CXCL12-CXCR7轴在胰腺癌迁移侵袭中的作用及机制研究
摘要
研究背景
胰腺癌已被公认为预后极差的恶性肿瘤之一,其死亡率接近发病率。美国癌症协会对美国肿瘤发病率及死亡率的统计结果表明,胰腺癌占全部肿瘤死亡原因的第四位,其发病率有逐年升高趋势,过去10年间,胰腺癌的发病率增高了15%左右,但其5年生存率依然在5%以下。由于缺乏特异的临床表现,难以早期诊断,往往发现时已有淋巴和血运转移,失去根治性治疗机会。其死亡的主要原因是发现时已处于进展期,很多患者在确诊时肿瘤已包绕血管或发生远处转移。目前胰腺癌的侵袭转移机制尚不明确,因此明确胰腺癌侵袭与转移的分子机制对胰腺癌的治疗有重要的意义。
趋化因子既往被认为主要参与炎症反应。近年来,研究发现其在肿瘤的发生发展,尤其是在迁移侵袭方面发挥重要作用。本课题组前期通过DMBA诱导大鼠胰腺癌模型,进行基因芯片筛查,确定CXCR7为大鼠胰腺癌和正常胰腺组织显著差异表达的重要基因之一。CXCR7是近年来新发现的趋化因子受体,在肿瘤的发生发展,尤其是侵袭转移方面发挥重要作用。CXCL12作为CXCR7的重要配体,在许多肿瘤细胞中显著表达,而正常细胞则很少表达。许多研究表明CXCL12-CXCR7轴可促进肿瘤生长及侵袭转移,但其对胰腺癌侵袭转移的影响及相关机制仍然未知。因此,探讨CXCL12-CXCR7轴在胰腺癌的侵袭转移中的作用对于加深我们对胰腺癌分子机理的认识有重要意义。
研究目的
1)观察CXCL12-CXCR7轴对胰腺癌细胞增殖、迁移和侵袭的影响；
2)探讨CXCL12-CXCR7轴在胰腺癌细胞中的作用机制；
3)体内实验验证CXCR7对胰腺癌裸鼠移植瘤生长和转移的影响；
41分析CXCL12和CXCR7在胰腺癌患者预后评估中的价值。
研究方法
1)通过慢病毒载体将CXCR7的干扰miRNA或CXCR7基因导入胰腺癌细胞株BxPC-3和Capan-1中,经过抗性筛选,建立稳定沉默和稳定过表达CXCR7的胰腺癌细胞株。
2)CCK8法观察各组细胞增殖,Transwell法确定各组细胞迁移和侵袭,Westernblot检测mTOR通路相关蛋白表达及磷酸化,探讨CXCR7对胰腺癌细胞表型的影响及相关机制。
3)不同浓度CXCL12处理细胞(及在CXCL12加入的情况下,再加入或不加入CXCR4的抑制剂AMD3100), Transwell法检测细胞株的迁移和侵袭,Western blot检测相关蛋白表达及磷酸化,探讨CXCL12影响胰腺癌细胞生物学行为的分子机制。
4)在稳定过表达CXCR7的胰腺癌细胞株中加入mTOR的抑制剂雷帕霉素或Torinl, Transwell法检测细胞迁移和侵袭,Western blot检测mTOR通路蛋白表达及磷酸化。免疫共沉淀检测CXCR7和mTOR蛋白之间的相互作用。在稳定沉默CXCR7的胰腺癌细胞株中Western blot法检测mTOR下游ROCK通路蛋白的表达。在稳定沉默CXCR7及亲本胰腺癌细胞株中,加入mTOR抑制剂雷帕霉素或Torinl,免疫荧光染色检测F-actin的表达。
5)建立BALB/C-neu雌性裸鼠胰腺癌原位移植瘤肝转移模型,分别原位植入各组细胞。2个月后处死裸鼠,测量胰腺肿瘤体积,计数肝脏转移灶数目。
6)免疫组织化学染色探讨CXCL12和CXCR7在胰腺癌中的预后价值。
研究结果
1)以BxPC-3和Capan-1为亲本株,成功构建稳定沉默或过表达CXCR7蛋白的胰腺癌细胞株Si-CXCR7和OE-CXCR7。
2) CXCR7稳定沉默或过表达胰腺癌细胞株的增殖与对照组比较无明显变化(p>0.05); CXCR7稳定过表达的胰腺癌细胞的迁移和侵袭较对照组明显增强,伴有mTOR、4EBP1和P70S6K蛋白磷酸化水平的明显升高；而CXCR7稳定下调的胰腺癌细胞呈现相反的趋势,相应蛋白的磷酸化水平亦明显降低；无论稳定过表达或稳定沉默CXCR7的胰腺癌细胞株的AKT及p-AKT蛋白表达无明显变化。
3)不同浓度的CXCL12处理胰腺癌细胞株BxPC-3及Capan-1后,两株细胞的迁移和侵袭明显增强,CXCR7蛋白表达显著上调,mTOR、4EBP1和P70S6K磷酸化水平也明显升高。在加入CXCL12的同时,加入CXCR4抑制剂AMD3100并未引起细胞迁移和侵袭(p>0.05)、CXCR7表达、mTOR、4EBP1和P70S6K蛋白表达及磷酸化水平水平的明显变化。
41在稳定过表达CXCR7的细胞中加入mTOR的抑制剂雷帕霉素和Torinl之后,细胞的迁移和侵袭明显降低,mTOR、4EBP1和P70S6K磷酸化水平明显降低。免疫共沉淀实验显示mTOR蛋白和CXCR7之间存在直接结合。稳定沉默CXCR7的细胞株的ROCK通路蛋白的表达水平明显降低。免疫荧光染色发现,CXCR7稳定沉默后细胞F-actin明显呈现出紊乱的解聚状态。同样,用mTOR抑制剂雷帕霉素和Torin1处理细胞之后,F-actin亦明显呈现出紊乱的解聚状态。
51在胰腺癌裸鼠原位移植瘤模型中,CXCR7稳定沉默或过表达细胞株原位肿瘤的增殖与对照组相比没有明显差异。CXCR7稳定沉默细胞肝转移灶与较对照组相比明显减少(p<0.05), CXCR7稳定过表达细胞肝转移灶较对照组相比显著增多(p<0.05)。
6)对人胰腺癌组织标本的免疫组化研究发现,CXCL12和CXCR7在胰腺癌组织的表达水均显著高于癌旁组织(p<0.05),且CXCL12和CXCR7在胰腺癌组织中的表达水平与神经浸润呈正相关(p<0.05)。单因素生存分析显示,性别、肿瘤分化程度、淋巴结转移、CXCL12和CXCR7的表达与预后有相关性(p<0.05), Cox回归显示男性、低分化肿瘤、淋巴结转移、CXCL12和CXCR7共同高表达是患者不良预后的独立危险因素(p<0.05)。
研究结论
1) CXCL12-CXCR7轴对胰腺癌细胞增殖没有明显影响,但是显著加速细胞迁移和侵袭。
2) CXCL12-CXCR7轴可通过激活mTOR通路增加肿瘤细胞的迁移和侵袭,而这是通过CXCR7直接和mTOR的直接相互作用进而通过ROCK通路影响细胞的运动能力来实现的。
3) CXCR7可促进裸鼠胰腺原位移植瘤肝转移,但对于原位肿瘤的生长没有明显影响。
4) CXCL12和CXCR7在胰腺癌组织中高表达,二者共同高表达是胰腺癌患者预后的独立危险因素。
Background
Pancreatic cancer is well acknowledged as one of malignancies with extremely dismal prognosis, because the mortality is close to the incidence. A survey of American Cancer Society about cancer incidence and mortality in the United States showed that pancreatic cancer ranked the fourth of all malignant tumors. During the past10years, the incidence of pancreatic cancer increased by about15%, but its5-year survival rate is still below5%. Because of absence of specific clinical manifestations, early diagnosis of pancreatic cancer is difficult, and lymphatic/blood metastases are common. Thus, many patients lost the opportunity of radical treatments. The main reason of death is common advanced disease with invasion of blood vessels and distant metastasis in many patients when diagnosed. The mechanisms of invasion and metastasis of pancreatic cancer is currently unclear. Therefore, investigations concerning invasion and metastasis of pancreatic cancer are of great significance. Chemokines were previously thought to be involved in the inflammatory response. In recent years, they are found to play important roles in initiation and development of cancer, especially in migration and invasion. Our research group identified CXCR7as one of the important differentially expressed genes between pancreatic cancer and normal pancreatic tissues by microarray screening in the DMBA-induced pancreatic cancer model in rats. CXCR7is a recently discovered chemokine receptor, which plays important roles in tumor development, invasion and metastasis. CXCL12, an important ligand of CXCR7, is extensively expressed in many malignant cells, but is rarely expressed in normal cells. Many studies have shown that CXCL12-CXCR7axis promotes tumor growth, invasion and metastasis. However, there is no study referring to its impact on invasion and metastasis of pancreatic cancer, and relative mechanisms. Therefore, exploration of effects of CXCL12-CXCR7axis in the invasion and metastasis in pancreatic cancer is quite important for deepening our understanding for molecular mechanisms of pancreatic cancer.
Objectives:
1) To observe the effect of CXCL12-CXCR7axis in pancreatic cancer cell proliferation, migration and invasion;
2) To explore mechanisms of CXCL12-CXCR7axis in pancreatic cancer cells;
3) To validate the impact of CXCR7on growth and metastasis of implanted pancreatic cancer cell in nude mice;
4) To analyze the value of CXCL12and CXCR7in predicting the prognosis of pancreatic cancer patients.
Methods
1) Lentiviral vectors in that CXCR7gene or interfering miRNA of CXCR7was inserted were transferred into pancreatic cancer cell lines, BxPC-3and Capan-1. After antibiotic resistant screening, CXCR7stably silenced or overexpressed pancreatic cancer cell lines were established.
