生长抑素联合血管生长抑素基因治疗人胰腺癌的实验研究
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摘要
目的研究生长抑素联合血管生长抑素基因治疗人胰腺癌的作用,观察二者联合应用是否有协同增强效应。
方法重组pcDNA3/anglo质粒转染人胰腺癌BXPC—3细胞,利用RT—PCR和Western Blot检测血管生长抑素表达及分泌情况,MTT法和流式细胞仪分别检测生长抑素和血管生长抑素对BXPC—3细胞和血管内皮细胞ECV—304增殖的影响。建立裸鼠移植瘤模型,观察生长抑素和血管生长抑素基因影响肿瘤生长情况,免疫组化检测各组血管内皮生长因子(VEGF)表达情况和微血管密度(MVD)差异,透射电镜检测肿瘤细胞凋亡情况。
结果血管生长抑素对血管内皮细胞ECV—304的增殖有明显抑制作用,并能诱导其凋亡;一定浓度(≥10ug/ml)生长抑素类似物思他宁对人胰腺癌细胞BXPC—3有抗增殖作用,并呈剂量依赖性。生长抑素和血管生长抑素均能降低肿瘤细胞VEGF表达,减少肿瘤微血管的生成;抗胰腺癌细胞增殖,并能促进其凋亡、坏死,有效抑制人胰腺癌裸鼠移植瘤的生长。以重组pcDNA3/angio质粒+思他宁组效果最明显。
结论(1)生长抑素主要通过抗胰腺癌细胞增殖,促进其凋亡坏死和减少肿瘤血供发挥作用。(2)血管生长抑素主要通过特异性抑制胰腺癌血管内皮细胞的增殖并诱导其凋亡,而发挥抗胰腺癌血管生成的作用。在血管生成过程中,血管生长抑素调节着血管内皮细胞的增殖和迁移。(3)体内转染血管生长抑素基因并联合应用生长抑素能更显著抑制人胰腺癌裸鼠移植瘤的血管生长和瘤体生长,抗胰腺癌的作用更为显著,有协同增强效应。
Objective To investigate the effect of somastatin combined with angiostatin genc to inhibit human pancreatic cancinoma cell proliferation and to induce apoptosis in vitro and in vivo.
Methods The pcDNA3/angio was transfected into human BXPC-3 pancreatic cancer cell by liposome-mediated gene transfer method.RT-PCR and Western blot were used to detect the expression of angiostatin gene.Method:In vitro,MIT and flow cytometry(FCM)were used to detect whether somastatin combined with angiostatin can effect inhibit the growth of BXPC-3 and ECV-304 cells.Xengraft human pancreatic cancer models were established through BXPC-3 cells subcutaneously,in nude mice They received injection of pcDNA3,pcDNA3/angio, somastatin more injection into the tumor.We observed the growth of tumor and measured the volume of xenografts.The VEGF and MVD expression were detected by immunohistochemistry.The apoptosis of pancreatic cancer cell more detected by transmission electron microscope.
Result A 700bp specific base pair was obtained by RT-PCR.The expression of angiostatin protein was confirmed by Western blot.In vitro,the result of MIT and FCM showed that somastatin(≥10ug/ml)can inhibit the growth of BXPC-3 and induce apoptosis.But it can't inhibit the growth of ECV-304.It was confirmed that angiostatin can inhibit the growth of ECV-304 and induce apoptosis by MTI、FCM detection.But angiostatin can't inhibit the growth of BXPC -3.In vivo,somastatin and angiostatin can inhibit the growth of human pancreatic cancer.They can inhibit the production of new blood vessel in human pancreatic cancer.They decrease the expression of VEGF and induce the apoptosis of human pancreatic cancer cell.
Conclusion:(1).Somastain can directly inhibit the proliferation of human pancreatic cancer cells and induce apoptosis.They can't directly inhibit angiogenesiso of human pancreatic cancer.(2).Angiostatin can specially inhibit the proliferation of ECV-304 and induce apoptosis.It can inhibit angiogenesis of human pancreatic cancer. (3).Somastatin combined with angiostatin gene have coe-synergistic effect of anti-angiogenesis and inhibiting the proliferation of human pancreatic cancer.
