胃癌干细胞的分离鉴定及其在胃癌侵袭转移中的作用与分子机制
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摘要
胃癌是严重危害人类健康的恶性肿瘤，在东亚、东欧和南美等地区高发，其死亡率居恶性肿瘤第二位，尽管近年来手术、化疗及生物治疗等多种治疗方法的进步，胃癌患者的5年生存率仍然较低，究其原因是我们对胃癌的发生发展机制尚不十分清楚。
近年来肿瘤干细胞（cancer stem cells, CSCs）理论的兴起为我们深入认识胃癌的发生发展机制提供了新的思路。本研究中我们使用成球培养法从胃癌细胞中分离/富集了胃癌干细胞（gastric cancer stem cells, GCSCs），并发现GCSCs具有高侵袭转移和多药耐药的特性。通过芯片分析，我们筛选出在GCSCs中一系列差异表达的基因及miRNA分子，发现炭疽毒素2型受体（anthrax toxin receptor2，ANTXR2）在GCSCs中表达增高尤为突出，因此进一步研究了ANTXR2在调控GCSCs自我更新维持及侵袭转移中的作用及其可能的分子机制，并探讨了其在胃癌标本中表达的临床意义。
主要方法、研究结果及结论如下：
1、使用成球培养法成功分离/富集GCSCs，并进行了生物学特性鉴定。
（1）建立了胃癌细胞成球培养的方法，胃癌细胞SGC7901、MGC803和BGC823在无血清干细胞培养基和低黏附培养板培养条件下能够成球生长，并能够连续传代；（2）实时定量PCR及Western blot方法检测发现细胞球细胞（sphere cells，SC）较单层培养细胞（monolayer cells，MN）高表达干性相关基因Sox2、Oct4和Bmi1；（3）克隆形成实验表明SGC7901-SC的克隆形成能力强于SGC7901-MN细胞(156±5vs35±2, P<0.05)；（4）SGC7901-SC细胞于含血清的培养基中培养时，可发现其分化标记物CK18，氢钾ATP酶（H-K-ATPase）阳性的细胞增加；（5）移植瘤实验表明同数量级的SGC7901-SC比SGC7901-MN细胞具有更强的肿瘤形成能力，且SGC7901-SC形成的移植瘤中CK18和H-K-ATPase阳性细胞的比例比SGC7901-MN低（分别为13%±4%vs94%±2%，20%±4%vs42%±3%, P<0.05），说明SGC7901-SC细胞更加幼稚。上述结果从干性基因表达、克隆形成能力、多向分化能力和成瘤能力等几个主要方面证实了成球生长的细胞具有CSCs的特性。2、GCSCs呈EMT表型并具有高侵袭转移潜能。
（1）在SGC7901-SC及SGC7901-MN形成的体内移植瘤中我们发现，SGC7901-SC形成的移植瘤浸润周围组织并有淋巴结转移，而SGC7901-MN细胞形成的移植瘤具有完整的包膜。（2）实时定量PCR及Western blot检测发现SGC7901-SC较SGC7901-MN高表达Vimentin和MMP2，低表达E-cadherin，呈现EMT表型。（3）体外Transwell小室侵袭实验发现SGC7901-SC较SGC7901-MN具有更强的侵袭能力（153±16vs51±12，P<0.05）；
3、GCSCs具有多药耐药特性。
（1）化疗药杀伤实验发现SGC7901-SC较SGC7901-MN具有更强的化疗药5-Fu、DDP和ADR耐受能力。（2）实时定量PCR检测发现SGC7901-SC较SGC7901-MN高表达ABCC4，低表达MDR1，而MRP1和ABCG2的表达无明显差异。
4、发现GCSCs与单层培养细胞差异表达的一系列基因及miRNA分子。通过信号通路分析发现Wnt、Notch信号通路、TGFβ信号通路、VEGF信号通路、p450细胞色素家族及抗凋亡信号通路在GCSCs活化，提示其可能在GCSCs的自我更新、侵袭转移、多药耐药和诱导脉管生成中发挥重要作用。
5、通过基因芯片筛选出GCSCs高表达分子ANTXR2，发现ANTXR2在调控胃癌细胞的成球及成瘤能力及侵袭转移中具有重要作用。
（1）实时定量PCR及流式分析发现ANTXR2在GCSCs上高表达；（2）免疫荧光双染发现ANTXR2与GCSCs标志物CD44具有共定位现象；（3）利用慢病毒干扰SGC7901和XN0422细胞ANTXR2的表达后，可以显著抑制胃癌细胞的成球能力、增殖能力、成瘤能力和侵袭转移能力；（4）发现过表达ANTXR2后可以增强胃癌细胞AGS和HGC27的克隆形成能力。
6、探讨了ANTXR2调控胃癌细胞干性维持及侵袭转移的可能分子机制。
（1）利用慢病毒干扰SGC7901和XN0422细胞ANTXR2的表达后，可以显著抑制胃癌细胞干性相关分子β-catenin、Sox2、Bmi1和CD44的表达，同时其EMT标志物Vimentin表达降低，E-cadherin上升；（2）对稳定干扰ANTXR2的SGC7901细胞进行基因芯片及信号通路分析，发现MAPK信号通路改变最大。使用MAPK信号通路关键靶点抑制剂SB203580、PD98059及SP600125作用于过表达ANTXR2的HGC27细胞发现，ERK磷酸化抑制剂PD98059及JNK磷酸化SP600125都能显著抑制该细胞的克隆形成能力，而以PD98059的作用更为显著；（3）Western blot检测发现在稳定干扰ANTXR2的SGC7901细胞中ERK的磷酸化水平降低，同时Src-Tyr416磷酸化降低，Src-Tyr527磷酸化增加，提示ANTXT2的作用可能通过Src/ERK信号通路。