2) CCK8assay was used to observe cell proliferation; Transwell migration and invasion models were allied to determine the migration and invasion capabilities of cells; expression and phosphorylation of the proteins in mTOR pathway were detected by Western blot. Through these experiments, influences of CXCR7on phenotypes of pancreatic cancer cells and relative mechanisms were explored.
3) Different concentrations of recombinant human CXCL12was used to treat cells (with or without AMD3100, a inhibitor of CXCR4), Transwell model was used to detect migration and invasion, Western blot analysis was adopted to detect expression and phosphorylation of related proteins. All the experiments focused on molecular mechanisms of CXCL12in biological behaviors of pancreatic cancer cells.
4) In CXCR7stably silenced or overexpressed cells, the mTOR inhibitor, rapamycin or Torinl, was added, then cell migration and invasion was detected by Transwell assay, expression and phosphorylation of proteins in mTOR pathway was determined by Western blotting. Co-immunoprecipitation was used to show the interaction between CXCR7and mTOR. In cell lines in that CXCR7was stably silenced, Western blot was used to detect expression of proteins in ROCK pathway, downstream of mTOR. In CXCR7stably silenced and parent cells, the mTOR inhibitor, rapamycin or Torinl, was added, then F-actin expression was detected by immunofluorescence staining.
5) Orthotopic xenograft liver metastasis model of pancreatic cancer was established in BALB/C nude female mice. Cells were injected orthotopically. Two months later, the mice were sacrificed, the pancreatic tumor volumes of tumor were calculated, and the liver metastatic numbers were counted.
6) The prognostic value of CXCL12and CXCR7was explored using immunohistochemical staining.
Results
1) Based on pancreatic cancer cell lines, BxPC-3and Capan-1, CXCR7stably silenced or overexpressed cell lines were successfully established.
2) There was no significant change in proliferation between CXCR7stably silenced or overexpressed cells and control ones (p>0.05). Migration and invasion of CXCR7overexpressed cells were significantly increased compared with control cells, accompanied by enhanced phosphorylation of mTOR,4EBP1and P70S6K; while the opposite trend was observed in CXCR7stably silenced cells, phosphorylation of corresponding proteins was also significantly reduced; regardless of cells in that CXCR7was stably silenced or overexpressed, expression of AKT and p-AKT was not significantly changed.
3) After BxPC-3and Capan-1cells were treated with different concentrations of recombinant human CXCL12, migration and invasion of both cell lines were significantly enhanced, CXCR7expression was significantly up-regulated, phosphorylation of mTOR,4EBP1and P70S6K was also significantly increased. Application of AMD3100, the CXCR4inhibitor, in CXCL12-treated cells, did not cause alterations in migration and invasion (p>0.05), CXCR7expression and expression as well as phosphorylation of mTOR,4EBP1and P70S6K.
4) After the mTOR inhibitor, rapamycin or Torinl, was added in cells stably overexpressing CXCR7, migration and invasion were significantly reduced, and phosphorylation of mTOR,4EBP1and P70S6K was significantly reduced. Co-immunoprecipitation showed the direct interaction between mTOR and CXCR7. The expression of proteins in ROCK pathway was significantly reduced in CXCR7stably silenced cells. Immunofluorescence staining showed that F-actin was disorganized and depolymerized, when CXCR7was stably silenced, or the mTOR inhibitor, rapamycin or Torinl, was used.
5) In pancreatic cancer orthotopic xenograft model in nude mice, growth of orthotopic implanted tumors in the CXCR7stably silenced or overexpressed group was not significantly changed compared with the control groups; the liver metastatic nodule number of CXCR7stably overexpressed group was significantly more than that of the control group (p<0.05), while that of CXCR7stably silenced group was significantly decreased in contrast to the control group (p<0.05).
6) Immunohistochemical staining showed that expression of CXCL12and CXCR7was significantly higher in tumor tissues than in para-tumor tissues (p<0.05), and high expression of CXCL12and CXCR7was positively correlated with perineural invasion (p<0.05). Univariate analysis showed that gender, tumor differentiation, lymph node metastasis, CXCL12and CXCR7expression were associated with prognosis (p<0.05), whereas Cox regression analysis identified male gender, poor differentiation, lymph node metastasis, CXCL12and CXCR7co-expression as independent risk factors of unfavorable prognosis (p<0.05).
Conclusions
1) CXCL12-CXCR7axis had no significant influence on the proliferation of pancreatic cancer cells, but it can extensively accelerate cell migration and invasion.
2) Activation of mTOR signaling pathway is involved in the promotion of CXCL12-CXCR7axis for migration and invasion of tumor cells, which is based on the direct interaction between CXCR7and mTOR and its subsequent impact on cell motility through ROCK pathway.
3) CXCR7can promote liver metastasis in the pancreatic cancer orthotopic xenograft model, but had no significant effect on the growth of orthotopic tumors.
4) CXCL12and CXCR7were highly expressed in pancreatic cancer tissues, and their co-expression was an independent prognostic risk factor.
胰腺癌已被公认为预后极差的恶性肿瘤之一,其死亡率接近发病率。美国癌症协会对美国肿瘤发病率及死亡率的统计结果表明,胰腺癌占全部肿瘤死亡原因的第四位,其发病率有逐年升高趋势,过去10年间,胰腺癌的发病率增高了15%左右,但其5年生存率依然在5%以下。由于缺乏特异的临床表现,难以早期诊断,往往发现时已有淋巴和血运转移,失去根治性治疗机会。其死亡的主要原因是发现时已处于进展期,很多患者在确诊时肿瘤已包绕血管或发生远处转移。目前胰腺癌的侵袭转移机制尚不明确,因此明确胰腺癌侵袭与转移的分子机制对胰腺癌的治疗有重要的意义。
趋化因子既往被认为主要参与炎症反应。近年来,研究发现其在肿瘤的发生发展,尤其是在迁移侵袭方面发挥重要作用。本课题组前期通过DMBA诱导大鼠胰腺癌模型,进行基因芯片筛查,确定CXCR7为大鼠胰腺癌和正常胰腺组织显著差异表达的重要基因之一。CXCR7是近年来新发现的趋化因子受体,在肿瘤的发生发展,尤其是侵袭转移方面发挥重要作用。CXCL12作为CXCR7的重要配体,在许多肿瘤细胞中显著表达,而正常细胞则很少表达。许多研究表明CXCL12-CXCR7轴可促进肿瘤生长及侵袭转移,但其对胰腺癌侵袭转移的影响及相关机制仍然未知。因此,探讨CXCL12-CXCR7轴在胰腺癌的侵袭转移中的作用对于加深我们对胰腺癌分子机理的认识有重要意义。
研究目的
1)观察CXCL12-CXCR7轴对胰腺癌细胞增殖、迁移和侵袭的影响；
2)探讨CXCL12-CXCR7轴在胰腺癌细胞中的作用机制；
3)体内实验验证CXCR7对胰腺癌裸鼠移植瘤生长和转移的影响；
41分析CXCL12和CXCR7在胰腺癌患者预后评估中的价值。
研究方法
1)通过慢病毒载体将CXCR7的干扰miRNA或CXCR7基因导入胰腺癌细胞株BxPC-3和Capan-1中,经过抗性筛选,建立稳定沉默和稳定过表达CXCR7的胰腺癌细胞株。
2)CCK8法观察各组细胞增殖,Transwell法确定各组细胞迁移和侵袭,Westernblot检测mTOR通路相关蛋白表达及磷酸化,探讨CXCR7对胰腺癌细胞表型的影响及相关机制。
3)不同浓度CXCL12处理细胞(及在CXCL12加入的情况下,再加入或不加入CXCR4的抑制剂AMD3100), Transwell法检测细胞株的迁移和侵袭,Western blot检测相关蛋白表达及磷酸化,探讨CXCL12影响胰腺癌细胞生物学行为的分子机制。
4)在稳定过表达CXCR7的胰腺癌细胞株中加入mTOR的抑制剂雷帕霉素或Torinl, Transwell法检测细胞迁移和侵袭,Western blot检测mTOR通路蛋白表达及磷酸化。免疫共沉淀检测CXCR7和mTOR蛋白之间的相互作用。在稳定沉默CXCR7的胰腺癌细胞株中Western blot法检测mTOR下游ROCK通路蛋白的表达。在稳定沉默CXCR7及亲本胰腺癌细胞株中,加入mTOR抑制剂雷帕霉素或Torinl,免疫荧光染色检测F-actin的表达。
5)建立BALB/C-neu雌性裸鼠胰腺癌原位移植瘤肝转移模型,分别原位植入各组细胞。2个月后处死裸鼠,测量胰腺肿瘤体积,计数肝脏转移灶数目。
6)免疫组织化学染色探讨CXCL12和CXCR7在胰腺癌中的预后价值。
研究结果
1)以BxPC-3和Capan-1为亲本株,成功构建稳定沉默或过表达CXCR7蛋白的胰腺癌细胞株Si-CXCR7和OE-CXCR7。
2) CXCR7稳定沉默或过表达胰腺癌细胞株的增殖与对照组比较无明显变化(p>0.05); CXCR7稳定过表达的胰腺癌细胞的迁移和侵袭较对照组明显增强,伴有mTOR、4EBP1和P70S6K蛋白磷酸化水平的明显升高；而CXCR7稳定下调的胰腺癌细胞呈现相反的趋势,相应蛋白的磷酸化水平亦明显降低；无论稳定过表达或稳定沉默CXCR7的胰腺癌细胞株的AKT及p-AKT蛋白表达无明显变化。
3)不同浓度的CXCL12处理胰腺癌细胞株BxPC-3及Capan-1后,两株细胞的迁移和侵袭明显增强,CXCR7蛋白表达显著上调,mTOR、4EBP1和P70S6K磷酸化水平也明显升高。在加入CXCL12的同时,加入CXCR4抑制剂AMD3100并未引起细胞迁移和侵袭(p>0.05)、CXCR7表达、mTOR、4EBP1和P70S6K蛋白表达及磷酸化水平水平的明显变化。
41在稳定过表达CXCR7的细胞中加入mTOR的抑制剂雷帕霉素和Torinl之后,细胞的迁移和侵袭明显降低,mTOR、4EBP1和P70S6K磷酸化水平明显降低。免疫共沉淀实验显示mTOR蛋白和CXCR7之间存在直接结合。稳定沉默CXCR7的细胞株的ROCK通路蛋白的表达水平明显降低。免疫荧光染色发现,CXCR7稳定沉默后细胞F-actin明显呈现出紊乱的解聚状态。同样,用mTOR抑制剂雷帕霉素和Torin1处理细胞之后,F-actin亦明显呈现出紊乱的解聚状态。
51在胰腺癌裸鼠原位移植瘤模型中,CXCR7稳定沉默或过表达细胞株原位肿瘤的增殖与对照组相比没有明显差异。CXCR7稳定沉默细胞肝转移灶与较对照组相比明显减少(p<0.05), CXCR7稳定过表达细胞肝转移灶较对照组相比显著增多(p<0.05)。
6)对人胰腺癌组织标本的免疫组化研究发现,CXCL12和CXCR7在胰腺癌组织的表达水均显著高于癌旁组织(p<0.05),且CXCL12和CXCR7在胰腺癌组织中的表达水平与神经浸润呈正相关(p<0.05)。单因素生存分析显示,性别、肿瘤分化程度、淋巴结转移、CXCL12和CXCR7的表达与预后有相关性(p<0.05), Cox回归显示男性、低分化肿瘤、淋巴结转移、CXCL12和CXCR7共同高表达是患者不良预后的独立危险因素(p<0.05)。
研究结论
1) CXCL12-CXCR7轴对胰腺癌细胞增殖没有明显影响,但是显著加速细胞迁移和侵袭。
2) CXCL12-CXCR7轴可通过激活mTOR通路增加肿瘤细胞的迁移和侵袭,而这是通过CXCR7直接和mTOR的直接相互作用进而通过ROCK通路影响细胞的运动能力来实现的。
3) CXCR7可促进裸鼠胰腺原位移植瘤肝转移,但对于原位肿瘤的生长没有明显影响。
4) CXCL12和CXCR7在胰腺癌组织中高表达,二者共同高表达是胰腺癌患者预后的独立危险因素。
Background
