物抗肿瘤分子机制的研究相比,对于其所含化学成分的报道少之又少,且大部分是关于槐耳多糖的研究,极少有小分子化合物分离鉴定及药理活性的报道,这在一定程度上给槐耳的质量控制、品质评价及机制研究造成了挑战。其次,目前槐耳还没有药代动力学-药效学模型方面的研究,且多中心、随机临床研究的数量仍然很少,样本数据库不足和高缺失率也是限制槐耳进一步开发利用的原因之一。因此,加强对槐耳药效物质基础的研究,构建化合物-靶点相互作用网络,从多靶点协同作用角度对其抗肿瘤作用及机制进行研究具有重要意义,将为深入开发利用这一真菌资源提供理论依据。
参考文献
Effect of huaier on the proliferation of mesangial cells in anti-Thy-1 nephritis
DOI:10.1159/000480198 URL [本文引用: 1]
Coinhibitory pathways in immunotherapy for cancer
DOI:10.1146/annurev-immunol-032414-112049
PMID:26927206
[本文引用: 1]
The immune system is capable of recognizing tumors and eliminates many early malignant cells. However, tumors evolve to evade immune attack, and the tumor microenvironment is immunosuppressive. Immune responses are regulated by a number of immunological checkpoints that promote protective immunity and maintain tolerance. T cell coinhibitory pathways restrict the strength and duration of immune responses, thereby limiting immune-mediated tissue damage, controlling resolution of inflammation, and maintaining tolerance to prevent autoimmunity. Tumors exploit these coinhibitory pathways to evade immune eradication. Blockade of the PD-1 and CTLA-4 checkpoints is proving to be an effective and durable cancer immunotherapy in a subset of patients with a variety of tumor types, and additional combinations are further improving response rates. In this review we discuss the immunoregulatory functions of coinhibitory pathways and their translation to effective immunotherapies for cancer.
The spindle checkpoint, aneuploidy, and cancer
DOI:10.1038/sj.onc.1207374 URL [本文引用: 1]
Comprehensive molecular portraits of human breast tumours
DOI:10.1038/nature11412
URL
[本文引用: 1]
We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer.
Effect of huaier granule on recurrence after curative resection of HCC: a multicentre, randomised clinical trial
DOI:10.1136/gutjnl-2018-315983 URL [本文引用: 1]
Cancer statistics in China, 2015
DOI:10.3322/caac.21338 URL [本文引用: 2]
Research progress of anti-tumor medicine of huaier
Traditional Chinese medicine extract from huaier increases the expression of duffy antigen receptor for chemokines and reduces the expression of its ligands
PET imaging on dynamic metabolic changes after combination therapy of paclitaxel and the traditional Chinese medicine in breast cancer-bearing mice
DOI:10.1007/s11307-017-1108-4
PMID:28795272
[本文引用: 1]
The aim of the study was to non-invasively evaluate the anticancer activity of a traditional Chinese medicine-Huaier, combined with paclitaxel (PTX) in breast cancer bearing mice by detecting dynamic metabolic changes with positron emission tomography (PET).Balb/c nude mice were randomly divided into one of the four groups: Huaier, PTX, PTX + Huaier, or the control. PET imaging with 2-deoxy-2-[F]fluoro-D-glucose ([F]FDG) was performed to monitor the metabolic changes in BT474 (luminal B) and MDA-MB-231 (triple-negative) breast cancer xenografts. Immunohistochemistry (IHC) study was performed immediately after the final PET scan to assess the expressions of phosphatidylinositol 3-kinase (PI3K), phospho-AKT (p-AKT), caspase-3, and vascular endothelial growth factor (VEGF).Compared to the control group, [F]FDG accumulation demonstrated a significant decrease in PTX + Huaier (p < 0.01) or Huaier group (p < 0.05), which was consistent to the decreased expression of PI3K (p < 0.05) and p-AKT (p < 0.05) in the breast cancer xenografts.The therapeutic effect of Huaier combined with PTX was superior than the PTX alone in BT474 and MDA-MB-231 breast cancer-bearing mice. [F]FDG PET imaging could be a potential non-invasive approach to assess the metabolic changes after chemotherapy combined with traditional Chinese medicine in the breast cancer.
