血清肝细胞生长因子在大肠癌肝转移患者中的临床价值
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摘要
研究背景:大肠癌是消化道常见的恶性肿瘤之一,每年全世界约有50万人发病,在西方国家大肠癌死亡率仅次于肺癌和乳腺瘤,居恶性肿瘤死亡率第3位[1]。近年来我国大肠癌发病率及死亡率亦呈升高趋势,据1993～1997年中国1/10人口死因抽样调查结果[2]显示,中国大肠癌居恶性肿瘤死因第五位。在临床就诊的大肠癌病人,其中约1/3病人在就诊时肿瘤已至晚期不能切除或有弥漫性转移,这类病人预后很差,平均生存期约7个月。而另外2/3的病人即使对原发肿瘤能行“根治性切除”,但仍约50%的病人生存期不超过5年,其中大部分(约占40%)患者死于肝转移。如何早期预测大肠癌的转移,一直是医学界十分关注的问题。
肝细胞生长因子(hepatocyte growth factor,HGF)是一种多功能的细胞因子,有研究表明,HGF能调节细胞生长和运动,促进多种细胞组织形态的发生,是上皮细胞和间质细胞相互作用的体液介质,具有强大的促分裂、组织形成、诱导上皮迁移、侵袭以及诱发血管生成的作用。在肿瘤细胞中HGF和c-met结合导致受体自身磷酸化,增强了酪氨酸激酶的活性,导致多种底物蛋白的酪氨酸磷酸化。由于肿瘤组织中HGF和c-met的同时高表达,形成正反馈,导致肿瘤的无限生长和侵袭行为。而这种正反馈作用已经在神经胶质瘤、骨肉瘤、乳腺癌、多发性骨髓瘤等恶性肿瘤中得到证实,并显示HGF在恶性肿瘤体液中显著升高,并与侵袭状态密切相关。
国内外虽已有许多学者就HGF在各类恶性肿瘤方面进行了研究,但大多仅限于组织中的研究。如国内谢倩、罗运权等通过检测肝癌组织中HGF及其受体的表达,认为HGF与肝癌的转移有密切关系。Eichbaum MH等报道了原发乳腺癌组织中HGF浓度是一个独立的预后指标。
近几年来对于血清中HGF含量的研究也越来越多,Tanaka等的研究表明,早期胃癌和进展期胃癌患者的血清HGF显著高于正常对照组,提示在早期胃癌和进展期胃癌中,血清HGF水平可能是一个有临床价值的肿瘤标志物。国内尹家俊等也报道了乳腺癌术后转移组的血清HGF浓度显著高于无复发转移组及对照组。国外虽已有学者针对血清中HGF水平与大肠癌分期的关系进行了研究,但就大肠癌肝转移方面的研究仍局限在组织中,特别是在血清中的表达情况的研究仍是甚少。
目的:鉴于目前诊断大肠癌是否有肝转移的存在,大多是依靠影像学如B超、CT或MR,以及术后或治疗后血清CEA是否升高等来确定。而临床上,当影像学已有诊断时,病情往往已进入晚期,给临床治疗已带来了一定的困难,而且患者的预后也已较差。所以,目前临床上通常采取大肠癌术后肝脏介入化疗来预防肝转移的可能性。因此,如何能早期预测大肠癌是否具有发生肝转移的可能性,对提高大肠癌预后的预测和指导更有效的治疗方法都有着重要的意义。
本研究以52例大肠癌患者为研究对象,应用双抗体夹心法ELISA对大肠癌患者血清中肝细胞生长因子的测定,来分析其与大肠癌发生肝转移的关系,试图探讨HGF对判断肝转移的价值。
方法:自2004年6月至2006年12月选择病例52例,均为大肠癌患者,且所有患者均经过病理证实,其中男、女之比为27:25,年龄31～75岁,平均年龄54.17岁。在52例患者中,根据Duke's分期,分为A和B期13例、C期17例、D期22例,此D期的22例中,17例合并有肝转移(均有影像学诊断),5例为其他部位转移(无肝脏转移)。另设健康对照20例(均来自于我院体检科健康体检人群),年龄25岁～72岁,平均40.3岁,男女之比为13:7。
取受检患者新鲜血10ml,立即于4℃300rmin离心15min,取上清液1ml分装后置-70℃深低温冰箱冻存备用至测定。
实验方法按照购自广州康润公司的人HGF检测试剂盒(美国RD公司产品,标号:063402)上说明书的操作步骤进行检测。具体测定步骤为:(1)取样品室温解冻;(2)双蒸水稀释洗涤液至500ml校准稀释液倍比稀释HGF标准品浓度至8000μg/L;(3)分别加入5μl标准品(Standards)、5μl已稀释血清或血浆于反应板孔中,轻轻混匀10s;(4)每孔加入200μl Biotin anti HGF,轻轻混匀30s,37℃温育30min;(5)洗板:甩尽板内液体,用洗涤液洗涤反应板,并去除水滴(在厚叠吸水纸上拍干),这样反复洗涤5次;(6)每孔加入200μl HRP,轻轻混匀10s,37℃温育30min;(7)洗板:甩尽板内液体,用洗涤液洗涤反应板,并去除水滴(在厚叠吸水纸上拍干),这样反复洗涤5次;(8)每孔加入100μl TMB显色液,轻轻混匀10s,置暗处室温温育20min;(9)每孔加入100μl终止液(StopSolution),轻轻混匀30s;15min内在酶标仪中以450nm处读光密度值,再根据标准曲线计算出各样本HGF含量。我们将所有数据输入SPSS13.0软件包进行处理,采用独立样本t检验和One-Way ANOVA检验,其中P<0.05认为具有统计学上显著差异。
结果:
一、血清HGF值在实验组和对照组之间的比较
所有研究对象在入选时均确诊为大肠癌,并均有病理证实。同时选择20例健康体检者作为对照组进行检测。并且将检测结果分别输入SPSS13.0软件包内进行计算和分析。通过检查发现,大肠癌患者血清中HGF的含量普遍较高,实验组与健康对照组之间存在着显著的差异(P<0.005),说明大肠癌患者的血清中HGF的含量远高于健康人群。
二、有肝转移和无肝转移两组之间的比较。