Pancreatic cancer is well acknowledged as one of malignancies with extremely dismal prognosis, because the mortality is close to the incidence. A survey of American Cancer Society about cancer incidence and mortality in the United States showed that pancreatic cancer ranked the fourth of all malignant tumors. During the past10years, the incidence of pancreatic cancer increased by about15%, but its5-year survival rate is still below5%. Because of absence of specific clinical manifestations, early diagnosis of pancreatic cancer is difficult, and lymphatic/blood metastases are common. Thus, many patients lost the opportunity of radical treatments. The main reason of death is common advanced disease with invasion of blood vessels and distant metastasis in many patients when diagnosed. The mechanisms of invasion and metastasis of pancreatic cancer is currently unclear. Therefore, investigations concerning invasion and metastasis of pancreatic cancer are of great significance. Chemokines were previously thought to be involved in the inflammatory response. In recent years, they are found to play important roles in initiation and development of cancer, especially in migration and invasion. Our research group identified CXCR7as one of the important differentially expressed genes between pancreatic cancer and normal pancreatic tissues by microarray screening in the DMBA-induced pancreatic cancer model in rats. CXCR7is a recently discovered chemokine receptor, which plays important roles in tumor development, invasion and metastasis. CXCL12, an important ligand of CXCR7, is extensively expressed in many malignant cells, but is rarely expressed in normal cells. Many studies have shown that CXCL12-CXCR7axis promotes tumor growth, invasion and metastasis. However, there is no study referring to its impact on invasion and metastasis of pancreatic cancer, and relative mechanisms. Therefore, exploration of effects of CXCL12-CXCR7axis in the invasion and metastasis in pancreatic cancer is quite important for deepening our understanding for molecular mechanisms of pancreatic cancer.
Objectives:
1) To observe the effect of CXCL12-CXCR7axis in pancreatic cancer cell proliferation, migration and invasion;
2) To explore mechanisms of CXCL12-CXCR7axis in pancreatic cancer cells;
3) To validate the impact of CXCR7on growth and metastasis of implanted pancreatic cancer cell in nude mice;
4) To analyze the value of CXCL12and CXCR7in predicting the prognosis of pancreatic cancer patients.
Methods
1) Lentiviral vectors in that CXCR7gene or interfering miRNA of CXCR7was inserted were transferred into pancreatic cancer cell lines, BxPC-3and Capan-1. After antibiotic resistant screening, CXCR7stably silenced or overexpressed pancreatic cancer cell lines were established.
2) CCK8assay was used to observe cell proliferation; Transwell migration and invasion models were allied to determine the migration and invasion capabilities of cells; expression and phosphorylation of the proteins in mTOR pathway were detected by Western blot. Through these experiments, influences of CXCR7on phenotypes of pancreatic cancer cells and relative mechanisms were explored.
3) Different concentrations of recombinant human CXCL12was used to treat cells (with or without AMD3100, a inhibitor of CXCR4), Transwell model was used to detect migration and invasion, Western blot analysis was adopted to detect expression and phosphorylation of related proteins. All the experiments focused on molecular mechanisms of CXCL12in biological behaviors of pancreatic cancer cells.
4) In CXCR7stably silenced or overexpressed cells, the mTOR inhibitor, rapamycin or Torinl, was added, then cell migration and invasion was detected by Transwell assay, expression and phosphorylation of proteins in mTOR pathway was determined by Western blotting. Co-immunoprecipitation was used to show the interaction between CXCR7and mTOR. In cell lines in that CXCR7was stably silenced, Western blot was used to detect expression of proteins in ROCK pathway, downstream of mTOR. In CXCR7stably silenced and parent cells, the mTOR inhibitor, rapamycin or Torinl, was added, then F-actin expression was detected by immunofluorescence staining.
5) Orthotopic xenograft liver metastasis model of pancreatic cancer was established in BALB/C nude female mice. Cells were injected orthotopically. Two months later, the mice were sacrificed, the pancreatic tumor volumes of tumor were calculated, and the liver metastatic numbers were counted.
6) The prognostic value of CXCL12and CXCR7was explored using immunohistochemical staining.
Results
1) Based on pancreatic cancer cell lines, BxPC-3and Capan-1, CXCR7stably silenced or overexpressed cell lines were successfully established.
2) There was no significant change in proliferation between CXCR7stably silenced or overexpressed cells and control ones (p>0.05). Migration and invasion of CXCR7overexpressed cells were significantly increased compared with control cells, accompanied by enhanced phosphorylation of mTOR,4EBP1and P70S6K; while the opposite trend was observed in CXCR7stably silenced cells, phosphorylation of corresponding proteins was also significantly reduced; regardless of cells in that CXCR7was stably silenced or overexpressed, expression of AKT and p-AKT was not significantly changed.
3) After BxPC-3and Capan-1cells were treated with different concentrations of recombinant human CXCL12, migration and invasion of both cell lines were significantly enhanced, CXCR7expression was significantly up-regulated, phosphorylation of mTOR,4EBP1and P70S6K was also significantly increased. Application of AMD3100, the CXCR4inhibitor, in CXCL12-treated cells, did not cause alterations in migration and invasion (p>0.05), CXCR7expression and expression as well as phosphorylation of mTOR,4EBP1and P70S6K.
4) After the mTOR inhibitor, rapamycin or Torinl, was added in cells stably overexpressing CXCR7, migration and invasion were significantly reduced, and phosphorylation of mTOR,4EBP1and P70S6K was significantly reduced. Co-immunoprecipitation showed the direct interaction between mTOR and CXCR7. The expression of proteins in ROCK pathway was significantly reduced in CXCR7stably silenced cells. Immunofluorescence staining showed that F-actin was disorganized and depolymerized, when CXCR7was stably silenced, or the mTOR inhibitor, rapamycin or Torinl, was used.
5) In pancreatic cancer orthotopic xenograft model in nude mice, growth of orthotopic implanted tumors in the CXCR7stably silenced or overexpressed group was not significantly changed compared with the control groups; the liver metastatic nodule number of CXCR7stably overexpressed group was significantly more than that of the control group (p<0.05), while that of CXCR7stably silenced group was significantly decreased in contrast to the control group (p<0.05).
6) Immunohistochemical staining showed that expression of CXCL12and CXCR7was significantly higher in tumor tissues than in para-tumor tissues (p<0.05), and high expression of CXCL12and CXCR7was positively correlated with perineural invasion (p<0.05). Univariate analysis showed that gender, tumor differentiation, lymph node metastasis, CXCL12and CXCR7expression were associated with prognosis (p<0.05), whereas Cox regression analysis identified male gender, poor differentiation, lymph node metastasis, CXCL12and CXCR7co-expression as independent risk factors of unfavorable prognosis (p<0.05).
Conclusions
1) CXCL12-CXCR7axis had no significant influence on the proliferation of pancreatic cancer cells, but it can extensively accelerate cell migration and invasion.
2) Activation of mTOR signaling pathway is involved in the promotion of CXCL12-CXCR7axis for migration and invasion of tumor cells, which is based on the direct interaction between CXCR7and mTOR and its subsequent impact on cell motility through ROCK pathway.
3) CXCR7can promote liver metastasis in the pancreatic cancer orthotopic xenograft model, but had no significant effect on the growth of orthotopic tumors.
4) CXCL12and CXCR7were highly expressed in pancreatic cancer tissues, and their co-expression was an independent prognostic risk factor.
引文
[1]Siegel R, Ma J, Zou Z, et al. Cancer statistics,2014. CA Cancer J Clin,2014,64:9-29.
[2]王启俊,邢秀梅.北京城区居民1982年～1997年癌症发病趋势.中国肿瘤, 2001：14-16.
