【作者】 姜磊；

【导师】 胡祥；

【作者基本信息】 大连医科大学 ， 外科学， 2011， 硕士

【摘要】 背景:胃癌是人类常见的恶性肿瘤之一,约25%的胃癌患者在术前或术中被诊断为腹膜转移,进展期胃癌术后也有50%的患者出现腹膜转移,是胃癌死亡的主要原因。胃癌腹膜转移的机制目前比较认可的是“种子-土壤”学说,即具有生物活性的癌细胞脱落于腹腔,形成所谓的“种子”,腹膜组织由于手术等机械性创伤而易于肿瘤细胞的增殖,形成所谓的“土壤”,两者间相互作用和其他细胞因子共同促使腹膜转移的发生,近年来的研究表明趋化因子及其受体可能在肿瘤的转移中发挥重要的作用。趋化因子是一种能够趋化细胞定向移动的小分子细胞因子,依据N-末端半胱氨酸残基的排列顺序分为4类:CXC、CC、C、CX3C趋化因子,相应的受体为CXCR、CCR、XCR、CX3CR。大量研究表明趋化因子受体CXCR1、CXCR2、CCR7在多种肿瘤的播散和转移中起到重要的作用。目的:通过检测趋化因子受体CXCR1、CXCR2、CCR7在癌旁组织、胃癌原发灶、腹膜转移灶中的表达情况来分析其在胃癌腹膜转移中的作用。方法:选择大连医科大学附属第一医院2002年-2010年胃癌腹膜转移的标本37例,要求标本要有癌旁组织(距离肿瘤病灶5cm以上)、原发灶、腹膜转移灶。另随机选择同期100例无腹膜转移的胃癌标本,所有的病例在手术前均未进行放化疗,标本行福尔马林固定,石蜡包埋后免疫组化SP法测定趋化因子受体CXCR1、CXCR2、CCR7的表达情况。单变量分析CXCR1、CXCR2、CCR7在胃癌腹膜转移中各临床病理参数间的表达,对胃癌腹膜转移的病人进行电话随访,分别分析趋化因子受体CXCR1、CXCR2、CCR7表达阳性和阴性的中位生存时间,logistic回归进行多因素分析。结果:趋化因子受体CXCR1、CXCR2、CCR7主要表达在肿瘤细胞的胞浆及胞膜中。在37例腹膜转移的病例中,CXCR1在癌旁组织、原发灶、腹膜转移灶中的表达率分别为:45.9%,81.1%,94.6%;CXCR2在癌旁组织、原发灶、腹膜转移灶中的表达率分别为:40.5%,75.6%,91.9%;CCR7在三者中的表达率为:5%,78.3%,89.2%。CXCR2、CCR7在腹膜转移灶与原发灶中的表达有显著性差异(P<0.05);CXCR1在腹膜转移灶与原发灶中的表达无显著性差异(p>0.05)。CXCR1、CXCR2、CCR7在原发灶和癌旁组织中的表达有显著性差异(p<0.05)。在100例无腹膜转移胃癌的标本原发灶中CXCR1、CXCR2、CCR7的表达率分别为:57%,51%,60%。发生腹膜转移和未发生腹膜转移的标本原发灶之间CXCR2、CCR7的表达有显著性差异(P<0.05),而CXCR1的表达无差异(p>0.05)。单变量分析CXCR1、CXCR2、CCR7在胃癌腹膜转移各临床病理参数之间的表达情况:CXCR2在胃癌腹膜转移灶中的阳性表达与肿瘤的浸润深度、分化程度、肿瘤大小相关(p<0.05),与病人的年龄、性别、肿瘤部位、淋巴转移无相关性(p>0.05);CCR7在胃癌腹膜转移灶中的阳性表达与肿瘤的浸润深度、分化程度、淋巴转移相关(p<0.05),与病人的年龄、性别、肿瘤部位、肿瘤大小无相关性(p>0.05);而CXCR1在胃癌腹膜转移灶中的表达与肿瘤的浸润深度、分化程度、肿瘤大小、肿瘤部位、淋巴转移、年龄、性别无相关性(p>0.05)。对生存资料的分析得出腹膜转移灶中CXCR1表达阳性的患者中位生存时间是10个月,CXCR1表达阴性的患者中位生存时间是11个月;CXCR2表达阳性的患者中位生存时间是9.5个月,CXCR2表达阴性的患者中位生存时间是15个月;CCR7表达阳性的患者中位生存时间是9个月,CCR7表达阴性的患者中位生存时间是16个月。多因素的回归分析显示原发肿瘤的大小、浸润深度、分化程度、原发灶中CXCR2、CCR7的表达是胃癌腹膜转移的危险因素。结论:1.胃癌腹膜转移与未发生腹膜转移的胃癌比较,在浸润深度、分化程度、肿瘤大小、淋巴结转移方面有显著性的差异(p<0.05);而在性别、年龄、肿瘤部位方面无差异性(p>0.05)。2.趋化因子受体CXCR1、CXCR2、CCR7的表达水平与胃癌肿瘤的生长有关;CXCR2、CCR7的表达与胃癌腹膜转移有关。3.CXCR2在胃癌腹膜转移灶中的阳性表达与肿瘤的浸润深度、分化程度、肿瘤大小相关;与病人的年龄、性别、肿瘤部位无相关性;CCR7在胃癌腹膜转移灶中的阳性表达与肿瘤的浸润深度、分化程度、淋巴转移程度相关;与病人的年龄、性别、肿瘤部位、肿瘤大小无相关性。而CXCR1在胃癌腹膜转移灶中的表达与肿瘤的浸润深度、分化程度、肿瘤大小、肿瘤部位、淋巴转移、年龄、性别均无相关性。4. CXCR2和CCR7表达阳性的患者的预后生存时间明显低于CXCR2和CCR7表达阴性的患者。肿瘤的大小、浸润深度、分化程度、趋化因子受体CXCR2和CCR7的表达构成了胃癌腹膜转移的危险因素。更多还原

【Abstract】 Background: Gastric cancer is one of the most common malignant tumors in humans, about 25% of gastric cancer patients are preoperatively or intraoperative diagnosed of peritoneal metastasis. Advanced gastric cancer patients have 50% of the patients’peritoneal metastasis of gastric cancer mortality. The mechanism of peritoneal metastasis of gastric cancer is comparing the current approved of“the seed - soil theory”, in which the biological activity of cancer cells shed in the abdominal cavity, and formed the so-called "seed". While peritoneal tissue trauma due to surgery and other mechanical is easy to tumor cell proliferation, and formats the so-called "soil", the interaction between cytokines and other cytokines molecules co-promotes the