Angiostatin Gene Combined with Somatostatin in Growth Inhibition of Human Pancreatic Cancer in Vitro_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHU Hong ¹ , GUO Yongzhang ² , YANG Hongwei ¹ , ZOU Hao ¹ , WANG Kun ¹ , HUANG Songquan ¹

1.Department of Hepatobiliary Surgery Ⅱ， The Second Affiliated Hospital of Kunming Medical College, Kunming 650101， China;;
2.Kunming Medical College, Kunming 650031, China;

Corresponding author：

Keywords：

Somatostatin; Angiostatin; Pancreatic cancer; Gene therapy

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Objective To investigate the effect of angiostatin gene combined with somastatin on inhibiting proliferation of human pancreatic cancer cell BXPC-3 and endothelial cell of vascular ECV-304 and on inducing their apoptosis in vitro. Methods The pcDNA3/angio was transfected BXPC-3 by liposome-mediated gene transfer method. RT-PCR and Western blot were used to detect the expression of angiostatin gene. In vitro, MTT and flow cytometry (FCM) were used to detect whether angiostatin gene combined with somastatin could effect the growth inhibition of BXPC-3 and ECV-304 cells. Results Angiostatin was expressed and secreted by transfected BXPC-3. The growth of BXPC-3 was inhibited by certain concentration of somatostatin (≥10 μg/ml, P＜0.01）, which was dependent on the dose of somatostatin in a concentration extent; Simultaneity apoptosis was induced （P＜0.01）. But the growth of ECV-304 was not inhibited with somatostation （P gt;0.05）. Angiostatin could inhibit the growth of ECV-304 and induced apoptosis （P＜0.01）, but it had no effect on the growth of BXPC-3 （P gt;0.05）. Angiostation gene combined with somatostation could inhibit the growth both of BXPC-3 and ECV-304 （P＜0.01）, and induce apoptosis of them （P＜0.01）; but the effect couldn’t be additived. Conclusions ①Somatostatin directly inhibits the proliferation of human pancreatic cancer cells and induces apoptosis, but it doesn’t directly inhibit angiogenesiso of human pancreatic cancer. ②Angiostatin specially inhibits the proliferation of endothelial cell of vascular and induces apoptosis. Angiostatin could inhibit angiogenesis of human pancreatic cancer to induce necrosis of cancer cell.

Citation： ZHU Hong,GUO Yongzhang,YANG Hongwei,ZOU Hao,WANG Kun,HUANG Songquan. Angiostatin Gene Combined with Somatostatin in Growth Inhibition of Human Pancreatic Cancer in Vitro. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2009, 16(6): 460-465. doi: Copy