[3]李新建,沈玉珍,韩阿琴.上海市胰腺癌的流行现状和趋势研究.外科理论与实践,2002：342-345.
[4]陈可欣,李连弟.中国胰腺癌死亡情况报告.中华流行病学杂志,2003：96-98.
[5]Mihaljevic AL, Michalski CW, Friess H, et al. Molecular mechanism of pancreatic cancer--understanding proliferation, invasion, and metastasis. Langenbecks Arch Surg, 2010,395:295-308.
[6]Hidalgo M. Pancreatic cancer. N Engl J Med,2010,362:1605-17.
[7]Sun X, Cheng G, Hao M, et al. CXCL12/CXCR4/CXCR7 chemokine axis and cancer progression. Cancer Metastasis Rev,2010,29:709-22.
[8]Guo JC, Li J, Yang YC, et al. Oligonucleotide microarray identifies genes differentially expressed during tumorigenesis of DMBA-induced pancreatic cancer in rats. PLOS ONE, 2013,8:e82910.
[9]Burns JM, Summers BC, Wang Y, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med, 2006,203:2201-13.
[10]Miao Z, Luker KE, Summers BC, et al. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc Natl Acad Sci U S A,2007,104:15735-40.
[11]Wang J, Shiozawa Y, Wang J, et al. The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J Biol Chem,2008,283:4283-94.
[12]Walters MJ, Ebsworth K, Berahovich RD, et al. Inhibition of CXCR7 extends survival following irradiation of brain tumours in mice and rats. Br J Cancer,2014,110:1179-88.
[13]Burns JM, Summers BC, Wang Y, et al. A novel chemokine receptor for SDF-I and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med, 2006,203:2201-13.
[14]Marechal R, Demetter P, Nagy N, et al. High expression of CXCR4 may predict poor survival in resected pancreatic adenocarcinoma. Br J Cancer,2009,100:1444-51.
[15]Gebauer F, Tachezy M, Effenberger K, et al. Prognostic impact of CXCR4 and CXCR7 expression in pancreatic adenocarcinoma. J Surg Oncol,2011,104:140-5.
[1]Guo JC, Li J, Yang YC, et al. Oligonucleotide Microarray Identifies Genes Differentially Expressed during Tumorigenesis of DMBA-Induced Pancreatic Cancer in Rats. PLOS ONE,2013,8:e82910.
[2]Tan MH, Nowak NJ, Loor R, et al. Characterization of a new primary human pancreatic tumor line. Cancer Invest,1986,4:15-23.
[3]Fogh J, Wright WC, Loveless JD. Absence of HeLa cell contamination in 169 cell lines derived from human tumors. J Natl Cancer Inst,1977,58:209-14.
[4]Tripathi V, Kumar R, Dinda AK, et al. CXCL12-CXCR7 Signaling Activates ERK and Akt Pathways in Human Choriocarcinoma Cells. Cell Commun Adhes,2014.
[5]Schrevel M, Karim R, ter HNT, et al. CXCR7 expression is associated with disease-free and disease-specific survival in cervical cancer patients. Br J Cancer,2012,106:1520-5.
[6]Hao M, Zheng J, Hou K, et al. Role of chemokine receptor CXCR7 in bladder cancer progression. Biochem Pharmacol,2012,84:204-14.
[7]Singh RK, Lokeshwar BL. The IL-8-regulated chemokine receptor CXCR7 stimulates EGFR signaling to promote prostate cancer growth. Cancer Res,2011,71:3268-77.
[1]Kijowski J, Baj-Krzyworzeka M, Majka M, et al. The SDF-1-CXCR4 axis stimulates VEGF secretion and activates integrins but does not affect proliferation and survival in lymphohematopoietic cells. Stem Cells,2001,19:453-66.
[2]Majka M, Ratajczak J, Villaire G, et al. Thrombopoietin, but not cytokines binding to gp130 protein-coupled receptors, activates MAPKp42/44, AKT, and STAT proteins in normal human CD34+cells, megakaryocytes, and platelets. Exp Hematol,2002,30:751-60.
[3]Burns JM, Summers BC, Wang Y, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med, 2006,203:2201-13.
[4]Wang J, Shiozawa Y, Wang J, et al. The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J Biol Chem,2008,283:4283-94.
[5]Boimel PJ, Smirnova T, Zhou ZN, et al. Contribution of CXCL12 secretion to invasion of breast cancer cells. Breast Cancer Res,2012,14:R23.
[6]Burns JM, Summers BC, Wang Y, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med, 2006,203:2201-13.
[7]Iwakiri S, Mino N, Takahashi T, et al. Higher expression of chemokine receptor CXCR7 is linked to early and metastatic recurrence in pathological stage I nonsmall cell lung cancer. Cancer,2009,115:2580-93.
[8]Wang Y, Liu Y, Lu J, et al. Rapamycin inhibits FBXW7 loss-induced epithelial-mesenchymal transition and cancer stem cell-like characteristics in colorectal cancer cells. Biochem Biophys Res Commun,2013,434:352-6.
[9]Tsaur I, Makarevic J, Juengel E, et al. Resistance to the mTOR-inhibitor RAD001 elevates integrin alpha2-and betal-triggered motility, migration and invasion of prostate cancer cells. Br J Cancer,2012,107:847-55.
[10]Lee H, Kim JS, Kim E. Fucoidan from seaweed Fucus vesiculosus inhibits migration and invasion of human lung cancer cell via PI3K-Akt-mTOR pathways. PLOS ONE, 2012,7:e50624.
[1]Rot A, von AUH. Chemokines in innate and adaptive host defense:basic chemokinese grammar for immune cells. Annu Rev Immunol,2004,22:891-928.
[2]Wang J, Shiozawa Y, Wang J, et al. The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J Biol Chem,2008,283:4283-94.
[3]Zhang Y, Wen G, Shao G, et al. TGFBI deficiency predisposes mice to spontaneous tumor development. Cancer Res,2009,69:37-44.
[4]Iwakiri S, Mino N, Takahashi T, et al. Higher expression of chemokine receptor CXCR7 is linked to early and metastatic recurrence in pathological stage I nonsmall cell lung cancer. Cancer,2009,115:2580-93.
[5]Schwarz MK, Wells TN. New therapeutics that modulate chemokine networks. Nat Rev Drug Discov,2002,1:347-58.
[6]Balabanian K, Lagane B, Infantino S, et al. The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem, 2005,280:35760-6.
[7]Balabanian K, Lagane B, Infantino S, et al. The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem, 2005,280:35760-6.
[8]Burns JM, Summers BC, Wang Y, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med, 2006,203:2201-13.
[9]Vandercappellen J, Van Damme J, Struyf S. The role of CXC chemokines and their receptors in cancer. Cancer Lett,2008,267:226-44.
[10]Perlin JR, Talbot WS. Signals on the move:chemokine receptors and organogenesis in zebrafish. Sci STKE,2007,2007:pe45.
[11]Levoye A, Balabanian K, Baleux F, et al. CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling. Blood,2009,113:6085-93.
[12]Mazzinghi B, Ronconi E, Lazzeri E, et al. Essential but differential role for CXCR4 and CXCR7 in the therapeutic homing of human renal progenitor cells. J Exp Med, 2008,205:479-90.
[13]Yates TJ, Knapp J, Gosalbez M, et al. C-X-C chemokine receptor 7:a functionally associated molecular marker for bladder cancer. Cancer,2013,119:61-71.
[14]Harrison SM, Knifley T, Chen M, et al. LPA, HGF, and EGF utilize distinct combinations of signaling pathways to promote migration and invasion of MDA-MB-231 breast carcinoma cells. BMC Cancer,2013,13:501.
[15]Heitman J, Movva NR, Hall MN. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science,1991,253:905-9.
[16]Rutter GA, Da SXG, Leclerc I. Roles of 5'-AMP-activated protein kinase (AMPK) in mammalian glucose homoeostasis. Biochem J,2003,375:1-16.
[17]Wang Y, Liu Y, Lu J, et al. Rapamycin inhibits FBXW7 loss-induced epithelial-mesenchymal transition and cancer stem cell-like characteristics in colorectal cancer cells. Biochem Biophys Res Commun,2013,434:352-6.
[18]Tsaur I, Makarevic J, Juengel E, et al. Resistance to the mTOR-inhibitor RAD001 elevates integrin alpha2- and betal-triggered motility, migration and invasion of prostate cancer cells. Br J Cancer,2012,107:847-55.
[19]Lee H, Kim JS, Kim E. Fucoidan from seaweed Fucus vesiculosus inhibits migration and invasion of human lung cancer cell via PI3K-Akt-mTOR pathways. PLOS ONE, 2012,7:e50624.
[20]Ohsawa M, Kobayashi T, Okura H, et al. TSC1 controls distribution of actin fibers through its effect on function of Rho family of small GTPases and regulates cell migration and polarity. PLOS ONE,2013,8:e54503.
[21]Imam JS, Plyler JR, Bansal H, et al. Genomic loss of tumor suppressor miRNA-204 promotes cancer cell migration and invasion by activating AKT/mTOR/Racl signaling and actin reorganization. PLOS ONE,2012,7:e52397.
[22]Muller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature,2001,410:50-6.
[23]Burns JM, Summers BC, Wang Y, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med, 2006,203:2201-13.
[24]Madden SL, Cook BP, Nacht M, et al. Vascular gene expression in nonneoplastic and malignant brain. Am J Pathol,2004,165:601-8.
[25]Miao Z, Luker KE, Summers BC, et al. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc Natl Acad Sci U S A,2007,104:15735-40.
[1]Rygaard J, Povlsen CO. Heterotransplantation of a human malignant tumour to "Nude" mice. Acta Pathol Microbiol Scand,1969,77:758-60.
[2]Miao Z, Luker KE, Summers BC, et al. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc Natl Acad Sci U S A,2007,104:15735-40.