occurrence of peritoneal metastasis. Recent studies show that chemokines and their receptors may play an important role in the tumor metastasis. Chemokines is a kind of small cytokines molecules cans Chemokines directional movement, According to the N-terminal sequence of cysteine residues into four categories: CXC, CC, and C, CX3C chemokines, the corresponding subject body for the CXCR, CCR, XCR, and CX3CR. Numerous studies show that the chemokine receptor CXCR1, CXCR2, CCR7 plays an important role in a variety of tumor dissemination and metastasis.Objective: To detect the chemokine receptors CXCR1, CXCR2, CCR7 in primary lesion, paracarcinomatous tissue, peritoneal metastasis to analyze the situation in the role of peritoneal metastasis of gastric cancer.Methods: First Affiliated Hospital of Dalian Medical University, 2002 -2010 peritoneal metastasis of gastric cancer specimens in 37cases,required to have paracarcinomatous tissue (more than 5cm from the tumor lesions), primary tumor, peritoneal metastasis. Another 100 cases were randomly selected over the same period without peritoneal metastasis of gastric cancer specimens, all of the cases were not conducted in the chemotherapy before surgery, specimens were fixed in formalin, embedded in paraffin after immunohistochemical SP method for the determination of chemokine receptors CXCR1, CXCR2, CCR7 expression. Univariate analysis of CXCR1, CXCR2, CCR7 in gastric cancer peritoneal metastasis in the clinical and pathological parameters of the expression of peritoneal metastasis of gastric cancer patients, telephone follow-up, respectively, analysis of chemokine receptor CXCR1, CXCR2, CCR7 expression, the median positive and negative survival time, logistic regression multivariate analysis.Results: The chemokine receptors CXCR1, CXCR2, CCR7 expression mainly in cytoplasm and membrane in the tumor cells. In 37 patients with peritoneal metastasis cases, CXCR1 in adjacent tissue, primary tumor, expression of peritoneal metastasis rates were: 45.9%, 81.1%, 94.6%; CXCR2 in adjacent tissue, primary tumor, peritoneal metastasis tissues espression rates were: 40.5%, 75.6%, 91.9%; CCR7 expression among the three rate: 5%, 78.3%, 89.2%. CXCR2, CCR7 in the peritoneal metastases and primary tumors, the expression of significant differences (p<0.05); CXCR1 in peritoneal metastases and primary tumors, the expression was not significantly different (p> 0.05). CXCR1, CXCR2, CCR7 in primary tumors and adjacent tissues are significantly different (p <0.05).In 100 gastric cancer patients without peritoneal metastasis in primary tumor specimens of CXCR1, CXCR2, CCR7 expression rates were: 57%, 51%, 60%. Without peritoneal metastasis and peritoneal metastasis of primary tumor specimens between the CXCR2, CCR7 expression was significantly different (p<0.05), while the expression of CXCR1 was no significant