将所有研究对象,通过各项检查,包括BUS、CT等检查,区分为有肝转移和无肝转移两组,并分别把数据进行统计学分析,通过分析发现,有肝转移组其HGF的含量要远高于无肝转移组患者(P<0.005)。从检验中我们还发现,除了有肝转移的患者血清中HGF含量较高外,其他部位转移的大肠癌患者,其血清中HGF的含量也远高于无转移组的患者。说明除了肝脏在受到损害时,自身会释放肝细胞生长因子外,原发肿瘤本身在瘤细胞脱落时,也可以分泌该因子。
三、血清中HGF的含量与大肠癌分期的关系。
正如与有、无肝转移分组一样,我们将患者按照Duck分期方法,将患者分成Ⅵ个期别,从实验的结果也可以发现,血清中HGF的含量与大肠癌的分期也有着密切的关系,而且分期越晚,血清中HGF的含量就越高(P<0.005)。由此可以看出,大肠癌患者血清中HGF的含量,不仅可以作为大肠癌的一个标志物,更可以作为预测大肠癌有无肝转移的一个指标。
结论:通过本实验研究发现,大肠癌患者与对照组之间相比,HGF值的升高有着显著的差异性,说明了HGF与大肠癌确实有着密切的关系。另外,从本实验结果还发现,HGF与大肠癌的分期也有着密切的关系,而且分期越晚,其血清HGF值就越高,特别是有肝转移的患者,其HGF血清中的表达也远远高于无肝转移组,从而进一步的提示了血清HGF在大肠癌中可能预示了一种更具有侵袭性的生物学行为。然而值得一提的是,在Duck'D的患者中,其中有5例只有其他部位转移,而不存在肝脏转移,虽然其血清HGF值较高,但与Duck'A、B相比较,却无明显差异性,分析其原因,可能与例数较少有关。总之,血清中HGF值的测定,有可能不仅只成为应用于大肠癌患者诊断的一项肿瘤标记物,更可能可以作为预测大肠癌有无肝转移的一个指标,对于大肠癌转移、分期及预后的判断和制订治疗方案均可能有着一定的指导意义。
Background:The colon cancer is one of the digestive tract malignant tumors, and the all world approximately has 500,000 people to be taken bad every year.The mortality rate of the colon cancer at the Western country is only next to the lung and the breast cancer.And that ranks the third in malignant tumor mortality rate~[1].In recent years,the incidence and mortality trends of China's colorectal cancer was also increased.According to the 1993-1997 Chinese 1/10 the population sample survey results showed that the cause of death~[2]The death of colon cancer is the fifth cause of in the Chinese malignant tumor.In the clinical treatment of patients with colorectal cancer,of which about 1/3 patients when they seek medical treatment to the tumor has advanced stage that should not have to remove or diffuse metastasis,poor prognosis of these patients,the average survival time is about 7 months.While the other 2/3 of patients even if the original tumor can do it "radical resection",but still about 50%of patients survive a period of not more than five years,most of which (about 40%) patients died of liver metastasis.How has the early prediction that colorectal cancer metastasis,the medical specialist has always been an issue of great concern..
Hepatocyte growth factor(HGF) is a multifunctional cytokine.Research has shown that,HGF can regulate cell growth and exercise,and promote generation about the various cell morphology,is the body fluids medium of interaction of epithelial cells and mesenchymal cells.HGF has strong functions to the mitogenesis,the tissues formation,inducing epithelium migration and