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1、胃癌干细胞,上海交通大学医学院,癌肿与炎症,1863年Virchow 观察到许多肿瘤在慢性炎 症的情况下发生，提出炎症中淋巴网状结 构是癌肿细胞来源 Dvorak 描写癌肿是“不会愈合的伤口”估计全球15%的癌肿与慢性感染、炎症有关,Balkwill F,Mantovani A.Lancet 357;539,2001,炎症与癌肿的联系：,埃及血吸虫 膀胱癌（S.Hematobium)乳头瘤病毒 子宫颈癌 慢性盆腔炎 卵巢癌 第8型人带状病毒 Kaposis 肉瘤,炎症与消化道癌肿的联系：Barretts 食管 食管腺癌 IBD 结直肠癌 病毒性肝炎 肝细胞癌 慢性胰腺炎 胰腺癌 H.pylor
2、i 感染 胃癌、胃MALT淋巴瘤,胃癌和H.pylori,Carcinogenicity in HumansWHO/IARC(1994)Group I Definite carcinogen Group 2A Probable carcinogen Group 2B Possible carcinogen Group 3 Uncertain Group 4 Not a carcinogen,慢性感染与慢性炎症可刺激与恶性肿瘤发生有关的细胞因子和趋化因子,Balkwill F,Mantovani A.Lancet 357;539,2001,DNA损伤P53失活血管生成刺激生长,传统观点认为胃癌来
3、源于胃上皮细胞产生突变而形成胃癌Houghton等的小鼠实验发现：胃癌是发生在幽门螺杆菌感染的慢性炎症基础上，骨髓源性干细胞参与了上皮细胞损伤修复并产生突变，形成胃癌。,Houghton J,et al.Science 2004;306:):1568-71,胃癌细胞来源于骨髓源性干细胞的突变,干细胞分为胚胎干细胞和成体干细胞，后者定居 在各组织，包括骨髓干细胞 成体干细胞具有自我更新和多向分化的潜能，分 化为祖细胞及有功能的成熟细胞，在组织修复和 重建中发挥作用 骨髓干细胞通过血循环参与多种组织的再生、修 复，具有可塑性,骨髓干细胞（Bone Marrow Stem Cells）,造血干细胞（
4、Hematopoietic stem cells）间充质干细胞（Mesenchymal stem cells）,间充质干细胞（Mesenchymal stem cells）,C57BL/6 小鼠,Helicobacter felis infection,Lethal irradiation 900 rads,New bone marrowtransplantation,markedGFP/ROSA26,beta-galactosidase/Y-chromosome,20 weeks-1 year,gastritis,atrophy and intestinal metaplasia,dyspl
5、asia,Gastric cancer,Evaluate for GFP,beta-galactosidase Activity and Y-chromosome,Houghton J,et al.Science 2004;306:):1568-71,IHC/Beta-galactosidase,ROSA26 marrow,IHC/Beta-galactosidase,ROSA26 marrow,H.felisinfected,GIN,WT marrow,H.felisinfected,GIN,ROSA26 marrow,H.felisinfected,F WT BONE MARROW,IHC
6、/GFP,F,M GFP BONE MARROW,IHC/GFP,F,F WT BONE MARROW,FISH/Y-CHROMOSOME,F,M GFP BONE MARROW,FISH/Y-CHROMOSOME,F,癌肿干细胞为原始癌细胞，与肿瘤发 病、耐药有关 与正常干细胞相似，虽数量不多，能 自我更新分化并维持肿瘤生长,癌肿干细胞（Cancer Stem Cells),癌肿干细胞分化为癌细胞,癌肿干细胞,癌细胞,总结:,持续的幽门螺杆菌感染、炎症是人胃癌的重要病因 Houghton等的研究证实长期感染幽门螺杆菌引起胃黏膜损伤与炎性细胞浸润，胃组织干细胞参与损伤修复，一旦耗尽，骨髓源性干
7、细胞迁移至胃黏膜，参与上皮细胞的再生与修复，并突变为癌细胞根除幽门螺杆菌感染可减少胃癌的发病,Cancer and Stem Cell Research laboratory,-Since 2002,Prof.Shudong XIAO,Stem Cell-Embryonic Stem Cells,Cell types derived from human ES cells in vitro Nerve,astrocyte,oligodendrocyte Hematopietic stem cells Insulin producing cells Cardiomyocytes Hepatocy
8、tes Endothelial cells,Undifferentiated stem cells with capacity to differentiate,Embryonic Stem Cell Adult Stem Cell Cord Blood Stem Cell iPS cell,?,Form Teratoma in vivo,Differentiation potential,Survival Forever!Not die!,hESC,t-hESC(Tumor hESCs),Prolongedculture,Characteristic Feature of t-hESCs,H
9、igh expression of stem cell markers:SSEA-4;Oct-4(60%)Rapidly growth ratio:(1 weeks/two passages)Loss of hESCs differentiated capacity.,Tumor may originate from normal foreskin-derived cells(Fibroblast)after prolonged culture,Expansion,2 weeks,4 weeks,(Zheng WANG et al,2009),EB Like Structure,Stem ce
10、lls may cause tumor in vivo after expansion Loss of cells capacity to differentiate,Embryonic stem cells(Mickie Bhatia et al)Normal tussue stem cells(Zheng WANG et al unpublished data)Bone marrow derived stem cells(Neoplasia.vol 8(9)2006,pp716-724.Cord blood stem cells(XD Chen et al.Unpublished data
11、),Human Gastric Cancer Study,Human Gastric Cancer Cells,Relationship between CD44And ROS level,Relationship between CD44And apoptosis after Chemotherapy,FACS,MDR analysis,IHC,Samples from patients,Stem cell sphere,Animalanalysis,CD44 siRNA silencing assay,Gastric cancer cell lines:(Differentiated Grades),High Grade MKN28,Moderate Grade SGC7901,Low Grade MGC803,Low Grade MKN45,Control,Control,Control,Control,CD44 expression,Table:FACS analysis of CD44 expression in differentiated grades of gastric cancer cell lines,Cell markers alone are not enough to distinguish CSC,