7、发现ANTXR2在胃癌标本中表达具有重要的临床意义。对181例胃癌标本免疫组化染色检测结果显示，ANTXR2的表达与胃癌患者TNM分期（P=0.024），浸润深度（P=0.03）成正相关，而与患者的生存时间成负相关(P=0.006)。ANTXR2可以用作判断胃癌预后的指标。
本文的主要结论如下：成球培养法是一种能够成功分离/富集GCSCs的有效方法；所获得的GCSCs具有自我更新、高成瘤、高侵袭转移和多药耐药的特性；其特性可能依赖于Wnt、Notch信号通路、TGFβ信号通路、p450细胞色素家族和抗凋亡信号通路的活化；ANTXR2在GCSCs干性维持及侵袭转移调控中发挥重要作用，其调控作用的发挥可能主要依赖Src/ERk信号通路的激活。ANTXR2的表达与临床病理参数成正相关，与患者生存时间成负相关，可以用作判断胃癌预后的指标。
Gastric cancer is the second leading cause of cancer related mortality, especially in EastAsia, East European and South America. Despite of the development of surgery andchemotherapy, the five year survival rate remains low. Recently, emerging of cancer stem cell(CSC) hypothesis provides us a new way insight into the mechanism underlining gastriccancer initiation and progression. To demonstrate the existence of gastric cancer stem cells(GCSCs) and explore their malignant behavior, we established a method of sphere formingculture to gain the tumor spheres from gastric cancer cell lines. Tumor sphere cells possessedself-renew, multi-potent differentiation ability and highly tumorigenicity, indicating thattumor spheres enriched GCSCs. Moreover, GCSCs exhibited properties of high invasion,metastasis and multi-drug resistance. A series of genes and miRNAs differential expressionbetween GCSCs and Monolayer cells were screened by gene microarray and miRNA arrayanalysis. Among the differential expression molecular, ANTXR2was particularlyover-expressed in GCSCs. Then, roles of ANTXR2in gastric cancer stemness, invasion andmetastasis were explored.
Main methods, results and conclusion as follow:
1. Tumor spheres formed from gastric cancer cells possess stem cell properties.1)Gastric cancer cells of SGC7901，MGC803and BGC823could grow as tumor sphere inserum free conditioned medium.2) Compared with monolayer cells (MN), sphere cells(SC)highly expressed stemness genes Sox2，Oct4and Bmi1;3) SGC7901-SC possessed highercolony formation ability than SGC7901-MN cells (156±5vs35±2, p<0.05);4) CulturedSGC7901-SC in medium supplemented with10%FBS, the cells could produce more maturecells expressing CK18and H-K-ATPase;5) Xenograft assay showed that SGC7901-SC werehighly tumorigenic, and the xenograft formed by SGC7901-SC with lower proportion ofCK18and H-K-ATPase positive cells compared to xenograft formed by SGC7901-MN（13%±4%vs94%±2%，p<0.05and20%±4%vs42%±3%, p<0.05respectively）, indicating that xenografte formed by SGC7901-SC are immature. Those data suggesting that sphere cellspossess stem cell properties.
2. GCSCs possess highly invasive and metastatic ability in association with epithelialmesenchymal transition.1) We found xenograft tumors formed by SGC7901-SC cells invadedinto the capsule and metastasized to lymph nodes. In contrast, there were compact capsulessurrounding SGC7901-MN-xenografts without any invasion or metastasis；2）Invasive abilityof SGC7901-SC were measured by Transwell invasion assay, and we found that SGC7901-SCwith higher invasive ability in vitro compared to SGC7901-MN（153±16vs51±12，p<0.05）;3) Expression of invasive related genes in SGC7901-SC were detected by Real time PCR andWestern blot, we found that SGC7901-SC with increased expression of Vimentin, MMP2anddecreased expression of E-cadherin.
3. GCSCs show the property of multi-drug resistance.1) SGC7901-SC were moreresistant to chemo-drugs5-Fu，DDP and ADR compared to SGC7901-MN;2) SGC7901-SCshowed higher expression of ABCC4, lower expression of MDR1compared to SGC7901-MN.There was no significant difference of MRP1and ABCG2expression between SGC7901-SCand SGC7901-MN.
4. We found a series of genes and miRNAs differentially expressed betweenSGC7901-SC and SGC7901-MN by gene array and miRNA array analysis. Signalingpathways of Wnt, Notch, TGFβ, VEGF, p450and anti-apoptosis were activated in GCSCs,indicating these signaling pathways may be involved in the self-renewal, invasion, metastasis,multi-drug resistance and angiogenesis in GCSCs.
5. ANTXR2plays important roles in gastric cancer stemness maintenance, invasion andmetastasis.1) ANTXR2was found highly expressed in GCSCs by gene array analysis andconfirmed by real time PCR and FACS;2) ANTXR2was co-localized with stem cell markerCD44in gastric cancer samples;3) Silenced ANTXR2expression in gastric cancer cells byshRNA, the ability of sphere formation, proliferation, invasion and metastasis was impaired;4)Over-expressing ANTXR2, the colony formation ability of gastric cancer cells was increased.
6. The possible molecular mechanisms of ANTXR2in stemness maintenance, invasionand metastasis of gastric cancer cells were explored.1) Silenced ANTXR2expression ingastric cancer cells by shRNA, the expression of stemness and EMT related genes Sox2，Bmi1，CD44, β-catenin and Vimentin was down-regulated, meanwhile, the expression of E-cadherin was up-regulated;2) Gene array analysis showed that silencing ANTXR2expression mainly resulted in change of MAPK signaling pathway. Using the inhibitors ofMAPK signaling pathway, the result was confirmed. ERK inhibitor PD98059and JNKinhibitor SP600125could significantly inhibited the colony formation of gastric cancer cellswith over-expression of ANTXR2, and the ERK inhibitor PD98059is more effective;3)Silencing ANTXR2expression resulted in decreased phosphorylation of ERK, Src-Tyr416and increased phosphorylation of Src-Tyr527in gastric cancer cells, indicating that thefunction of ANTXT2may be dependent on the Src/ERK signaling pathway.
7. ANTXR2expression has important clinical significance in patients with gastric cancer.Immunohistochemistry(IHC) was used to detect the expression of ANTXR2in181specimensof gastric cancer, the result showed that the expression of ANTXR2was correlated withinvasive depth (p=0.03）, TNM stage (p=0.024) and shorter survival time (p=0.006),indicating that ANTXR2is an indicator of poor prognosis in gastric cancer.
In summary, sphere formation culture is an effective method for isolation/enrichment ofGCSCs. GCSCs possesses highly invasive, metastasis and multi-drug resistant properties.Multi-signaling pathways, such as Wnt, Notch, TGF-beta, p450metabolism enzyme familyand anti-apoptosis signaling pathway, may be involved in regulation of the GCSCs behaviors;Our results also demonstrated that ANTXR2play important roles in stemness maintenance,invasion and metastasis of GCSCs. The function of ANTXR2may be dependent on Src/ERKsignaling pathway. Expression of ANTXR2is positively correlated with clinic pathologicparameters and negatively correlated with survival time, indicating that it can be used as anindicator of poor prognosis of patients with gastric cancer.