invasion,and inducing vasculogenesis. The combination of HGF and the c-met in the tumour cells results in acceptor autophosphorylation,and enhanced the activity of Tyrosine Kinase.So it was bring about many kinds of substrate proteins the tyrosine phosphorylation.As a result of high expression and forming a positive feedback of HGF and c-met in the tumor tissues,the tumor became indefinite growth and Invasion.And this positive feedback action has been confirmed in the malignant tumor such as the gliomas,osteosarcoma, breast cancer and multiple myeloma,etc.And this positive feedback action has been confirmed in the malignant tumor such as the gliomas,osteosarcoma,breast cancer and multiple myeloma,etc.It indicated that HGF in body liquid of patient with malignant is significantly elevated.And this positive feedback action has been confirmed in the many malignant tumor such as the gliomas,osteosarcoma,breast cancer and multiple myeloma,etc.It indicated that HGF in body liquid of patient with malignant is significantly elevated and concerns invasion status very nearly.
Although there is many scholars at home and abroad to studied HGF in various malignant,but mostly cases limited to research in tumor tissues.HGF have been consider to be bound up with liver cancer metastasis through the study of HGF and acceptor's expression in liver cancer tissues by Xie Qian,Luo Yun Quan,etc. Eichbaum MH,etc reported that HGF consistence in the breast cancer tissues is an independent prognostic indicators.
In the last years,there are more and more researches with reference to contents of HGF in the serum.Tanaka etc.researches indicated that HGF in the serum of the early and advanced gastric cancer is significantly higher than the normal control group.It prompted that the serum HGF levels may have clinical value as a tumor marker in the early gastric cancer and advanced gastric cancer.YIN Jia-jun,etc.were also reported the serum HGF concentrations in breast cancer metastasis group were significantly higher than those without recurrence and metastasis group and control group.Although there is foreign specialist to have been study about the relationship with serum HGF levels and stages of colorectal cancer,but the researches in the liver metastasis of colorectal cancer is still confined to the tissues,especially investigation in the serum expression is still rarely.