[3]Wang J, Shiozawa Y, Wang J, et al. The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J Biol Chem,2008,283:4283-94.
[4]Raggo C, Ruhl R, McAllister S, et al. Novel cellular genes essential for transformation of endothelial cells by Kaposi's sarcoma-associated herpesvirus. Cancer Res, 2005,65:5084-95.
[5]Burns JM, Summers BC, Wang Y, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med, 2006,203:2201-13.
[6]Meijer J, Ogink J, Roos E. Effect of the chemokine receptor CXCR7 on proliferation of carcinoma cells in vitro and in vivo. Br J Cancer,2008,99:1493-501.
[1]Marechal R, Demetter P, Nagy N, et al. High expression of CXCR4 may predict poor survival in resected pancreatic adenocarcinoma. Br J Cancer,2009,100:1444-51.
[2]Miao Z, Luker KE, Summers BC, et al. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc Natl Acad Sci U S A,2007,104:15735-40.
[3]Maishi N, Ohga N, Hida Y, et al. CXCR7:a novel tumor endothelial marker in renal cell carcinoma. Pathol Int,2012,62:309-17.
[4]Wang J, Shiozawa Y, Wang J, et al. The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J Biol Chem,2008,283:4283-94.
[5]Iwakiri S, Mino N, Takahashi T, et al. Higher expression of chemokine receptor CXCR7 is linked to early and metastatic recurrence in pathological stage I nonsmall cell lung cancer. Cancer,2009,115:2580-93.
[6]Schrevel M, Karim R, ter HNT, et al. CXCR7 expression is associated with disease-free and disease-specific survival in cervical cancer patients. Br J Cancer,2012,106:1520-5.
[7]Gelmini S, Mangoni M, Castiglione F, et al. The CXCR4/CXCL12 axis in endometrial cancer. Clin Exp Metastasis,2009,26:261-8.
[8]Marechal R, Demetter P, Nagy N, et al. High expression of CXCR4 may predict poor survival in resected pancreatic adenocarcinoma. Br J Cancer,2009,100:1444-51.
[9]Gebauer F, Tachezy M, Effenberger K, et al. Prognostic impact of CXCR4 and CXCR7 expression in pancreatic adenocarcinoma. J Surg Oncol,2011,104:140-5.
[10]Balkwill F. The significance of cancer cell expression of the chemokine receptor CXCR4. Semin Cancer Biol,2004,14:171-9.
[11]Oliveira FV, Rubie C, Ghadjar P, et al. Changes in CXCL12/CXCR4-chemokine expression during onset of colorectal malignancies. Tumour Biol,2011,32:189-96.
[12]Wang L, Chen W, Gao L, et al. High expression of CXCR4, CXCR7 and SDF-1 predicts poor survival in renal cell carcinoma. World J Surg Oncol,2012,10:212.
[13]Liang JJ, Zhu S, Bruggeman R, et al. High levels of expression of human stromal cell-derived factor-1 are associated with worse prognosis in patients with stage Ⅱ pancreatic ductal adenocarcinoma. Cancer Epidemiol Biomarkers Prev,2010,19:2598-604.
[14]Ying J, Xu Q, Zhang G, et al. The expression of CXCL12 and CXCR4 in gastric cancer and their correlation to lymph node metastasis. Med Oncol,2012,29:1716-22.
[15]Wagner PL, Hyjek E, Vazquez MF, et al. CXCL12 and CXCR4 in adenocarcinoma of the lung:association with metastasis and survival. J Thorac Cardiovasc Surg, 2009,137:615-21.
[16]Guo L, Cui ZM, Zhang J, et al. Chemokine axes CXCL12/CXCR4 and CXCL16/CXCR6 correlate with lymph node metastasis in epithelial ovarian carcinoma. Chin J Cancer, 2011,30:336-43.
[17]Wang DF, Lou N, Zeng CG, et al. Expression of CXCL12/CXCR4 and its correlation to prognosis in esophageal squamous cell carcinoma. Ai Zheng,2009,28:154-8.
[18]Sasaki K, Natsugoe S, Ishigami S, et al. Expression of CXCL12 and its receptor CXCR4 in esophageal squamous cell carcinoma. Oncol Rep,2009,21:65-71.
[19]Kim JH, Lee JY, Lee KT, et al. RGS16 and FosB underexpressed in pancreatic cancer with lymph node metastasis promote tumor progression. Tumour Biol,2010,31:541-8.
[20]Liang JJ, Zhu S, Bruggeman R, et al. High levels of expression of human stromal cell-derived factor-1 are associated with worse prognosis in patients with stage Ⅱ pancreatic ductal adenocarcinoma. Cancer Epidemiol Biomarkers Prev,2010,19:2598-604.
[21]王铮,徐勤鸿,李徐奇,等.CXCL12/CXCR4轴在胰腺癌-神经交互作用中的研究.西安交通大学学报(医学版),2012：214-219.
[1]Rot A, von AUH. Chemokines in innate and adaptive host defense:basic chemokinese grammar for immune cells. Annu Rev Immunol,2004,22:891-928.
[2]Zlotnik A, Yoshie O. Chemokines:a new classification system and their role in immunity. Immunity,2000,12:121-7.
[3]Schwarz MK, Wells TN. New therapeutics that modulate chemokine networks. Nat Rev Drug Discov,2002,1:347-58.
[4]Balabanian K, Lagane B, Infantino S, et al. The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem, 2005,280:35760-6.
[5]Ma Q, Jones D, Springer TA. The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity,1999,10:463-71.
[6]Egawa T, Kawabata K, Kawamoto H, et al. The earliest stages of B cell development require a chemokine stromal cell-derived factor/pre-B cell growth-stimulating factor. Immunity,2001,15:323-34.
[7]Balabanian K, Lagane B, Infantino S, et al. The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem, 2005,280:35760-6.
[8]Burns JM, Summers BC, Wang Y, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med, 2006,203:2201-13.
[9]Vandercappellen J, Van Damme J, Struyf S. The role of CXC chemokines and their receptors in cancer. Cancer Lett,2008,267:226-44.
[10]Perlin JR, Talbot WS. Signals on the move:chemokine receptors and organogenesis in zebrafish. Sci STKE,2007,2007:pe45.
[11]Levoye A, Balabanian K, Baleux F, et al. CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling. Blood,2009,113:6085-93.
[12]Mazzinghi B, Ronconi E, Lazzeri E, et al. Essential but differential role for CXCR4 and CXCR7 in the therapeutic homing of human renal progenitor cells. J Exp Med, 2008,205:479-90.
[13]Yates TJ, Knapp J, Gosalbez M, et al. C-X-C chemokine receptor 7:a functionally associated molecular marker for bladder cancer. Cancer,2013,119:61-71.
[14]Miao Z, Luker KE, Summers BC, et al. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc Natl Acad Sci U S A,2007,104:15735-40.
[15]Maishi N, Ohga N, Hida Y, et al. CXCR7:a novel tumor endothelial marker in renal cell carcinoma. Pathol Int,2012,62:309-17.
[16]Wang J, Shiozawa Y, Wang J, et al. The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J Biol Chem,2008,283:4283-94.
[17]Iwakiri S, Mino N, Takahashi T, et al. Higher expression of chemokine receptor CXCR7 is linked to early and metastatic recurrence in pathological stage I nonsmall cell lung cancer. Cancer,2009,115:2580-93.
[18]Schrevel M, Karim R, ter HNT, et al. CXCR7 expression is associated with disease-free and disease-specific survival in cervical cancer patients. Br J Cancer,2012,106:1520-5.
[19]Gelmini S, Mangoni M, Castiglione F, et al. The CXCR4/CXCL12 axis in endometrial cancer. Clin Exp Metastasis,2009,26:261-8.
[20]Marechal R, Demetter P, Nagy N, et al. High expression of CXCR4 may predict poor survival in resected pancreatic adenocarcinoma. Br J Cancer,2009,100:1444-51.
[21]Gebauer F, Tachezy M, Effenberger K, et al. Prognostic impact of CXCR4 and CXCR7 expression in pancreatic adenocarcinoma. J Surg Oncol,2011,104:140-5.
[22]Balkwill F. The significance of cancer cell expression of the chemokine receptor CXCR4. Semin Cancer Biol,2004,14:171-9.
[23]Oliveira FV, Rubie C, Ghadjar P, et al. Changes in CXCL12/CXCR4-chemokine expression during onset of colorectal malignancies. Tumour Biol,2011,32:189-96.
[24]Wang L, Chen W, Gao L, et al. High expression of CXCR4, CXCR7 and SDF-1 predicts poor survival in renal cell carcinoma. World J Surg Oncol,2012,10:212.
[25]Liang JJ, Zhu S, Bruggeman R, et al. High levels of expression of human stromal cell-derived factor-1 are associated with worse prognosis in patients with stage Ⅱ pancreatic ductal adenocarcinoma. Cancer Epidemiol Biomarkers Prev,2010,19:2598-604.
[26]Ying J, Xu Q, Zhang G, et al. The expression of CXCL12 and CXCR4 in gastric cancer and their correlation to lymph node metastasis. Med Oncol,2012,29:1716-22.
[27]Wagner PL, Hyjek E, Vazquez MF, et al. CXCL12 and CXCR4 in adenocarcinoma of the lung:association with metastasis and survival. J Thorac Cardiovasc Surg, 2009,137:615-21.
[28]Guo L, Cui ZM, Zhang J, et al. Chemokine axes CXCL12/CXCR4 and CXCL16/CXCR6 correlate with lymph node metastasis in epithelial ovarian carcinoma. Chin J Cancer, 2011,30:336-43.
[29]Wang DF, Lou N, Zeng CG, et al. Expression of CXCL12/CXCR4 and its correlation to prognosis in esophageal squamous cell carcinoma. Ai Zheng,2009,28:154-8.
[30]Sasaki K, Natsugoe S, Ishigami S, et al. Expression of CXCL12 and its receptor CXCR4 in esophageal squamous cell carcinoma. Oncol Rep,2009,21:65-71.