Huaier granule extract inhibit the proliferation and metastasis of lung cancer cells through down- regulation of MTDH, JAK2/STAT3 and MAPK signaling pathways
DOI:10.1016/j.biopha.2018.02.028 URL [本文引用: 1]
The tuberous sclerosis complex
DOI:10.1056/NEJMra055323 URL [本文引用: 1]
Species diversity, taxonomy and phylogeny of Polyporaceae (Basidiomycota) in China
DOI:10.1007/s13225-019-00427-4 URL [本文引用: 1]
Pathogenic wood-decaying fungi on woody plants in China
The paper deals with the pathogenic wood-decaying fungi on woody plants in China. One hundred and fifty-two species have been recorded, of which 49 species (accounting for 34% of the total pathogenic species) are firstly reported as pathogenic fungi in China. Their host, type of rot, occurrence and distribution were given according to field inventories. Among these fungi, 135 species (accounting for 89%) cause a white rot, while 17 species resulted in a brown rot. Among these fungi 67, 33 and 52 species belong to common, occasional and rare species respectively.
Notes on the nomenclature of six important medicinal fungi in China
According to International Code of Botanical Nomenclature and Nomenclatural Code for Chinese Scientific Names of Fungi and Lichens adopted by the Mycological Society of China in 1986, the nomenclature of the following six important Chinese medicinal fungi is suggested: Taiwanofungus camphoratus (M. Zang & C.H. Su) Sheng H. Wu et al., Inonotus obliquus (Ach. ex Pers.) Pilát, Auricularia auricula-judae (Bull.) Quél., Perenniporia robiniophila (Murrill) Ryvarden, Pholiota microspora (Berk.) Sacc. and Ophiocordyceps sinensis (Berk.) G.H. Sung, J.M. Sung, Hywel-Jones & Spatafora.
Breast cancer statistics, 2019
DOI:10.3322/caac.21583
PMID:31577379
[本文引用: 1]
This article is the American Cancer Society's biennial update on female breast cancer statistics in the United States, including data on incidence, mortality, survival, and screening. Over the most recent 5-year period (2012-2016), the breast cancer incidence rate increased slightly by 0.3% per year, largely because of rising rates of local stage and hormone receptor-positive disease. In contrast, the breast cancer death rate continues to decline, dropping 40% from 1989 to 2017 and translating to 375,900 breast cancer deaths averted. Notably, the pace of the decline has slowed from an annual decrease of 1.9% during 1998 through 2011 to 1.3% during 2011 through 2017, largely driven by the trend in white women. Consequently, the black-white disparity in breast cancer mortality has remained stable since 2011 after widening over the past 3 decades. Nevertheless, the death rate remains 40% higher in blacks (28.4 vs 20.3 deaths per 100,000) despite a lower incidence rate (126.7 vs 130.8); this disparity is magnified among black women aged <50 years, who have a death rate double that of whites. In the most recent 5-year period (2013-2017), the death rate declined in Hispanics (2.1% per year), blacks (1.5%), whites (1.0%), and Asians/Pacific Islanders (0.8%) but was stable in American Indians/Alaska Natives. However, by state, breast cancer mortality rates are no longer declining in Nebraska overall; in Colorado and Wisconsin in black women; and in Nebraska, Texas, and Virginia in white women. Breast cancer was the leading cause of cancer death in women (surpassing lung cancer) in four Southern and two Midwestern states among blacks and in Utah among whites during 2016-2017. Declines in breast cancer mortality could be accelerated by expanding access to high-quality prevention, early detection, and treatment services to all women.© 2019 American Cancer Society.
Philadelphia chromosome-positive acute lymphoblastic leukemia
DOI:10.1179/1024533215Z.000000000402 PMID:26574786 [本文引用: 1]
Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries
DOI:10.3322/caac.21492
PMID:30207593
[本文引用: 1]
This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.© 2018 American Cancer Society.
Huaier extract restrains the proliferative potential of endocrine- resistant breast cancer cells through increased ATM by suppressing miR-203
DOI:10.1038/s41598-017-07550-9 URL [本文引用: 1]
Clinical practice guidelines on the evidence-based use of integrative therapies during and after breast cancer treatment
Huaier polysaccharide inhibits the stem-like characteristics of ERalpha-36 high triple negative breast cancer cells via inactivation of the ERα-36 signaling pathway
Huaier restrains proliferative and invasive potential of human hepatoma SKHEP-1 cells partially through decreased Lamin B1 and elevated NOV
Acute lymphoblastic leukemia in children
DOI:10.1056/NEJMra1400972 URL [本文引用: 1]
In vivo immunostimulatory and tumor-inhibitory activities of polysaccharides isolated from solid-state-cultured Trametes robiniophila Murrill
DOI:10.1007/s11274-009-0109-0 URL [本文引用: 1]
EMT and MET: necessary or permissive for metastasis?