Purpose:In view of the colorectal cancer whether have been liver metastases, most of them are to rely on imaging such as BUS,CT or MR,and postoperatively or after treatment,such as serum CEA to determine whether the increase.The one's illness often has taken a turn for the last stage when the imaging has been diagnosis. Not only clinical treatment has been brought about difficulties,and the patient's prognosis has been poor.Therefore,the current clinical practice is usually taken interventional chemotherapy after the postoperative of colorectal cancer to prevent the possibility of liver metastasis.How can the early prediction for colorectal cancer whether have been transformed into liver,there are great significance for improvement prognosis prediction and guidance of more effective treatment methods. In this study,there are 52 patients with colorectal cancer as the research object.We use the ELISA to mensurate the HGF in serum on those patients,and then analyze the relationship between HGF and colorectal cancer patients with liver metastasis. Attempt to explore the value of HGF on colorectal cancer patients with liver metastasis.
Mehod:Since June 2004 to December 2006,we selected 52 cases of patients with colorectal cancer.All of patients have been confirmed by pathology.Among them,the male:female was 27:25,ages range from 31 to 75,the average age is 54.17 years old.
According to Duke's stages,52 patients divide into stage A and B 13 cases, stage C 17 cases,stage D 22 cases.Among the stage D,17 cases have the liver metastasis(all have imaging diagnosis),5 cases have other parts of the transfer (Non-liver metastasis).Another 20 cases serve as healthy controls.
Experimental methods are conducted in accordance with Human HGF detection kit (RD America Inc.products,labeling:063,402) instructions which purchased from Guangzhou Kang companies.We use SPSS 13.0 software to deal with all data.Using independent samples t test and One-Way ANOVA test,when P＜0.05 considered statistically significant.
Results:
1.The serum HGF values comparisons between the experimental group and control group
All research object with colorectal cancer,when they were selected,had have been diagnosed and had been confirmed by pathology.At the same time,the control group is composed of 20 healthy cases.The results will input SPSS13.0 software package and will calculate and analysis.Through the inspection found that the HGF content in the serum of patients with colorectal cancer is commonly higher,and there are significant differences(P＜0.005) between the experimental group and the healthy control group.It shows that serum HGF levels of patients with colorectal cancer are much higher than that of the healthy population.
2.Comparison serum HGF contents between the two groups whether the liver metastasis.
All subjects divided into two groups after various test such as BUS、CT etc,one group is liver metastasis and another one is no liver metastasis.Through the statistical analysis,the serum HGF contents of liver metastasis group were much higher than that of no metastasis group(P＜0.005).In addition to the patients with liver metastasis,we also found that the serum HGF contents of the patients with other places metastasis were also much higher than that of patients of no liver metastasis.It was show that the HGF released not only when the liver itself suffering from damage, but also when the tumor cell detachment from primary malignant tumor itself.
3.Relationship with each different staging of colon cancers about HGF contents in serum
Just as like grouping of liver metastasis or no,we will divide colorectal cancer patients intoⅣstages according to Duck stage.From results of experimental,we can also found that the serum HGF content have a very close relationship with colorectal cancer stages.And the latter the stage is,the higher the HGF content in serum will be (P＜0.005).It can be seen that the HGF content in serum of colorectal cancer patients not only can be used as a marker of colorectal cancer,but also can be used as an indicator to prediction of colorectal cancer whether the liver metastasis.
Conclusion:Through this experimental study found that patients with colorectal cancer compared with the control groups,HGF values rising were significantly different.In addition,through this experimental study we found that HGF also has relationship with colorectal cancer stage.And the later the colorectal cancer's stage is, the higher the serum HGF value will be.Especially the serum HGF expression in patients who have liver metastases was far higher than those without liver metastasis group.Thus this result farther prompted the serum HGF in colorectal carcinoma may indicate a more aggressive biological behavior.However it is worth mentioning of only 5 patients in the Duck'D that had other parts of the transfer(no liver metastases). Although they had the higher value of serum HGF,but had not significant difference to compare with Duck'A and B.Analysis of its causes may be related to the small number of cases.In short,the serum HGF values are likely to become a kind of tumor markers to be used diagnosis for colorectal cancer patients,and may be have certain of guiding significance for colorectal cancer patients at metastasis,stages,prognosis judgement and develop treatment programs.