difference (p> 0.05).Univariate analysis of CXCR1, CXCR2, CCR7 peritoneal metastasis in gastric cancer between the different clinical expression of pathological parameters: CXCR2 in gastric cancer peritoneal metastasis were correlated with tumor invasion depth, differentiation, tumor size-related (p <0.05), with the patient’s age, sex, tumor location, lymph node metastasis had no correlation (p>0.05); CCR7 in gastric cancer peritoneal metastasis were correlated with tumor invasion depth, differentiation degree, lymph node metastasis (p<0.05), and the patient’s age, sex, tumor location, tumor size had no correlation (p> 0.05); and peritoneal metastasis in gastric cancer CXCR1 expression and tumor invasion depth, differentiation, tumor size, tumor site, lymph node metastasis, age, no correlation between gender (p> 0.05). Analysis of information obtained on the survival of peritoneal metastasis in patients with positive expression of CXCR1 median survival time was 10 months, CXCR1 expression of negative patients the median survival time was 11 months; CXCR2 expression was positive in the median survival time was 9.5 months, CXCR2 expression in negative median survival time was 15 months; CCR7 positive expression median survival time was 9 months, CCR7 expression of negative median survival time was 16 months. Multivariate regression analysis showed that the size of primary tumor, depth of invasion, differentiation, primary tumors, CXCR2, CCR7 positive expression is a risk factor for peritoneal metastasis of gastric cancer.Conclusion: 1.Peritoneal metastasis and no peritoneal metastasis of gastric cancer compared in the depth of invasion, differentiation, tumor size, lymph node metastasis were significantly different (p <0.05); and in gender, age, tumor site areas no difference (p> 0.05).2.Chemokine receptors CXCR1, CXCR2, CCR7 expression on tumor growth of gastric cancer; CXCR2, CCR7 expression and peritoneal metastasis of gastric cancer.3.CXCR2 peritoneal metastasis in gastric cancer, the positive expression and tumor invasion, differentiation, tumor size-related; and the patient’s age, sex, tumor site no correlation; CCR7 in gastric cancer peritoneal metastasis were correlated with tumor depth of invasion, differentiation, lymphatic metastasis related; and the patient’s age, sex, tumor location, tumor size had no correlation. And peritoneal metastasis in gastric cancer CXCR1 expression and tumor invasion depth, differentiation, tumor size, tumor site, lymph node metastasis, age, gender were not correlated.4.CXCR2 and CCR7 expression in the prognosis of patients with positive survival time was significantly lower than the expression of CXCR2 and CCR7-negative patients. Tumor size, depth of invasion, differentiation, chemokine receptor CXCR2 and CCR7 expression constitutes a risk factor for peritoneal metastasis of gastric cancer.更多还原