1.	Chi SL, Pizzo SV. Angiostatin is directly cytotoxic to tumor cells at low extracellular pH: a mechanism dependent on cell surface-associated ATP synthase[Ｊ]. Cancer Res, 2006; 66(2): 875-882.
2.	张延龄. 胰腺癌的基因治疗研究 [Ｊ]. 临床外科杂志, 2004; 12(4): 242-243.
3.	Tirone TA, Wang XP, Templeton NS, et al. Cell-specific cytotoxicity of human pancreatic adenocarcinoma cells using rat insulin promoter thymidine kinase-directed gene therapy [Ｊ]. World J Surg, 2004; 28(8): 826-833.
4.	Mkinen K, Loimas S, Wahlfors J, et al. Evaluation of herpes simplex thymidine kinase mediated gene therapy in experimental pancreatic cancer [Ｊ]. J Gene Med, 2000; 2(5): 361-367.
5.	Carrió M, Visa J, Cascante A, et al. Intratumoral activation of cyclophosphamide by retroviral transfer of the cytochrome P450 2B1 in a pancreatic tumor model. Combination with the HSVtk/GCV system [Ｊ]. J Gene Med, 2002; 4(2):141-149.
6.	Shen GH, Ghazizadeh M, Kawanami O, et al. Prognostic significance of vascular endothelial growth factor expression in human ovarian carcinoma[Ｊ]. Br J Cancer, 2000; 83(2):196-203.
7.	Ikeda N, Nakajima Y, Sho M, et al. The association of K-ras gene mutation and vascular endothelial growth factor gene expression in pancreatic carcinoma[Ｊ]. Cancer, 2001; 92(3): 488-499.
8.	李继坤，郑淼，李远芳，等. p53及VEGF表达与结、直肠癌血道转移发生的关系 [Ｊ]. 中国普外基础与临床杂志， 2002； 9（2）： 112-114.
9.	Benjamin LE, Keshet E. Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal [Ｊ]. Proc Natl Acad Sci USA, 1997; 94(16): 8761-8766.
10.	Gourley M, Williamson JS. Angiogenesis: new targets for the development of anticancer chemotherapies [Ｊ]. Curr Pharm Des, 2000; 6(4): 417-439.
11.	Niedergethmann M, Hildenbrand R, Wostbrock B, et al. High expression of vascular endothelial growth factor predicts early recurrence and poor prognosis after curative resection for ductal adenocarcinoma of the pancreas [Ｊ]. Pancreas, 2002; 25(2): 122-129.
12.	刘江伟，李开宗，窦科峰. 环氧化酶-2和血管内皮生长因子在胰腺癌组织中的表达及其相关性研究 [Ｊ]. 中国普外基础与临床杂志, 2003; 10（6）: 539-541.
13.	Galaup A, Opolon P, Bouquet C, et al. Combined effects of docetaxel and angiostatin gene therapy in prostate tumor model [Ｊ]. Mol Ther, 2003; 7(6): 731-740.
14.	何长生，全竹富. 生长抑素抗肿瘤机制及其对胰腺癌的治疗展望 [Ｊ]. 肠外与肠内营养， 2006; 13(6): 373-376.
15.	Kouroumalis E, Skordilis P, Thermos K, et al. Treatment of hepatocellular carcinoma with octreotide: a randomised controlled study[Ｊ]. Gut, 1998; 42(3): 442-447.
16.	Casini Raggi C, Calabrò A, Renzi D, et al. Quantitative evaluation of somatostatin receptor subtype 2 expression in sporadic colorectal tumor and in the corresponding normal mucosa [Ｊ]. Clin Cancer Res, 2002; 8(2): 419-427.
17.	华赟鹏，赖佳明，梁力建，等. 奥曲肽下调cMet的表达抑制肝细胞癌的生长 [Ｊ]. 中国普外基础与临床杂志, 2006; 13（2）: 158-162.
18.	张燕玲，张正. 生长抑素类似物对肝癌细胞凋亡及c-myc蛋白表达的影响 [Ｊ]. 中国普外基础与临床杂志, 2003; 10（1）： 25-27.
19.	Radulovic S, Comaru-Schally AM, Milovanovic S, et al. Somatostatin analogue RC-160 and LH-RH antagonist SB-75 inhibit growth of MIA PaCa-2 human pancreatic cancer xenografts in nude mice [Ｊ]. Pancreas， 1993; 8(1): 88-97.
20.	刘正人，吴高松，杜志勇，等. 奥曲肽对胰腺癌细胞转染SSTR2后的作用 [Ｊ]. 中国普通外科杂志， 2004； 13(6)： 424-427.
21.	Patel YC, Panetta R, Escher E, et al. Expression of multiple somatostatin receptor genes in AtT-20 cells. Evidence for a novel somatostatin-28 selective receptor subtype [Ｊ]. J Biol Chem， 1994; 269(2): 1506-1509.
22.	张浩, 李昱骥, 周建平, 等. 表皮生长因子促进胰腺癌细胞侵袭和转移的实验研究 [Ｊ]. 中国普外基础与临床杂志, 2008; 15(3): 180-184.
23.	张群华，倪泉兴，沈兆中，等. 生长抑素对胰腺癌生长抑制和凋亡作用的实验研究 [Ｊ]. 外科理论与实践， 2002； 7（5）：352-355.
24.	Zalatnai A, Szegedi Z, Bocsi J. Flow cytometric evidence of apoptosis in human pancreatic cancer xenografts treated with Sandostatin (octreotide) [Ｊ]. Anticancer Res， 2000; 20(3A): 1663-1666.
25.	Qin RY, Fang RL, Gupta MK, et al. Alteration of somatostatin receptor subtype 2 gene expression in pancreatic tumor angiogenesis [Ｊ]. World J Gastroenterol， 2004; 10(1): 132-135.
26.	Kumar M, Liu ZR, Thapa L, et al. Antiangiogenic effect of somatostatin receptor subtype 2 on pancreatic cancer cell line: Inhibition of vascular endothelial growth factor and matrix metalloproteinase-2 expression in vitro [Ｊ]. World J Gastroenterol， 2004; 10(3): 393-399.
27.	Ren SG, Ezzat S, Melmed S, et al. Somatostatin analog induces insulin-like growth factor binding protein-1 (IGFBP-1) expression in human hepatoma cells [Ｊ]. Endocrinology, 1992; 131(5): 2479-2481.

1. Chi SL, Pizzo SV. Angiostatin is directly cytotoxic to tumor cells at low extracellular pH: a mechanism dependent on cell surface-associated ATP synthase[Ｊ]. Cancer Res, 2006; 66(2): 875-882.
2. 张延龄. 胰腺癌的基因治疗研究 [Ｊ]. 临床外科杂志, 2004; 12(4): 242-243.
3. Tirone TA, Wang XP, Templeton NS, et al. Cell-specific cytotoxicity of human pancreatic adenocarcinoma cells using rat insulin promoter thymidine kinase-directed gene therapy [Ｊ]. World J Surg, 2004; 28(8): 826-833.
4. Mkinen K, Loimas S, Wahlfors J, et al. Evaluation of herpes simplex thymidine kinase mediated gene therapy in experimental pancreatic cancer [Ｊ]. J Gene Med, 2000; 2(5): 361-367.
5. Carrió M, Visa J, Cascante A, et al. Intratumoral activation of cyclophosphamide by retroviral transfer of the cytochrome P450 2B1 in a pancreatic tumor model. Combination with the HSVtk/GCV system [Ｊ]. J Gene Med, 2002; 4(2):141-149.
6. Shen GH, Ghazizadeh M, Kawanami O, et al. Prognostic significance of vascular endothelial growth factor expression in human ovarian carcinoma[Ｊ]. Br J Cancer, 2000; 83(2):196-203.
7. Ikeda N, Nakajima Y, Sho M, et al. The association of K-ras gene mutation and vascular endothelial growth factor gene expression in pancreatic carcinoma[Ｊ]. Cancer, 2001; 92(3): 488-499.
8. 李继坤，郑淼，李远芳，等. p53及VEGF表达与结、直肠癌血道转移发生的关系 [Ｊ]. 中国普外基础与临床杂志， 2002； 9（2）： 112-114.
9. Benjamin LE, Keshet E. Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal [Ｊ]. Proc Natl Acad Sci USA, 1997; 94(16): 8761-8766.
10. Gourley M, Williamson JS. Angiogenesis: new targets for the development of anticancer chemotherapies [Ｊ]. Curr Pharm Des, 2000; 6(4): 417-439.
11. Niedergethmann M, Hildenbrand R, Wostbrock B, et al. High expression of vascular endothelial growth factor predicts early recurrence and poor prognosis after curative resection for ductal adenocarcinoma of the pancreas [Ｊ]. Pancreas, 2002; 25(2): 122-129.
12. 刘江伟，李开宗，窦科峰. 环氧化酶-2和血管内皮生长因子在胰腺癌组织中的表达及其相关性研究 [Ｊ]. 中国普外基础与临床杂志, 2003; 10（6）: 539-541.
13. Galaup A, Opolon P, Bouquet C, et al. Combined effects of docetaxel and angiostatin gene therapy in prostate tumor model [Ｊ]. Mol Ther, 2003; 7(6): 731-740.
14. 何长生，全竹富. 生长抑素抗肿瘤机制及其对胰腺癌的治疗展望 [Ｊ]. 肠外与肠内营养， 2006; 13(6): 373-376.