[31]Kim JH, Lee JY, Lee KT, et al. RGS16 and FosB underexpressed in pancreatic cancer with lymph node metastasis promote tumor progression. Tumour Biol,2010,31:541-8.
[32]Liang JJ, Zhu S, Bruggeman R, et al. High levels of expression of human stromal cell-derived factor-1 are associated with worse prognosis in patients with stage II pancreatic ductal adenocarcinoma. Cancer Epidemiol Biomarkers Prev,2010,19:2598-604.
[33]Kijowski J, Baj-Krzyworzeka M, Majka M, et al. The SDF-1-CXCR4 axis stimulates VEGF secretion and activates integrins but does not affect proliferation and survival in lymphohematopoietic cells. Stem Cells,2001,19:453-66.
[34]Majka M, Ratajczak J, Villaire G, et al. Thrombopoietin, but not cytokines binding to gp130 protein-coupled receptors, activates MAPKp42/44, AKT, and STAT proteins in normal human CD34+ cells, megakaryocytes, and platelets. Exp Hematol,2002,30:751-60.
[35]Burns JM, Summers BC, Wang Y, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med, 2006,203:2201-13.
[36]Raggo C, Ruhl R, McAllister S, et al. Novel cellular genes essential for transformation of endothelial cells by Kaposi's sarcoma-associated herpesvirus. Cancer Res, 2005,65:5084-95.
[37]Meijer J, Ogink J, Roos E. Effect of the chemokine receptor CXCR7 on proliferation of carcinoma cells in vitro and in vivo. Br J Cancer,2008,99:1493-501.
[38]Kollmar O, Rupertus K, Scheuer C, et al. Stromal cell-derived factor-1 promotes cell migration and tumor growth of colorectal metastasis. Neoplasia,2007,9:862-70.
[39]Orimo A, Gupta PB, Sgroi DC, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell,2005,121:335-48.
[40]Dewan MZ, Ahmed S, Iwasaki Y, et al. Stromal cell-derived factor-1 and CXCR4 receptor interaction in tumor growth and metastasis of breast cancer. Biomed Pharmacother, 2006,60:273-6.
[41]Rupertus K, Sinistra J, Scheuer C, et al. Interaction of the chemokines I-TAC (CXCL11) and SDF-1 (CXCL12) in the regulation of tumor angiogenesis of colorectal cancer. Clin Exp Metastasis,2014.
[42]迟啸威,侯静波,于波CXCL12过表达促进骨髓基质干细胞整合素αv/β3介导的黏附和增殖.中国生物工程杂志,2008,28：32-36.
[43]Kijowski J, Baj-Krzyworzeka M, Majka M, et al. The SDF-1-CXCR4 axis stimulates VEGF secretion and activates integrins but does not affect proliferation and survival in lymphohematopoietic cells. Stem Cells,2001,19:453-66.
[44]Tan CT, Chu CY, Lu YC, et al. CXCL12/CXCR4 promotes laryngeal and hypopharyngeal squamous cell carcinoma metastasis through MMP-13-dependent invasion via the ERK1/2/AP-1 pathway. Carcinogenesis,2008,29:1519-27.
[45]Zhang Y, Wen G, Shao G, et al. TGFBI deficiency predisposes mice to spontaneous tumor development. Cancer Res,2009,69:37-44.
[46]Imam JS, Plyler JR, Bansal H, et al. Genomic loss of tumor suppressor miRNA-204 promotes cancer cell migration and invasion by activating AKT/mTOR/Racl signaling and actin reorganization. PLOS ONE,2012,7:e52397.
[47]Balkwill F. The significance of cancer cell expression of the chemokine receptor CXCR4. Semin Cancer Biol,2004,14:171-9.
[48]Muller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature,2001,410:50-6.
[49]Ohsawa M, Kobayashi T, Okura H, et al. TSC1 controls distribution of actin fibers through its effect on function of Rho family of small GTPases and regulates cell migration and polarity. PLOS ONE,2013,8:e54503.
[50]Madden SL, Cook BP, Nacht M, et al. Vascular gene expression in nonneoplastic and malignant brain. Am J Pathol,2004,165:601-8.
[51]Boimel PJ, Smirnova T, Zhou ZN, et al. Contribution of CXCL12 secretion to invasion of breast cancer cells. Breast Cancer Res,2012,14:R23.
[52]Kollmar O, Rupertus K, Scheuer C, et al. CXCR4 and CXCR7 regulate angiogenesis and CT26.WT tumor growth independent from SDF-1. Int J Cancer,2010,126:1302-15.
[53]Hao M, Zheng J, Hou K, et al. Role of chemokine receptor CXCR7 in bladder cancer progression. Biochem Pharmacol,2012,84:204-14.
[54]Guillemot E, Karimdjee-Soilihi B, Pradelli E, et al. CXCR7 receptors facilitate the progression of colon carcinoma within lung not within liver. Br J Cancer, 2012,107:1944-9.
[2]王启俊,邢秀梅.北京城区居民1982年～1997年癌症发病趋势.中国肿瘤, 2001：14-16.
[3]李新建,沈玉珍,韩阿琴.上海市胰腺癌的流行现状和趋势研究.外科理论与实践,2002：342-345.
[4]陈可欣,李连弟.中国胰腺癌死亡情况报告.中华流行病学杂志,2003：96-98.
[5]Mihaljevic AL, Michalski CW, Friess H, et al. Molecular mechanism of pancreatic cancer--understanding proliferation, invasion, and metastasis. Langenbecks Arch Surg, 2010,395:295-308.
[6]Hidalgo M. Pancreatic cancer. N Engl J Med,2010,362:1605-17.
[7]Sun X, Cheng G, Hao M, et al. CXCL12/CXCR4/CXCR7 chemokine axis and cancer progression. Cancer Metastasis Rev,2010,29:709-22.
[8]Guo JC, Li J, Yang YC, et al. Oligonucleotide microarray identifies genes differentially expressed during tumorigenesis of DMBA-induced pancreatic cancer in rats. PLOS ONE, 2013,8:e82910.
[9]Burns JM, Summers BC, Wang Y, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med, 2006,203:2201-13.
[10]Miao Z, Luker KE, Summers BC, et al. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc Natl Acad Sci U S A,2007,104:15735-40.
[11]Wang J, Shiozawa Y, Wang J, et al. The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J Biol Chem,2008,283:4283-94.
[12]Walters MJ, Ebsworth K, Berahovich RD, et al. Inhibition of CXCR7 extends survival following irradiation of brain tumours in mice and rats. Br J Cancer,2014,110:1179-88.
[13]Burns JM, Summers BC, Wang Y, et al. A novel chemokine receptor for SDF-I and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med, 2006,203:2201-13.
[14]Marechal R, Demetter P, Nagy N, et al. High expression of CXCR4 may predict poor survival in resected pancreatic adenocarcinoma. Br J Cancer,2009,100:1444-51.
[15]Gebauer F, Tachezy M, Effenberger K, et al. Prognostic impact of CXCR4 and CXCR7 expression in pancreatic adenocarcinoma. J Surg Oncol,2011,104:140-5.
[1]Guo JC, Li J, Yang YC, et al. Oligonucleotide Microarray Identifies Genes Differentially Expressed during Tumorigenesis of DMBA-Induced Pancreatic Cancer in Rats. PLOS ONE,2013,8:e82910.
[2]Tan MH, Nowak NJ, Loor R, et al. Characterization of a new primary human pancreatic tumor line. Cancer Invest,1986,4:15-23.
[3]Fogh J, Wright WC, Loveless JD. Absence of HeLa cell contamination in 169 cell lines derived from human tumors. J Natl Cancer Inst,1977,58:209-14.
[4]Tripathi V, Kumar R, Dinda AK, et al. CXCL12-CXCR7 Signaling Activates ERK and Akt Pathways in Human Choriocarcinoma Cells. Cell Commun Adhes,2014.
[5]Schrevel M, Karim R, ter HNT, et al. CXCR7 expression is associated with disease-free and disease-specific survival in cervical cancer patients. Br J Cancer,2012,106:1520-5.
[6]Hao M, Zheng J, Hou K, et al. Role of chemokine receptor CXCR7 in bladder cancer progression. Biochem Pharmacol,2012,84:204-14.
[7]Singh RK, Lokeshwar BL. The IL-8-regulated chemokine receptor CXCR7 stimulates EGFR signaling to promote prostate cancer growth. Cancer Res,2011,71:3268-77.
[1]Kijowski J, Baj-Krzyworzeka M, Majka M, et al. The SDF-1-CXCR4 axis stimulates VEGF secretion and activates integrins but does not affect proliferation and survival in lymphohematopoietic cells. Stem Cells,2001,19:453-66.
[2]Majka M, Ratajczak J, Villaire G, et al. Thrombopoietin, but not cytokines binding to gp130 protein-coupled receptors, activates MAPKp42/44, AKT, and STAT proteins in normal human CD34+cells, megakaryocytes, and platelets. Exp Hematol,2002,30:751-60.
[3]Burns JM, Summers BC, Wang Y, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med, 2006,203:2201-13.
[4]Wang J, Shiozawa Y, Wang J, et al. The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J Biol Chem,2008,283:4283-94.
[5]Boimel PJ, Smirnova T, Zhou ZN, et al. Contribution of CXCL12 secretion to invasion of breast cancer cells. Breast Cancer Res,2012,14:R23.
[6]Burns JM, Summers BC, Wang Y, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med, 2006,203:2201-13.
[7]Iwakiri S, Mino N, Takahashi T, et al. Higher expression of chemokine receptor CXCR7 is linked to early and metastatic recurrence in pathological stage I nonsmall cell lung cancer. Cancer,2009,115:2580-93.
[8]Wang Y, Liu Y, Lu J, et al. Rapamycin inhibits FBXW7 loss-induced epithelial-mesenchymal transition and cancer stem cell-like characteristics in colorectal cancer cells. Biochem Biophys Res Commun,2013,434:352-6.