近年来肿瘤干细胞（cancer stem cells, CSCs）理论的兴起为我们深入认识胃癌的发生发展机制提供了新的思路。本研究中我们使用成球培养法从胃癌细胞中分离/富集了胃癌干细胞（gastric cancer stem cells, GCSCs），并发现GCSCs具有高侵袭转移和多药耐药的特性。通过芯片分析，我们筛选出在GCSCs中一系列差异表达的基因及miRNA分子，发现炭疽毒素2型受体（anthrax toxin receptor2，ANTXR2）在GCSCs中表达增高尤为突出，因此进一步研究了ANTXR2在调控GCSCs自我更新维持及侵袭转移中的作用及其可能的分子机制，并探讨了其在胃癌标本中表达的临床意义。
主要方法、研究结果及结论如下：
1、使用成球培养法成功分离/富集GCSCs，并进行了生物学特性鉴定。
（1）建立了胃癌细胞成球培养的方法，胃癌细胞SGC7901、MGC803和BGC823在无血清干细胞培养基和低黏附培养板培养条件下能够成球生长，并能够连续传代；（2）实时定量PCR及Western blot方法检测发现细胞球细胞（sphere cells，SC）较单层培养细胞（monolayer cells，MN）高表达干性相关基因Sox2、Oct4和Bmi1；（3）克隆形成实验表明SGC7901-SC的克隆形成能力强于SGC7901-MN细胞(156±5vs35±2, P<0.05)；（4）SGC7901-SC细胞于含血清的培养基中培养时，可发现其分化标记物CK18，氢钾ATP酶（H-K-ATPase）阳性的细胞增加；（5）移植瘤实验表明同数量级的SGC7901-SC比SGC7901-MN细胞具有更强的肿瘤形成能力，且SGC7901-SC形成的移植瘤中CK18和H-K-ATPase阳性细胞的比例比SGC7901-MN低（分别为13%±4%vs94%±2%，20%±4%vs42%±3%, P<0.05），说明SGC7901-SC细胞更加幼稚。上述结果从干性基因表达、克隆形成能力、多向分化能力和成瘤能力等几个主要方面证实了成球生长的细胞具有CSCs的特性。2、GCSCs呈EMT表型并具有高侵袭转移潜能。
（1）在SGC7901-SC及SGC7901-MN形成的体内移植瘤中我们发现，SGC7901-SC形成的移植瘤浸润周围组织并有淋巴结转移，而SGC7901-MN细胞形成的移植瘤具有完整的包膜。（2）实时定量PCR及Western blot检测发现SGC7901-SC较SGC7901-MN高表达Vimentin和MMP2，低表达E-cadherin，呈现EMT表型。（3）体外Transwell小室侵袭实验发现SGC7901-SC较SGC7901-MN具有更强的侵袭能力（153±16vs51±12，P<0.05）；
3、GCSCs具有多药耐药特性。
（1）化疗药杀伤实验发现SGC7901-SC较SGC7901-MN具有更强的化疗药5-Fu、DDP和ADR耐受能力。（2）实时定量PCR检测发现SGC7901-SC较SGC7901-MN高表达ABCC4，低表达MDR1，而MRP1和ABCG2的表达无明显差异。
4、发现GCSCs与单层培养细胞差异表达的一系列基因及miRNA分子。通过信号通路分析发现Wnt、Notch信号通路、TGFβ信号通路、VEGF信号通路、p450细胞色素家族及抗凋亡信号通路在GCSCs活化，提示其可能在GCSCs的自我更新、侵袭转移、多药耐药和诱导脉管生成中发挥重要作用。
5、通过基因芯片筛选出GCSCs高表达分子ANTXR2，发现ANTXR2在调控胃癌细胞的成球及成瘤能力及侵袭转移中具有重要作用。
（1）实时定量PCR及流式分析发现ANTXR2在GCSCs上高表达；（2）免疫荧光双染发现ANTXR2与GCSCs标志物CD44具有共定位现象；（3）利用慢病毒干扰SGC7901和XN0422细胞ANTXR2的表达后，可以显著抑制胃癌细胞的成球能力、增殖能力、成瘤能力和侵袭转移能力；（4）发现过表达ANTXR2后可以增强胃癌细胞AGS和HGC27的克隆形成能力。
6、探讨了ANTXR2调控胃癌细胞干性维持及侵袭转移的可能分子机制。
（1）利用慢病毒干扰SGC7901和XN0422细胞ANTXR2的表达后，可以显著抑制胃癌细胞干性相关分子β-catenin、Sox2、Bmi1和CD44的表达，同时其EMT标志物Vimentin表达降低，E-cadherin上升；（2）对稳定干扰ANTXR2的SGC7901细胞进行基因芯片及信号通路分析，发现MAPK信号通路改变最大。使用MAPK信号通路关键靶点抑制剂SB203580、PD98059及SP600125作用于过表达ANTXR2的HGC27细胞发现，ERK磷酸化抑制剂PD98059及JNK磷酸化SP600125都能显著抑制该细胞的克隆形成能力，而以PD98059的作用更为显著；（3）Western blot检测发现在稳定干扰ANTXR2的SGC7901细胞中ERK的磷酸化水平降低，同时Src-Tyr416磷酸化降低，Src-Tyr527磷酸化增加，提示ANTXT2的作用可能通过Src/ERK信号通路。
7、发现ANTXR2在胃癌标本中表达具有重要的临床意义。对181例胃癌标本免疫组化染色检测结果显示，ANTXR2的表达与胃癌患者TNM分期（P=0.024），浸润深度（P=0.03）成正相关，而与患者的生存时间成负相关(P=0.006)。ANTXR2可以用作判断胃癌预后的指标。