15. Kouroumalis E, Skordilis P, Thermos K, et al. Treatment of hepatocellular carcinoma with octreotide: a randomised controlled study[Ｊ]. Gut, 1998; 42(3): 442-447.
16. Casini Raggi C, Calabrò A, Renzi D, et al. Quantitative evaluation of somatostatin receptor subtype 2 expression in sporadic colorectal tumor and in the corresponding normal mucosa [Ｊ]. Clin Cancer Res, 2002; 8(2): 419-427.
17. 华赟鹏，赖佳明，梁力建，等. 奥曲肽下调cMet的表达抑制肝细胞癌的生长 [Ｊ]. 中国普外基础与临床杂志, 2006; 13（2）: 158-162.
18. 张燕玲，张正. 生长抑素类似物对肝癌细胞凋亡及c-myc蛋白表达的影响 [Ｊ]. 中国普外基础与临床杂志, 2003; 10（1）： 25-27.
19. Radulovic S, Comaru-Schally AM, Milovanovic S, et al. Somatostatin analogue RC-160 and LH-RH antagonist SB-75 inhibit growth of MIA PaCa-2 human pancreatic cancer xenografts in nude mice [Ｊ]. Pancreas， 1993; 8(1): 88-97.
20. 刘正人，吴高松，杜志勇，等. 奥曲肽对胰腺癌细胞转染SSTR2后的作用 [Ｊ]. 中国普通外科杂志， 2004； 13(6)： 424-427.
21. Patel YC, Panetta R, Escher E, et al. Expression of multiple somatostatin receptor genes in AtT-20 cells. Evidence for a novel somatostatin-28 selective receptor subtype [Ｊ]. J Biol Chem， 1994; 269(2): 1506-1509.
22. 张浩, 李昱骥, 周建平, 等. 表皮生长因子促进胰腺癌细胞侵袭和转移的实验研究 [Ｊ]. 中国普外基础与临床杂志, 2008; 15(3): 180-184.
23. 张群华，倪泉兴，沈兆中，等. 生长抑素对胰腺癌生长抑制和凋亡作用的实验研究 [Ｊ]. 外科理论与实践， 2002； 7（5）：352-355.
24. Zalatnai A, Szegedi Z, Bocsi J. Flow cytometric evidence of apoptosis in human pancreatic cancer xenografts treated with Sandostatin (octreotide) [Ｊ]. Anticancer Res， 2000; 20(3A): 1663-1666.
25. Qin RY, Fang RL, Gupta MK, et al. Alteration of somatostatin receptor subtype 2 gene expression in pancreatic tumor angiogenesis [Ｊ]. World J Gastroenterol， 2004; 10(1): 132-135.
26. Kumar M, Liu ZR, Thapa L, et al. Antiangiogenic effect of somatostatin receptor subtype 2 on pancreatic cancer cell line: Inhibition of vascular endothelial growth factor and matrix metalloproteinase-2 expression in vitro [Ｊ]. World J Gastroenterol， 2004; 10(3): 393-399.
27. Ren SG, Ezzat S, Melmed S, et al. Somatostatin analog induces insulin-like growth factor binding protein-1 (IGFBP-1) expression in human hepatoma cells [Ｊ]. Endocrinology, 1992; 131(5): 2479-2481.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Angiostatin Gene Combined with Somatostatin in Growth Inhibition of Human Pancreatic Cancer in Vitro

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