方法重组pcDNA3/anglo质粒转染人胰腺癌BXPC—3细胞,利用RT—PCR和Western Blot检测血管生长抑素表达及分泌情况,MTT法和流式细胞仪分别检测生长抑素和血管生长抑素对BXPC—3细胞和血管内皮细胞ECV—304增殖的影响。建立裸鼠移植瘤模型,观察生长抑素和血管生长抑素基因影响肿瘤生长情况,免疫组化检测各组血管内皮生长因子(VEGF)表达情况和微血管密度(MVD)差异,透射电镜检测肿瘤细胞凋亡情况。
结果血管生长抑素对血管内皮细胞ECV—304的增殖有明显抑制作用,并能诱导其凋亡;一定浓度(≥10ug/ml)生长抑素类似物思他宁对人胰腺癌细胞BXPC—3有抗增殖作用,并呈剂量依赖性。生长抑素和血管生长抑素均能降低肿瘤细胞VEGF表达,减少肿瘤微血管的生成;抗胰腺癌细胞增殖,并能促进其凋亡、坏死,有效抑制人胰腺癌裸鼠移植瘤的生长。以重组pcDNA3/angio质粒+思他宁组效果最明显。
结论(1)生长抑素主要通过抗胰腺癌细胞增殖,促进其凋亡坏死和减少肿瘤血供发挥作用。(2)血管生长抑素主要通过特异性抑制胰腺癌血管内皮细胞的增殖并诱导其凋亡,而发挥抗胰腺癌血管生成的作用。在血管生成过程中,血管生长抑素调节着血管内皮细胞的增殖和迁移。(3)体内转染血管生长抑素基因并联合应用生长抑素能更显著抑制人胰腺癌裸鼠移植瘤的血管生长和瘤体生长,抗胰腺癌的作用更为显著,有协同增强效应。
Objective To investigate the effect of somastatin combined with angiostatin genc to inhibit human pancreatic cancinoma cell proliferation and to induce apoptosis in vitro and in vivo.
Methods The pcDNA3/angio was transfected into human BXPC-3 pancreatic cancer cell by liposome-mediated gene transfer method.RT-PCR and Western blot were used to detect the expression of angiostatin gene.Method:In vitro,MIT and flow cytometry(FCM)were used to detect whether somastatin combined with angiostatin can effect inhibit the growth of BXPC-3 and ECV-304 cells.Xengraft human pancreatic cancer models were established through BXPC-3 cells subcutaneously,in nude mice They received injection of pcDNA3,pcDNA3/angio, somastatin more injection into the tumor.We observed the growth of tumor and measured the volume of xenografts.The VEGF and MVD expression were detected by immunohistochemistry.The apoptosis of pancreatic cancer cell more detected by transmission electron microscope.
Result A 700bp specific base pair was obtained by RT-PCR.The expression of angiostatin protein was confirmed by Western blot.In vitro,the result of MIT and FCM showed that somastatin(≥10ug/ml)can inhibit the growth of BXPC-3 and induce apoptosis.But it can't inhibit the growth of ECV-304.It was confirmed that angiostatin can inhibit the growth of ECV-304 and induce apoptosis by MTI、FCM detection.But angiostatin can't inhibit the growth of BXPC -3.In vivo,somastatin and angiostatin can inhibit the growth of human pancreatic cancer.They can inhibit the production of new blood vessel in human pancreatic cancer.They decrease the expression of VEGF and induce the apoptosis of human pancreatic cancer cell.
Conclusion:(1).Somastain can directly inhibit the proliferation of human pancreatic cancer cells and induce apoptosis.They can't directly inhibit angiogenesiso of human pancreatic cancer.(2).Angiostatin can specially inhibit the proliferation of ECV-304 and induce apoptosis.It can inhibit angiogenesis of human pancreatic cancer. (3).Somastatin combined with angiostatin gene have coe-synergistic effect of anti-angiogenesis and inhibiting the proliferation of human pancreatic cancer.
引文
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