本文的主要结论如下：成球培养法是一种能够成功分离/富集GCSCs的有效方法；所获得的GCSCs具有自我更新、高成瘤、高侵袭转移和多药耐药的特性；其特性可能依赖于Wnt、Notch信号通路、TGFβ信号通路、p450细胞色素家族和抗凋亡信号通路的活化；ANTXR2在GCSCs干性维持及侵袭转移调控中发挥重要作用，其调控作用的发挥可能主要依赖Src/ERk信号通路的激活。ANTXR2的表达与临床病理参数成正相关，与患者生存时间成负相关，可以用作判断胃癌预后的指标。
Gastric cancer is the second leading cause of cancer related mortality, especially in EastAsia, East European and South America. Despite of the development of surgery andchemotherapy, the five year survival rate remains low. Recently, emerging of cancer stem cell(CSC) hypothesis provides us a new way insight into the mechanism underlining gastriccancer initiation and progression. To demonstrate the existence of gastric cancer stem cells(GCSCs) and explore their malignant behavior, we established a method of sphere formingculture to gain the tumor spheres from gastric cancer cell lines. Tumor sphere cells possessedself-renew, multi-potent differentiation ability and highly tumorigenicity, indicating thattumor spheres enriched GCSCs. Moreover, GCSCs exhibited properties of high invasion,metastasis and multi-drug resistance. A series of genes and miRNAs differential expressionbetween GCSCs and Monolayer cells were screened by gene microarray and miRNA arrayanalysis. Among the differential expression molecular, ANTXR2was particularlyover-expressed in GCSCs. Then, roles of ANTXR2in gastric cancer stemness, invasion andmetastasis were explored.
Main methods, results and conclusion as follow:
1. Tumor spheres formed from gastric cancer cells possess stem cell properties.1)Gastric cancer cells of SGC7901，MGC803and BGC823could grow as tumor sphere inserum free conditioned medium.2) Compared with monolayer cells (MN), sphere cells(SC)highly expressed stemness genes Sox2，Oct4and Bmi1;3) SGC7901-SC possessed highercolony formation ability than SGC7901-MN cells (156±5vs35±2, p<0.05);4) CulturedSGC7901-SC in medium supplemented with10%FBS, the cells could produce more maturecells expressing CK18and H-K-ATPase;5) Xenograft assay showed that SGC7901-SC werehighly tumorigenic, and the xenograft formed by SGC7901-SC with lower proportion ofCK18and H-K-ATPase positive cells compared to xenograft formed by SGC7901-MN（13%±4%vs94%±2%，p<0.05and20%±4%vs42%±3%, p<0.05respectively）, indicating that xenografte formed by SGC7901-SC are immature. Those data suggesting that sphere cellspossess stem cell properties.
2. GCSCs possess highly invasive and metastatic ability in association with epithelialmesenchymal transition.1) We found xenograft tumors formed by SGC7901-SC cells invadedinto the capsule and metastasized to lymph nodes. In contrast, there were compact capsulessurrounding SGC7901-MN-xenografts without any invasion or metastasis；2）Invasive abilityof SGC7901-SC were measured by Transwell invasion assay, and we found that SGC7901-SCwith higher invasive ability in vitro compared to SGC7901-MN（153±16vs51±12，p<0.05）;3) Expression of invasive related genes in SGC7901-SC were detected by Real time PCR andWestern blot, we found that SGC7901-SC with increased expression of Vimentin, MMP2anddecreased expression of E-cadherin.
3. GCSCs show the property of multi-drug resistance.1) SGC7901-SC were moreresistant to chemo-drugs5-Fu，DDP and ADR compared to SGC7901-MN;2) SGC7901-SCshowed higher expression of ABCC4, lower expression of MDR1compared to SGC7901-MN.There was no significant difference of MRP1and ABCG2expression between SGC7901-SCand SGC7901-MN.
4. We found a series of genes and miRNAs differentially expressed betweenSGC7901-SC and SGC7901-MN by gene array and miRNA array analysis. Signalingpathways of Wnt, Notch, TGFβ, VEGF, p450and anti-apoptosis were activated in GCSCs,indicating these signaling pathways may be involved in the self-renewal, invasion, metastasis,multi-drug resistance and angiogenesis in GCSCs.
5. ANTXR2plays important roles in gastric cancer stemness maintenance, invasion andmetastasis.1) ANTXR2was found highly expressed in GCSCs by gene array analysis andconfirmed by real time PCR and FACS;2) ANTXR2was co-localized with stem cell markerCD44in gastric cancer samples;3) Silenced ANTXR2expression in gastric cancer cells byshRNA, the ability of sphere formation, proliferation, invasion and metastasis was impaired;4)Over-expressing ANTXR2, the colony formation ability of gastric cancer cells was increased.
6. The possible molecular mechanisms of ANTXR2in stemness maintenance, invasionand metastasis of gastric cancer cells were explored.1) Silenced ANTXR2expression ingastric cancer cells by shRNA, the expression of stemness and EMT related genes Sox2，Bmi1，CD44, β-catenin and Vimentin was down-regulated, meanwhile, the expression of E-cadherin was up-regulated;2) Gene array analysis showed that silencing ANTXR2expression mainly resulted in change of MAPK signaling pathway. Using the inhibitors ofMAPK signaling pathway, the result was confirmed. ERK inhibitor PD98059and JNKinhibitor SP600125could significantly inhibited the colony formation of gastric cancer cellswith over-expression of ANTXR2, and the ERK inhibitor PD98059is more effective;3)Silencing ANTXR2expression resulted in decreased phosphorylation of ERK, Src-Tyr416and increased phosphorylation of Src-Tyr527in gastric cancer cells, indicating that thefunction of ANTXT2may be dependent on the Src/ERK signaling pathway.
7. ANTXR2expression has important clinical significance in patients with gastric cancer.Immunohistochemistry(IHC) was used to detect the expression of ANTXR2in181specimensof gastric cancer, the result showed that the expression of ANTXR2was correlated withinvasive depth (p=0.03）, TNM stage (p=0.024) and shorter survival time (p=0.006),indicating that ANTXR2is an indicator of poor prognosis in gastric cancer.
In summary, sphere formation culture is an effective method for isolation/enrichment ofGCSCs. GCSCs possesses highly invasive, metastasis and multi-drug resistant properties.Multi-signaling pathways, such as Wnt, Notch, TGF-beta, p450metabolism enzyme familyand anti-apoptosis signaling pathway, may be involved in regulation of the GCSCs behaviors;Our results also demonstrated that ANTXR2play important roles in stemness maintenance,invasion and metastasis of GCSCs. The function of ANTXR2may be dependent on Src/ERKsignaling pathway. Expression of ANTXR2is positively correlated with clinic pathologicparameters and negatively correlated with survival time, indicating that it can be used as anindicator of poor prognosis of patients with gastric cancer.
引文
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