DOI:10.1002/mol2.2017.11.issue-7 URL [本文引用: 1]
Identification of multi-target effects of huaier aqueous extract via microarray profiling in triple-negative breast cancer cells
DOI:10.3892/ijo.2015.2932 URL [本文引用: 1]
Multiple mechanisms confer different drug-resistant phenotypes in pancreatic carcinoma cells
DOI:10.1007/s00432-002-0349-y URL [本文引用: 1]
Trametes robiniophila Murr. in the treatment of breast cancer
A huaier polysaccharide restrains hepatocellular carcinoma growth and metastasis by suppression angiogenesis
DOI:10.1016/j.ijbiomac.2015.01.016 URL [本文引用: 1]
Huaier extract suppresses breast cancer via regulating tumor-associated macrophages
DOI:10.1038/srep20049 URL [本文引用: 1]
Metastatic heterogeneity of breast cancer: molecular mechanism and potential therapeutic targets
DOI:10.1016/j.semcancer.2019.08.012 URL [本文引用: 1]
Extraction of polysaccharides from Trametes robiniophila Murr. and their antioxidant properties
Cancer treatment and survivorship statistics, 2019
DOI:10.3322/caac.v69.5 URL [本文引用: 1]
Polyporaceae. North American flora. Vol. 9. New York Botanical Garden
An overview of the immune system
DOI:10.1016/S0140-6736(00)04904-7 URL [本文引用: 1]
Role of fulvestrant in the treatment of postmenopausal metastatic breast cancer patients
DOI:10.1080/17512433.2016.1215243 URL [本文引用: 1]
Macrophage diversity enhances tumor progression and metastasis
DOI:10.1016/j.cell.2010.03.014 URL [本文引用: 1]
Huaier extract enhances the treatment efficacy of imatinib in Ik6 + Ph + acute lymphoblastic leukemia
Hepatocellular carcinoma review: current treatment, and evidence-based medicine
DOI:10.3748/wjg.v20.i15.4115
PMID:24764650
[本文引用: 1]
Hepatocellular carcinoma (HCC) is the fifth most common tumor worldwide. Multiple treatment options are available for HCC including curative resection, liver transplantation, radiofrequency ablation, trans-arterial chemoembolization, radioembolization and systemic targeted agent like sorafenib. The treatment of HCC depends on the tumor stage, patient performance status and liver function reserve and requires a multidisciplinary approach. In the past few years with significant advances in surgical treatments and locoregional therapies, the short-term survival of HCC has improved but the recurrent disease remains a big problem. The pathogenesis of HCC is a multistep and complex process, wherein angiogenesis plays an important role. For patients with advanced disease, sorafenib is the only approved therapy, but novel systemic molecular targeted agents and their combinations are emerging. This article provides an overview of treatment of early and advanced stage HCC based on our extensive review of relevant literature.
Intermediate dose of imatinib in combination with chemotherapy followed by allogeneic stem cell transplantation improves early outcome in paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL): results of the Spanish Cooperative Group SHOP studies ALL-94, ALL-99 and ALL-2005
DOI:10.1111/j.1365-2141.2011.08783.x
URL
[本文引用: 1]
Philadelphia-chromosome acute lymphoblastic leukaemia (Ph+ ALL) is a subgroup of ALL with very high risk of treatment failure. We report here the results of the Sociedad Espanola de Hematologia y Oncologia Pediatricas (SEHOP/SHOP) in paediatric Ph+ ALL treated with intermediate-dose imatinib concurrent with intensive chemotherapy. The toxicities and outcome of these patients were compared with historical controls not receiving imatinib. Patients with Ph+ ALL aged 1-18 years were enrolled in three consecutive ALL/SHOP trials (SHOP-94/SHOP-99/SHOP-2005). In the SHOP-2005 trial, imatinib (260 mg/m(2) per day) was given on day-15 of induction. Allogeneic haematopoietic stem-cell transplantation (HSCT) from a matched related or unrelated donor was scheduled in first complete remission (CR1). Forty-three patients were evaluable (22 boys, median age 6.8 years, range, 1.2-15). Sixteen received imatinib whereas 27 received similar chemotherapy without imatinib. Seventeen of 27 and 15 of 16 patients in the non-imatinib and imatinib cohort, respectively, underwent HSCT in CRI. With a median follow-up of 109 and 39 months for the non-imatinib and imatinib cohorts, the 3-year event-free survival (EFS) was 29.6% and 78.7%, respectively (P = 0.01). These results show that, compared to historical controls, intermediate dose of imatinib given concomitantly with chemotherapy and followed by allogeneic HSCT markedly improved early EFS in paediatric Ph+ ALL.