肝细胞生长因子(hepatocyte growth factor,HGF)是一种多功能的细胞因子,有研究表明,HGF能调节细胞生长和运动,促进多种细胞组织形态的发生,是上皮细胞和间质细胞相互作用的体液介质,具有强大的促分裂、组织形成、诱导上皮迁移、侵袭以及诱发血管生成的作用。在肿瘤细胞中HGF和c-met结合导致受体自身磷酸化,增强了酪氨酸激酶的活性,导致多种底物蛋白的酪氨酸磷酸化。由于肿瘤组织中HGF和c-met的同时高表达,形成正反馈,导致肿瘤的无限生长和侵袭行为。而这种正反馈作用已经在神经胶质瘤、骨肉瘤、乳腺癌、多发性骨髓瘤等恶性肿瘤中得到证实,并显示HGF在恶性肿瘤体液中显著升高,并与侵袭状态密切相关。
国内外虽已有许多学者就HGF在各类恶性肿瘤方面进行了研究,但大多仅限于组织中的研究。如国内谢倩、罗运权等通过检测肝癌组织中HGF及其受体的表达,认为HGF与肝癌的转移有密切关系。Eichbaum MH等报道了原发乳腺癌组织中HGF浓度是一个独立的预后指标。
近几年来对于血清中HGF含量的研究也越来越多,Tanaka等的研究表明,早期胃癌和进展期胃癌患者的血清HGF显著高于正常对照组,提示在早期胃癌和进展期胃癌中,血清HGF水平可能是一个有临床价值的肿瘤标志物。国内尹家俊等也报道了乳腺癌术后转移组的血清HGF浓度显著高于无复发转移组及对照组。国外虽已有学者针对血清中HGF水平与大肠癌分期的关系进行了研究,但就大肠癌肝转移方面的研究仍局限在组织中,特别是在血清中的表达情况的研究仍是甚少。
目的:鉴于目前诊断大肠癌是否有肝转移的存在,大多是依靠影像学如B超、CT或MR,以及术后或治疗后血清CEA是否升高等来确定。而临床上,当影像学已有诊断时,病情往往已进入晚期,给临床治疗已带来了一定的困难,而且患者的预后也已较差。所以,目前临床上通常采取大肠癌术后肝脏介入化疗来预防肝转移的可能性。因此,如何能早期预测大肠癌是否具有发生肝转移的可能性,对提高大肠癌预后的预测和指导更有效的治疗方法都有着重要的意义。
本研究以52例大肠癌患者为研究对象,应用双抗体夹心法ELISA对大肠癌患者血清中肝细胞生长因子的测定,来分析其与大肠癌发生肝转移的关系,试图探讨HGF对判断肝转移的价值。
方法:自2004年6月至2006年12月选择病例52例,均为大肠癌患者,且所有患者均经过病理证实,其中男、女之比为27:25,年龄31～75岁,平均年龄54.17岁。在52例患者中,根据Duke's分期,分为A和B期13例、C期17例、D期22例,此D期的22例中,17例合并有肝转移(均有影像学诊断),5例为其他部位转移(无肝脏转移)。另设健康对照20例(均来自于我院体检科健康体检人群),年龄25岁～72岁,平均40.3岁,男女之比为13:7。
取受检患者新鲜血10ml,立即于4℃300rmin离心15min,取上清液1ml分装后置-70℃深低温冰箱冻存备用至测定。
实验方法按照购自广州康润公司的人HGF检测试剂盒(美国RD公司产品,标号:063402)上说明书的操作步骤进行检测。具体测定步骤为:(1)取样品室温解冻;(2)双蒸水稀释洗涤液至500ml校准稀释液倍比稀释HGF标准品浓度至8000μg/L;(3)分别加入5μl标准品(Standards)、5μl已稀释血清或血浆于反应板孔中,轻轻混匀10s;(4)每孔加入200μl Biotin anti HGF,轻轻混匀30s,37℃温育30min;(5)洗板:甩尽板内液体,用洗涤液洗涤反应板,并去除水滴(在厚叠吸水纸上拍干),这样反复洗涤5次;(6)每孔加入200μl HRP,轻轻混匀10s,37℃温育30min;(7)洗板:甩尽板内液体,用洗涤液洗涤反应板,并去除水滴(在厚叠吸水纸上拍干),这样反复洗涤5次;(8)每孔加入100μl TMB显色液,轻轻混匀10s,置暗处室温温育20min;(9)每孔加入100μl终止液(StopSolution),轻轻混匀30s;15min内在酶标仪中以450nm处读光密度值,再根据标准曲线计算出各样本HGF含量。我们将所有数据输入SPSS13.0软件包进行处理,采用独立样本t检验和One-Way ANOVA检验,其中P<0.05认为具有统计学上显著差异。
结果:
一、血清HGF值在实验组和对照组之间的比较
所有研究对象在入选时均确诊为大肠癌,并均有病理证实。同时选择20例健康体检者作为对照组进行检测。并且将检测结果分别输入SPSS13.0软件包内进行计算和分析。通过检查发现,大肠癌患者血清中HGF的含量普遍较高,实验组与健康对照组之间存在着显著的差异(P<0.005),说明大肠癌患者的血清中HGF的含量远高于健康人群。
二、有肝转移和无肝转移两组之间的比较。