[9]Tsaur I, Makarevic J, Juengel E, et al. Resistance to the mTOR-inhibitor RAD001 elevates integrin alpha2-and betal-triggered motility, migration and invasion of prostate cancer cells. Br J Cancer,2012,107:847-55.
[10]Lee H, Kim JS, Kim E. Fucoidan from seaweed Fucus vesiculosus inhibits migration and invasion of human lung cancer cell via PI3K-Akt-mTOR pathways. PLOS ONE, 2012,7:e50624.
[1]Rot A, von AUH. Chemokines in innate and adaptive host defense:basic chemokinese grammar for immune cells. Annu Rev Immunol,2004,22:891-928.
[2]Wang J, Shiozawa Y, Wang J, et al. The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J Biol Chem,2008,283:4283-94.
[3]Zhang Y, Wen G, Shao G, et al. TGFBI deficiency predisposes mice to spontaneous tumor development. Cancer Res,2009,69:37-44.
[4]Iwakiri S, Mino N, Takahashi T, et al. Higher expression of chemokine receptor CXCR7 is linked to early and metastatic recurrence in pathological stage I nonsmall cell lung cancer. Cancer,2009,115:2580-93.
[5]Schwarz MK, Wells TN. New therapeutics that modulate chemokine networks. Nat Rev Drug Discov,2002,1:347-58.
[6]Balabanian K, Lagane B, Infantino S, et al. The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem, 2005,280:35760-6.
[7]Balabanian K, Lagane B, Infantino S, et al. The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem, 2005,280:35760-6.
[8]Burns JM, Summers BC, Wang Y, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med, 2006,203:2201-13.
[9]Vandercappellen J, Van Damme J, Struyf S. The role of CXC chemokines and their receptors in cancer. Cancer Lett,2008,267:226-44.
[10]Perlin JR, Talbot WS. Signals on the move:chemokine receptors and organogenesis in zebrafish. Sci STKE,2007,2007:pe45.
[11]Levoye A, Balabanian K, Baleux F, et al. CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling. Blood,2009,113:6085-93.
[12]Mazzinghi B, Ronconi E, Lazzeri E, et al. Essential but differential role for CXCR4 and CXCR7 in the therapeutic homing of human renal progenitor cells. J Exp Med, 2008,205:479-90.
[13]Yates TJ, Knapp J, Gosalbez M, et al. C-X-C chemokine receptor 7:a functionally associated molecular marker for bladder cancer. Cancer,2013,119:61-71.
[14]Harrison SM, Knifley T, Chen M, et al. LPA, HGF, and EGF utilize distinct combinations of signaling pathways to promote migration and invasion of MDA-MB-231 breast carcinoma cells. BMC Cancer,2013,13:501.
[15]Heitman J, Movva NR, Hall MN. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science,1991,253:905-9.
[16]Rutter GA, Da SXG, Leclerc I. Roles of 5'-AMP-activated protein kinase (AMPK) in mammalian glucose homoeostasis. Biochem J,2003,375:1-16.
[17]Wang Y, Liu Y, Lu J, et al. Rapamycin inhibits FBXW7 loss-induced epithelial-mesenchymal transition and cancer stem cell-like characteristics in colorectal cancer cells. Biochem Biophys Res Commun,2013,434:352-6.
[18]Tsaur I, Makarevic J, Juengel E, et al. Resistance to the mTOR-inhibitor RAD001 elevates integrin alpha2- and betal-triggered motility, migration and invasion of prostate cancer cells. Br J Cancer,2012,107:847-55.
[19]Lee H, Kim JS, Kim E. Fucoidan from seaweed Fucus vesiculosus inhibits migration and invasion of human lung cancer cell via PI3K-Akt-mTOR pathways. PLOS ONE, 2012,7:e50624.
[20]Ohsawa M, Kobayashi T, Okura H, et al. TSC1 controls distribution of actin fibers through its effect on function of Rho family of small GTPases and regulates cell migration and polarity. PLOS ONE,2013,8:e54503.
[21]Imam JS, Plyler JR, Bansal H, et al. Genomic loss of tumor suppressor miRNA-204 promotes cancer cell migration and invasion by activating AKT/mTOR/Racl signaling and actin reorganization. PLOS ONE,2012,7:e52397.
[22]Muller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature,2001,410:50-6.
[23]Burns JM, Summers BC, Wang Y, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med, 2006,203:2201-13.
[24]Madden SL, Cook BP, Nacht M, et al. Vascular gene expression in nonneoplastic and malignant brain. Am J Pathol,2004,165:601-8.
[25]Miao Z, Luker KE, Summers BC, et al. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc Natl Acad Sci U S A,2007,104:15735-40.
[1]Rygaard J, Povlsen CO. Heterotransplantation of a human malignant tumour to "Nude" mice. Acta Pathol Microbiol Scand,1969,77:758-60.
[2]Miao Z, Luker KE, Summers BC, et al. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc Natl Acad Sci U S A,2007,104:15735-40.
[3]Wang J, Shiozawa Y, Wang J, et al. The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J Biol Chem,2008,283:4283-94.
[4]Raggo C, Ruhl R, McAllister S, et al. Novel cellular genes essential for transformation of endothelial cells by Kaposi's sarcoma-associated herpesvirus. Cancer Res, 2005,65:5084-95.
[5]Burns JM, Summers BC, Wang Y, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med, 2006,203:2201-13.
[6]Meijer J, Ogink J, Roos E. Effect of the chemokine receptor CXCR7 on proliferation of carcinoma cells in vitro and in vivo. Br J Cancer,2008,99:1493-501.
[1]Marechal R, Demetter P, Nagy N, et al. High expression of CXCR4 may predict poor survival in resected pancreatic adenocarcinoma. Br J Cancer,2009,100:1444-51.
[2]Miao Z, Luker KE, Summers BC, et al. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc Natl Acad Sci U S A,2007,104:15735-40.
[3]Maishi N, Ohga N, Hida Y, et al. CXCR7:a novel tumor endothelial marker in renal cell carcinoma. Pathol Int,2012,62:309-17.
[4]Wang J, Shiozawa Y, Wang J, et al. The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J Biol Chem,2008,283:4283-94.
[5]Iwakiri S, Mino N, Takahashi T, et al. Higher expression of chemokine receptor CXCR7 is linked to early and metastatic recurrence in pathological stage I nonsmall cell lung cancer. Cancer,2009,115:2580-93.
[6]Schrevel M, Karim R, ter HNT, et al. CXCR7 expression is associated with disease-free and disease-specific survival in cervical cancer patients. Br J Cancer,2012,106:1520-5.
[7]Gelmini S, Mangoni M, Castiglione F, et al. The CXCR4/CXCL12 axis in endometrial cancer. Clin Exp Metastasis,2009,26:261-8.
[8]Marechal R, Demetter P, Nagy N, et al. High expression of CXCR4 may predict poor survival in resected pancreatic adenocarcinoma. Br J Cancer,2009,100:1444-51.
[9]Gebauer F, Tachezy M, Effenberger K, et al. Prognostic impact of CXCR4 and CXCR7 expression in pancreatic adenocarcinoma. J Surg Oncol,2011,104:140-5.
[10]Balkwill F. The significance of cancer cell expression of the chemokine receptor CXCR4. Semin Cancer Biol,2004,14:171-9.
[11]Oliveira FV, Rubie C, Ghadjar P, et al. Changes in CXCL12/CXCR4-chemokine expression during onset of colorectal malignancies. Tumour Biol,2011,32:189-96.
[12]Wang L, Chen W, Gao L, et al. High expression of CXCR4, CXCR7 and SDF-1 predicts poor survival in renal cell carcinoma. World J Surg Oncol,2012,10:212.
[13]Liang JJ, Zhu S, Bruggeman R, et al. High levels of expression of human stromal cell-derived factor-1 are associated with worse prognosis in patients with stage Ⅱ pancreatic ductal adenocarcinoma. Cancer Epidemiol Biomarkers Prev,2010,19:2598-604.
[14]Ying J, Xu Q, Zhang G, et al. The expression of CXCL12 and CXCR4 in gastric cancer and their correlation to lymph node metastasis. Med Oncol,2012,29:1716-22.
[15]Wagner PL, Hyjek E, Vazquez MF, et al. CXCL12 and CXCR4 in adenocarcinoma of the lung:association with metastasis and survival. J Thorac Cardiovasc Surg, 2009,137:615-21.
[16]Guo L, Cui ZM, Zhang J, et al. Chemokine axes CXCL12/CXCR4 and CXCL16/CXCR6 correlate with lymph node metastasis in epithelial ovarian carcinoma. Chin J Cancer, 2011,30:336-43.
[17]Wang DF, Lou N, Zeng CG, et al. Expression of CXCL12/CXCR4 and its correlation to prognosis in esophageal squamous cell carcinoma. Ai Zheng,2009,28:154-8.
[18]Sasaki K, Natsugoe S, Ishigami S, et al. Expression of CXCL12 and its receptor CXCR4 in esophageal squamous cell carcinoma. Oncol Rep,2009,21:65-71.
[19]Kim JH, Lee JY, Lee KT, et al. RGS16 and FosB underexpressed in pancreatic cancer with lymph node metastasis promote tumor progression. Tumour Biol,2010,31:541-8.
[20]Liang JJ, Zhu S, Bruggeman R, et al. High levels of expression of human stromal cell-derived factor-1 are associated with worse prognosis in patients with stage Ⅱ pancreatic ductal adenocarcinoma. Cancer Epidemiol Biomarkers Prev,2010,19:2598-604.
[21]王铮,徐勤鸿,李徐奇,等.CXCL12/CXCR4轴在胰腺癌-神经交互作用中的研究.西安交通大学学报(医学版),2012：214-219.
[1]Rot A, von AUH. Chemokines in innate and adaptive host defense:basic chemokinese grammar for immune cells. Annu Rev Immunol,2004,22:891-928.
