【作者】 荚卫东；

【导师】 许戈良； 徐荣楠； 柴仲培； 李建生；

【作者基本信息】 安徽医科大学 ， 外科学， 2003， 硕士

【摘要】 原发性肝癌是一种典型的多血管性肿瘤，肿瘤细胞能够产生多种血管生长因子，诱导肿瘤血管生成，抗肿瘤血管生成的治疗能够抑制肝癌生长和复发转移。近年来研究发现生长抑素类似物奥曲肽在治疗不能切除的肝癌中可以明显的延长病人的生存期。我们先前的研究也证实奥曲肽对大鼠肝部分切除术后种植性肝癌生长具有抑制作用。然而，在非内分泌的实体肿瘤中，奥曲肽确切的抗肿瘤机制尚不清楚。最近有研究表明奥曲肽能够抑制实验性血管生成，并可以通过抑制肿瘤血管生成控制肿瘤生长。本研究应用MTT实验、侵袭实验、迁移实验、Matrigel实验、人肝癌LCI-D20裸鼠角膜微囊移植模型、皮下移植瘤模型和裸鼠人肝癌转移模型等手段，探讨奥曲肽对人肝癌肿瘤血管生成和肝癌切除术后复发转移的影响。体外研究表明，奥曲肽能够抑制血管内皮生长因子(VEGF)诱导的人脐静脉内皮细胞(HUVECs)增殖、侵袭和分化成血管能力，对源自人肝癌LCI-D20的肝癌细胞株MHCC97-H和MHCC97-L的增殖无明显抑制作用。体内研究表明：奥曲肽能够抑制LCI-D20肝癌组织诱导的裸鼠角膜新生血管形成；对LCI-D20皮下肿瘤生长具有抑制作用，免疫组化研究表明，治疗组肿瘤内微血管密度(MVD)比对照组MVD明显减少；并能够通过抗肿瘤血管生成抑制高转移性人肝癌切除术后的复发转移。这些结果提示奥曲肽对人肝癌肿瘤血管生成和肝癌切除术后的复发转移具有抑制作用。因此，生长抑素类似物奥曲肽作为抗肿瘤血管生成剂，与传统的手术、放疗和化疗联合应用，可能为肝癌的治疗提供新的途径。更多还原

【Abstract】 Hepatocellular carcinoma (HCC) is generally considered to be a hypervascular tumor. Tumor cells can produce several angiogenic factors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), which are supposed to induce neovascularization. Anti-angiogenic therapy can inhibit the growth, recurrence and metastasis of HCC. It has been recently reported that octreotide administration significantly improves survival and is a valuable alternative in the treatment of inoperable HCC. We had previously demonstrated that octreotide inhibited the growth of experimental liver tumor after partial hepatectomy. However, the exact mechanism of the antitumor effect of octreotide on HCC has not been elucidated. Octreotide has been recently suggested to inhibit experiment angiogenesis and suppress tumor growth through inhibition of angiogenesis. In this study, Using MTT assay, invasion assay, migration assay, and Matrigel assay, the effect of octreotide on endothelial cells stimulated by vascular endothelial growth factor (VEGF) was evaluated in vitro. LCI-D20 corneal micropocket model in nude mice was used to evaluate the effect of octreotide on angiogenesis induced by human HCC in vivo. Male nude mice were subcutaneously implanted with LCI-D20 tumor tissues for the tumor xenograft studies. Microvessel density was analyzed in CD34-stained tumor sections by immunohistochemical SP method. The metastatic model of human HCC in nude mice LCI-D20 was used to evaluate whether octreotide could suppress recurrence and metastasis of HCC after curative resection in nude mice through inhibition of angiogenesis. In vitro, octreotide inhibited the proliferation, invasion, anddifferentiation of HUVECs elicited by VEGF, while the effect of octreotide on the proliferation of HCC cells MHCC97-H and MHCC97-L was not obvious. In vivo, octreotide was sufficiently potent to suppress nude mice corneal neovascularization induced by tumor tissues from LCI-D20. Systemic administrations of octreotide produced a significant suppression of the growth of LCI-D20. Immunohistochemical studies of tumor tissues revealed decreased microvessel density in octreotide-treated animals as compared with controls. Octreotide dose-dependently inhibited recurrence and metastasis of HCC after curative resection in nude mice through inhibition of angiogenesis. The present study demonstrates that octreotide is able to inhibit angiogenesis induced by HCC and recurrence and metastasis of HCC after curative resection. It is reasonable to consider that the somatostatin analogue octreotide used as an adjuvant anti-angiogenic treatment administrated after or during conventional therapy (surgical, radiological and chemical), may provide a new approach to the treatment of HCC.更多还原