将所有研究对象,通过各项检查,包括BUS、CT等检查,区分为有肝转移和无肝转移两组,并分别把数据进行统计学分析,通过分析发现,有肝转移组其HGF的含量要远高于无肝转移组患者(P<0.005)。从检验中我们还发现,除了有肝转移的患者血清中HGF含量较高外,其他部位转移的大肠癌患者,其血清中HGF的含量也远高于无转移组的患者。说明除了肝脏在受到损害时,自身会释放肝细胞生长因子外,原发肿瘤本身在瘤细胞脱落时,也可以分泌该因子。
三、血清中HGF的含量与大肠癌分期的关系。
正如与有、无肝转移分组一样,我们将患者按照Duck分期方法,将患者分成Ⅵ个期别,从实验的结果也可以发现,血清中HGF的含量与大肠癌的分期也有着密切的关系,而且分期越晚,血清中HGF的含量就越高(P<0.005)。由此可以看出,大肠癌患者血清中HGF的含量,不仅可以作为大肠癌的一个标志物,更可以作为预测大肠癌有无肝转移的一个指标。
结论:通过本实验研究发现,大肠癌患者与对照组之间相比,HGF值的升高有着显著的差异性,说明了HGF与大肠癌确实有着密切的关系。另外,从本实验结果还发现,HGF与大肠癌的分期也有着密切的关系,而且分期越晚,其血清HGF值就越高,特别是有肝转移的患者,其HGF血清中的表达也远远高于无肝转移组,从而进一步的提示了血清HGF在大肠癌中可能预示了一种更具有侵袭性的生物学行为。然而值得一提的是,在Duck'D的患者中,其中有5例只有其他部位转移,而不存在肝脏转移,虽然其血清HGF值较高,但与Duck'A、B相比较,却无明显差异性,分析其原因,可能与例数较少有关。总之,血清中HGF值的测定,有可能不仅只成为应用于大肠癌患者诊断的一项肿瘤标记物,更可能可以作为预测大肠癌有无肝转移的一个指标,对于大肠癌转移、分期及预后的判断和制订治疗方案均可能有着一定的指导意义。
Background:The colon cancer is one of the digestive tract malignant tumors, and the all world approximately has 500,000 people to be taken bad every year.The mortality rate of the colon cancer at the Western country is only next to the lung and the breast cancer.And that ranks the third in malignant tumor mortality rate~[1].In recent years,the incidence and mortality trends of China's colorectal cancer was also increased.According to the 1993-1997 Chinese 1/10 the population sample survey results showed that the cause of death~[2]The death of colon cancer is the fifth cause of in the Chinese malignant tumor.In the clinical treatment of patients with colorectal cancer,of which about 1/3 patients when they seek medical treatment to the tumor has advanced stage that should not have to remove or diffuse metastasis,poor prognosis of these patients,the average survival time is about 7 months.While the other 2/3 of patients even if the original tumor can do it "radical resection",but still about 50%of patients survive a period of not more than five years,most of which (about 40%) patients died of liver metastasis.How has the early prediction that colorectal cancer metastasis,the medical specialist has always been an issue of great concern..
Hepatocyte growth factor(HGF) is a multifunctional cytokine.Research has shown that,HGF can regulate cell growth and exercise,and promote generation about the various cell morphology,is the body fluids medium of interaction of epithelial cells and mesenchymal cells.HGF has strong functions to the mitogenesis,the tissues formation,inducing epithelium migration and invasion,and inducing vasculogenesis. The combination of HGF and the c-met in the tumour cells results in acceptor autophosphorylation,and enhanced the activity of Tyrosine Kinase.So it was bring about many kinds of substrate proteins the tyrosine phosphorylation.As a result of high expression and forming a positive feedback of HGF and c-met in the tumor tissues,the tumor became indefinite growth and Invasion.And this positive feedback action has been confirmed in the malignant tumor such as the gliomas,osteosarcoma, breast cancer and multiple myeloma,etc.And this positive feedback action has been confirmed in the malignant tumor such as the gliomas,osteosarcoma,breast cancer and multiple myeloma,etc.It indicated that HGF in body liquid of patient with malignant is significantly elevated.And this positive feedback action has been confirmed in the many malignant tumor such as the gliomas,osteosarcoma,breast cancer and multiple myeloma,etc.It indicated that HGF in body liquid of patient with malignant is significantly elevated and concerns invasion status very nearly.
Although there is many scholars at home and abroad to studied HGF in various malignant,but mostly cases limited to research in tumor tissues.HGF have been consider to be bound up with liver cancer metastasis through the study of HGF and acceptor's expression in liver cancer tissues by Xie Qian,Luo Yun Quan,etc. Eichbaum MH,etc reported that HGF consistence in the breast cancer tissues is an independent prognostic indicators.
In the last years,there are more and more researches with reference to contents of HGF in the serum.Tanaka etc.researches indicated that HGF in the serum of the early and advanced gastric cancer is significantly higher than the normal control group.It prompted that the serum HGF levels may have clinical value as a tumor marker in the early gastric cancer and advanced gastric cancer.YIN Jia-jun,etc.were also reported the serum HGF concentrations in breast cancer metastasis group were significantly higher than those without recurrence and metastasis group and control group.Although there is foreign specialist to have been study about the relationship with serum HGF levels and stages of colorectal cancer,but the researches in the liver metastasis of colorectal cancer is still confined to the tissues,especially investigation in the serum expression is still rarely.
Purpose:In view of the colorectal cancer whether have been liver metastases, most of them are to rely on imaging such as BUS,CT or MR,and postoperatively or after treatment,such as serum CEA to determine whether the increase.The one's illness often has taken a turn for the last stage when the imaging has been diagnosis. Not only clinical treatment has been brought about difficulties,and the patient's prognosis has been poor.Therefore,the current clinical practice is usually taken interventional chemotherapy after the postoperative of colorectal cancer to prevent the possibility of liver metastasis.How can the early prediction for colorectal cancer whether have been transformed into liver,there are great significance for improvement prognosis prediction and guidance of more effective treatment methods. In this study,there are 52 patients with colorectal cancer as the research object.We use the ELISA to mensurate the HGF in serum on those patients,and then analyze the relationship between HGF and colorectal cancer patients with liver metastasis. Attempt to explore the value of HGF on colorectal cancer patients with liver metastasis.