[2]Zlotnik A, Yoshie O. Chemokines:a new classification system and their role in immunity. Immunity,2000,12:121-7.
[3]Schwarz MK, Wells TN. New therapeutics that modulate chemokine networks. Nat Rev Drug Discov,2002,1:347-58.
[4]Balabanian K, Lagane B, Infantino S, et al. The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem, 2005,280:35760-6.
[5]Ma Q, Jones D, Springer TA. The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity,1999,10:463-71.
[6]Egawa T, Kawabata K, Kawamoto H, et al. The earliest stages of B cell development require a chemokine stromal cell-derived factor/pre-B cell growth-stimulating factor. Immunity,2001,15:323-34.
[7]Balabanian K, Lagane B, Infantino S, et al. The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem, 2005,280:35760-6.
[8]Burns JM, Summers BC, Wang Y, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med, 2006,203:2201-13.
[9]Vandercappellen J, Van Damme J, Struyf S. The role of CXC chemokines and their receptors in cancer. Cancer Lett,2008,267:226-44.
[10]Perlin JR, Talbot WS. Signals on the move:chemokine receptors and organogenesis in zebrafish. Sci STKE,2007,2007:pe45.
[11]Levoye A, Balabanian K, Baleux F, et al. CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling. Blood,2009,113:6085-93.
[12]Mazzinghi B, Ronconi E, Lazzeri E, et al. Essential but differential role for CXCR4 and CXCR7 in the therapeutic homing of human renal progenitor cells. J Exp Med, 2008,205:479-90.
[13]Yates TJ, Knapp J, Gosalbez M, et al. C-X-C chemokine receptor 7:a functionally associated molecular marker for bladder cancer. Cancer,2013,119:61-71.
[14]Miao Z, Luker KE, Summers BC, et al. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc Natl Acad Sci U S A,2007,104:15735-40.
[15]Maishi N, Ohga N, Hida Y, et al. CXCR7:a novel tumor endothelial marker in renal cell carcinoma. Pathol Int,2012,62:309-17.
[16]Wang J, Shiozawa Y, Wang J, et al. The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J Biol Chem,2008,283:4283-94.
[17]Iwakiri S, Mino N, Takahashi T, et al. Higher expression of chemokine receptor CXCR7 is linked to early and metastatic recurrence in pathological stage I nonsmall cell lung cancer. Cancer,2009,115:2580-93.
[18]Schrevel M, Karim R, ter HNT, et al. CXCR7 expression is associated with disease-free and disease-specific survival in cervical cancer patients. Br J Cancer,2012,106:1520-5.
[19]Gelmini S, Mangoni M, Castiglione F, et al. The CXCR4/CXCL12 axis in endometrial cancer. Clin Exp Metastasis,2009,26:261-8.
[20]Marechal R, Demetter P, Nagy N, et al. High expression of CXCR4 may predict poor survival in resected pancreatic adenocarcinoma. Br J Cancer,2009,100:1444-51.
[21]Gebauer F, Tachezy M, Effenberger K, et al. Prognostic impact of CXCR4 and CXCR7 expression in pancreatic adenocarcinoma. J Surg Oncol,2011,104:140-5.
[22]Balkwill F. The significance of cancer cell expression of the chemokine receptor CXCR4. Semin Cancer Biol,2004,14:171-9.
[23]Oliveira FV, Rubie C, Ghadjar P, et al. Changes in CXCL12/CXCR4-chemokine expression during onset of colorectal malignancies. Tumour Biol,2011,32:189-96.
[24]Wang L, Chen W, Gao L, et al. High expression of CXCR4, CXCR7 and SDF-1 predicts poor survival in renal cell carcinoma. World J Surg Oncol,2012,10:212.
[25]Liang JJ, Zhu S, Bruggeman R, et al. High levels of expression of human stromal cell-derived factor-1 are associated with worse prognosis in patients with stage Ⅱ pancreatic ductal adenocarcinoma. Cancer Epidemiol Biomarkers Prev,2010,19:2598-604.
[26]Ying J, Xu Q, Zhang G, et al. The expression of CXCL12 and CXCR4 in gastric cancer and their correlation to lymph node metastasis. Med Oncol,2012,29:1716-22.
[27]Wagner PL, Hyjek E, Vazquez MF, et al. CXCL12 and CXCR4 in adenocarcinoma of the lung:association with metastasis and survival. J Thorac Cardiovasc Surg, 2009,137:615-21.
[28]Guo L, Cui ZM, Zhang J, et al. Chemokine axes CXCL12/CXCR4 and CXCL16/CXCR6 correlate with lymph node metastasis in epithelial ovarian carcinoma. Chin J Cancer, 2011,30:336-43.
[29]Wang DF, Lou N, Zeng CG, et al. Expression of CXCL12/CXCR4 and its correlation to prognosis in esophageal squamous cell carcinoma. Ai Zheng,2009,28:154-8.
[30]Sasaki K, Natsugoe S, Ishigami S, et al. Expression of CXCL12 and its receptor CXCR4 in esophageal squamous cell carcinoma. Oncol Rep,2009,21:65-71.
[31]Kim JH, Lee JY, Lee KT, et al. RGS16 and FosB underexpressed in pancreatic cancer with lymph node metastasis promote tumor progression. Tumour Biol,2010,31:541-8.
[32]Liang JJ, Zhu S, Bruggeman R, et al. High levels of expression of human stromal cell-derived factor-1 are associated with worse prognosis in patients with stage II pancreatic ductal adenocarcinoma. Cancer Epidemiol Biomarkers Prev,2010,19:2598-604.
[33]Kijowski J, Baj-Krzyworzeka M, Majka M, et al. The SDF-1-CXCR4 axis stimulates VEGF secretion and activates integrins but does not affect proliferation and survival in lymphohematopoietic cells. Stem Cells,2001,19:453-66.
[34]Majka M, Ratajczak J, Villaire G, et al. Thrombopoietin, but not cytokines binding to gp130 protein-coupled receptors, activates MAPKp42/44, AKT, and STAT proteins in normal human CD34+ cells, megakaryocytes, and platelets. Exp Hematol,2002,30:751-60.
[35]Burns JM, Summers BC, Wang Y, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med, 2006,203:2201-13.
[36]Raggo C, Ruhl R, McAllister S, et al. Novel cellular genes essential for transformation of endothelial cells by Kaposi's sarcoma-associated herpesvirus. Cancer Res, 2005,65:5084-95.
[37]Meijer J, Ogink J, Roos E. Effect of the chemokine receptor CXCR7 on proliferation of carcinoma cells in vitro and in vivo. Br J Cancer,2008,99:1493-501.
[38]Kollmar O, Rupertus K, Scheuer C, et al. Stromal cell-derived factor-1 promotes cell migration and tumor growth of colorectal metastasis. Neoplasia,2007,9:862-70.
[39]Orimo A, Gupta PB, Sgroi DC, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell,2005,121:335-48.
[40]Dewan MZ, Ahmed S, Iwasaki Y, et al. Stromal cell-derived factor-1 and CXCR4 receptor interaction in tumor growth and metastasis of breast cancer. Biomed Pharmacother, 2006,60:273-6.
[41]Rupertus K, Sinistra J, Scheuer C, et al. Interaction of the chemokines I-TAC (CXCL11) and SDF-1 (CXCL12) in the regulation of tumor angiogenesis of colorectal cancer. Clin Exp Metastasis,2014.
[42]迟啸威,侯静波,于波CXCL12过表达促进骨髓基质干细胞整合素αv/β3介导的黏附和增殖.中国生物工程杂志,2008,28：32-36.
[43]Kijowski J, Baj-Krzyworzeka M, Majka M, et al. The SDF-1-CXCR4 axis stimulates VEGF secretion and activates integrins but does not affect proliferation and survival in lymphohematopoietic cells. Stem Cells,2001,19:453-66.
[44]Tan CT, Chu CY, Lu YC, et al. CXCL12/CXCR4 promotes laryngeal and hypopharyngeal squamous cell carcinoma metastasis through MMP-13-dependent invasion via the ERK1/2/AP-1 pathway. Carcinogenesis,2008,29:1519-27.
[45]Zhang Y, Wen G, Shao G, et al. TGFBI deficiency predisposes mice to spontaneous tumor development. Cancer Res,2009,69:37-44.
[46]Imam JS, Plyler JR, Bansal H, et al. Genomic loss of tumor suppressor miRNA-204 promotes cancer cell migration and invasion by activating AKT/mTOR/Racl signaling and actin reorganization. PLOS ONE,2012,7:e52397.
[47]Balkwill F. The significance of cancer cell expression of the chemokine receptor CXCR4. Semin Cancer Biol,2004,14:171-9.
[48]Muller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature,2001,410:50-6.
[49]Ohsawa M, Kobayashi T, Okura H, et al. TSC1 controls distribution of actin fibers through its effect on function of Rho family of small GTPases and regulates cell migration and polarity. PLOS ONE,2013,8:e54503.
[50]Madden SL, Cook BP, Nacht M, et al. Vascular gene expression in nonneoplastic and malignant brain. Am J Pathol,2004,165:601-8.
[51]Boimel PJ, Smirnova T, Zhou ZN, et al. Contribution of CXCL12 secretion to invasion of breast cancer cells. Breast Cancer Res,2012,14:R23.
[52]Kollmar O, Rupertus K, Scheuer C, et al. CXCR4 and CXCR7 regulate angiogenesis and CT26.WT tumor growth independent from SDF-1. Int J Cancer,2010,126:1302-15.
[53]Hao M, Zheng J, Hou K, et al. Role of chemokine receptor CXCR7 in bladder cancer progression. Biochem Pharmacol,2012,84:204-14.
[54]Guillemot E, Karimdjee-Soilihi B, Pradelli E, et al. CXCR7 receptors facilitate the progression of colon carcinoma within lung not within liver. Br J Cancer, 2012,107:1944-9.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |