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肝细胞生长因子在乳腺癌增殖及血管生成中的作用

The Role of Hepatocyte Growth Factor in Tumor Proliferation and Angiogenesis in Breast Cancer

【作者】 郭慈仁

【导师】 李良庆; 张声;

【作者基本信息】 福建医科大学 , 外科学, 2005, 硕士

【摘要】 【背景和目的】肝细胞生长因子(Hepatocyte growth factor, HGF)又称扩散因子(Scatter factor, SF)是一种功能强大的多肽生长因子,在肿瘤细胞增殖、侵袭、转移以及肿瘤微血管生成中均发挥重要作用。本研究通过检测乳腺癌中HGF mRNA 的表达水平,探讨其在乳腺癌增殖及微血管生成中的作用,为进一步明确乳腺癌发生、发展的机制奠定基础;同时结合临床及随访资料,分析HGF 与有关临床病理因素及预后的关系,为临床上乳腺癌的病情预测及预后判断提供新的实验依据。【方法】运用原位杂交技术,检测75 例临床及随访资料完整的乳腺癌及10例乳腺良性肿瘤组织中HGF mRNA 表达,采用染色强度和阳性细胞数综合评分的方法对HGF 表达水平进行评估。同时,运用S-P 免疫组化技术检测上述75 例癌组织中细胞增殖抗原标记物K_i67 的表达和微血管密度分布(Microvesseldensity, MVD)(选用CD34 抗体标记血管内皮细胞,并根据CD34 的表达情况计算出乳腺癌组织的MVD)。统计学方法分析HGF 与K_i67 及MVD 间关系,以此阐明HGF 表达在乳腺癌增殖及微血管生成中的作用。最终结合随访资料,分别采用Kaplan-Meier 法与Cox 回归模型评估HGF 对乳腺癌预后的判断价值。【结果】1. 75 例乳腺癌中HGF 呈阳性表达者53 例(72%),10 例乳腺良性肿瘤中HGF阳性表达仅有1 例(10%),HGF 在乳腺癌中的表达率较其在乳腺良性肿瘤中显著增高(p<0.05);2. 乳腺癌中HGF 阳性表达组的K_i67 表达率高于HGF 阴性表达组,差异显著(p<0.05),且Pearson 相关分析表明,HGF 与K_i67 表达呈正相关关系(r=0.450,p<0.05);3. 乳腺癌中HGF 阳性表达组的MVD(33.6±11.5 个/200 倍视野)明显高于HGF 阴性表达组(21.5±5.3 个/200 倍视野),差异显著(p<0.05),且Spearman相关分析表明,HGF 表达与MVD 值呈正相关关系(r=0.520, p<0.01);

【Abstract】 【Background and Objective】Hepatocyte growth factor(HGF ), also known asScatter factor(SF), is a pleiotropic growth factor that induces tumor cell proliferation,invasion and metastasis, and tumor angiogensis. The aim of this study is to investigatethe expression level of HGFmRNA and the role of it in tumor proliferation andangiogenesis in breast cancer so as to offer the theoretic basis to the mechanism ofbreast cancer; At the same time, the relationship between HGF and prognosis of breastcancer patient was also explored in order to provide the theory of the possibility of anew prognosis predictor for breast carcinoma.【Methods】In situ hybridization method was used to detect the expression levelof HGFmRNA in 75 cases of full follow-up invasive ductal breast cancer and 10 casesof benign breast tumor tissues. The expression level of HGF was judged by the totalscores of the strength of staining and the percentage of positive cells per 1000 countedneoplastic cells for each case. S-P immunohistochemical staining was also used todetect the expression level of K_i67 and MVD in 75 cases of invasive ductal breastcancer tissues. MVD were highlighted by staining their endothelial cellsimmunohistochemically for CD34, and then were counted in the most intense areas ofneovascularization. The expression of K_i67 was judged by the percentage of positivecells per 1000 counted neoplastic cells for each case. Correlation between HGF, andK_i67 and MVD were statistically analyzed in order to explore the role of HGF intumor proliferation and angiogenesis in breast cancer. At last, Kaplan-Meier methodand Cox proportional hazard regression model were used to assess the value of HGFin breast cancer prognosis.【Results】It was found that the expression level of HGF in breast cancer wassignificantly higher than that in breast benign tumor(72% VS 10%, P<0.05);Theexpression level of K_i67 and the value of MVD in tumor with positive HGFexpression were significantly higher than those with negative HGF expression(p<0.05), and there was a closely positive correlation among HGF, Ki67 and MVD,and the correlation coefficient were 0.450 and 0.520, respectively(both P<0.05); Theexpression level of Ki67 and the value of MVD in patients with positive lymoph nodemetastasis were significantly higher than those with negative lymoph node metastasis(p<0.05), and there was also a closely positive correlation among Ki67, MVD andlymoph node metastasis , the correlation coefficient were 0.305 and 0.353,respectively(both P<0.05); The expression of HGF has no significantly correlationwith age, lesions position, menopausal status, ER and PR (p>0.05), but hassignificantly correlation with tumor size, histological grade, TNM stage and lymophnode metastasis (p<0.05); Breast cancer patients with positive HGF expression hadsignificantly lower overall survival rate (OS) and disease free survival rate (DFS)when compared to those with negative HGF expression (p<0.05). In multivariate coxregression analysis, HGF was found to be the most important independent factor inpredicting patients’ prognosis, even of greater import than lymoph node metastasis(RR=5.650). 【Conclusions】The results of experiment suggest that HGF was overexpressedin breast cancer tissue, and the overexpression of HGF was associated with tumoroccurrence, histological grade, TNM stage and lymoph node metastasis in patientswith breast cancer, which means that HGF may be a useful maker which can identifyhigh aggressive and metastatic potential in patients with breast cancer at early age.HGF was closely related with tumor proliferation and tumor angiogenesis, it mightplay a positive role in tumor invasion and metastasis by inducing tumor proliferationand tumor angiogenesis. HGF could be one of valuable prognosis indicators in breastcancer.

【关键词】 乳腺癌肝细胞生长因子增殖血管生成预后
【Key words】 breast cancerHGFproliferationangiogenesisprognosis
  • 【分类号】R737.9
  • 【下载频次】127
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