Type studies in the polyporaceae 14. Species described by N. Patouillard, either alone or with other mycologists
Cancer statistics, 2019
DOI:10.3322/caac.v69.1 URL [本文引用: 1]
Isolation and bioactivity of natural products from Croton caudatus var. tomentosus and Trametes robiniophila. Master Thesis,
The anticancer effect of huaier (review)
DOI:10.3892/or.2015.3950 URL [本文引用: 1]
The contribution of glomerular mesangial cells to progressive glomerulosclerosis
A polysaccharide from the fungi of huaier exhibits anti-tumor potential and immunomodulatory effects
DOI:10.1016/j.carbpol.2012.09.006
PMID:23218338
[本文引用: 1]
A neutral water-soluble polysaccharide (W-NTRP), with a molecular weight of 2.5 × 10(4)Da, was isolated from the fruit bodies of Trametes robiniophila (Huaier). Gas chromatography (GC) results indicated that W-NTRP was determined to be galactose (Gal), arabinose (Ara) and glucose (Glc), with a relative molar ratio of 4.2:2.5:0.7. Its antitumor and immunomodulatory activity were evaluated in vitro. W-NTRP showed remarkable inhibitory effect on three human cholangiocarcinoma cell lines (QBC939, Sk-ChA-1 and MZ-ChA-1), with respective IC(50) values of 47.8, 75.9, and 43.7 μg/mL, but had no cytotoxicity to L-929 normal cells. Furthermore, W-NTRP had proliferation promoting effect on mouse splenocytes with or without concanavalin A (ConA) or lipopolysaccharide (LPS) in a bell-shaped dose-response manner. In addition, W-NTRP could prominently stimulate macrophages to produce nitric oxide (NO) through the up-regulation of inducible NO synthase (iNOS) activity. These results suggest that W-NTRP could be explored as a potential antitumor agent for cholangiocarcinoma.Copyright © 2012 Elsevier Ltd. All rights reserved.
Global cancer statistics, 2012
DOI:10.3322/caac.21262 URL [本文引用: 1]
Advances in prostate cancer treatment
Epithelial-mesenchymal plasticity in carcinoma metastasis
Research and manufacture and clinical application of Trametes robiniphila Murr
Optimization of polysaccharides extraction from Trametes robiniophila and its antioxidant activities
Huaier n-butanol extract suppresses proliferation and metastasis of gastric cancer via c-Myc-Bmi1 axis
The anticancer effect of huaier extract in renal cancer 786-O Cells
Taxanes for adjuvant treatment of early breast cancer
Resource diversity of Chinese macrofungi: edible, medicinal and poisonous species
Huaier suppresses proliferation and induces apoptosis in human pulmonary cancer cells via upregulation of miR-26b-5p
Aqueous huaier extract suppresses gastric cancer metastasis and epithelial to mesenchymal transition by targeting twist
An immune- stimulating proteoglycan from the medicinal mushroom huaier up-regulates NF-kappaB and MAPK signaling via toll-like receptor 4
Huaier aqueous extract inhibits proliferation and metastasis of tuberous sclerosis complex cell models through downregulation of JAK2/STAT3 and MAPK signaling pathways
Research progress on anti-tumor effect of huaier
Study on effect and mechanism of huaier aqueous extract on growth and invasion of human prostate cancer PC3 cells
Huaier suppresses proliferative and metastatic potential of prostate cancer PC3 cells via downregulation of lamin B1 and induction of autophagy
Effect of genetic variants in two chemokine decoy receptor genes, DARC and CCBP2, on metastatic potential of breast cancer
Huaier extract enhances the treatment efficacy of paclitaxel in breast cancer cells via the NF-kappaB/ IkappaBalpha pathway
Immunomodulatory effect of huaier and its clinical application
Huaier extract exerts immunomodulatory effects by regulating serum cytokines in breast cancer
Huaier aqueous extract inhibits proliferation of breast cancer cells by inducing apoptosis
A polysaccharide from Trametes robiniophila inhibits human osteosarcoma xenograft tumor growth in vivo
A polysaccharide from Trametes robiniophila Murrill induces apoptosis through intrinsic mitochondrial pathway in human osteosarcoma (U-2 OS) cells
A mechanistic overview of herbal medicine and botanical compounds to target transcriptional factors in breast cancer
Report of cancer epidemiology in China, 2015
Huaier extract restrains pancreatic cancer by suppressing Wnt/beta-catenin pathway
A polysaccharide from mushroom Huaier retards human hepatocellular carcinoma growth, angiogenesis, and metastasis in nude mice