Mehod:Since June 2004 to December 2006,we selected 52 cases of patients with colorectal cancer.All of patients have been confirmed by pathology.Among them,the male:female was 27:25,ages range from 31 to 75,the average age is 54.17 years old.
According to Duke's stages,52 patients divide into stage A and B 13 cases, stage C 17 cases,stage D 22 cases.Among the stage D,17 cases have the liver metastasis(all have imaging diagnosis),5 cases have other parts of the transfer (Non-liver metastasis).Another 20 cases serve as healthy controls.
Experimental methods are conducted in accordance with Human HGF detection kit (RD America Inc.products,labeling:063,402) instructions which purchased from Guangzhou Kang companies.We use SPSS 13.0 software to deal with all data.Using independent samples t test and One-Way ANOVA test,when P＜0.05 considered statistically significant.
Results:
1.The serum HGF values comparisons between the experimental group and control group
All research object with colorectal cancer,when they were selected,had have been diagnosed and had been confirmed by pathology.At the same time,the control group is composed of 20 healthy cases.The results will input SPSS13.0 software package and will calculate and analysis.Through the inspection found that the HGF content in the serum of patients with colorectal cancer is commonly higher,and there are significant differences(P＜0.005) between the experimental group and the healthy control group.It shows that serum HGF levels of patients with colorectal cancer are much higher than that of the healthy population.
2.Comparison serum HGF contents between the two groups whether the liver metastasis.
All subjects divided into two groups after various test such as BUS、CT etc,one group is liver metastasis and another one is no liver metastasis.Through the statistical analysis,the serum HGF contents of liver metastasis group were much higher than that of no metastasis group(P＜0.005).In addition to the patients with liver metastasis,we also found that the serum HGF contents of the patients with other places metastasis were also much higher than that of patients of no liver metastasis.It was show that the HGF released not only when the liver itself suffering from damage, but also when the tumor cell detachment from primary malignant tumor itself.
3.Relationship with each different staging of colon cancers about HGF contents in serum
Just as like grouping of liver metastasis or no,we will divide colorectal cancer patients intoⅣstages according to Duck stage.From results of experimental,we can also found that the serum HGF content have a very close relationship with colorectal cancer stages.And the latter the stage is,the higher the HGF content in serum will be (P＜0.005).It can be seen that the HGF content in serum of colorectal cancer patients not only can be used as a marker of colorectal cancer,but also can be used as an indicator to prediction of colorectal cancer whether the liver metastasis.
Conclusion:Through this experimental study found that patients with colorectal cancer compared with the control groups,HGF values rising were significantly different.In addition,through this experimental study we found that HGF also has relationship with colorectal cancer stage.And the later the colorectal cancer's stage is, the higher the serum HGF value will be.Especially the serum HGF expression in patients who have liver metastases was far higher than those without liver metastasis group.Thus this result farther prompted the serum HGF in colorectal carcinoma may indicate a more aggressive biological behavior.However it is worth mentioning of only 5 patients in the Duck'D that had other parts of the transfer(no liver metastases). Although they had the higher value of serum HGF,but had not significant difference to compare with Duck'A and B.Analysis of its causes may be related to the small number of cases.In short,the serum HGF values are likely to become a kind of tumor markers to be used diagnosis for colorectal cancer patients,and may be have certain of guiding significance for colorectal cancer patients at metastasis,stages,prognosis judgement and develop treatment programs.
引文
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3、李连第,饶克勤,主编.1993-1997中国试点市、县恶性肿瘤的发病与死亡(第二卷)[M]。北京:中国医药科技出版社2002.28-34
4、Stangl R,Altendorf Hofmann A,Charnly RM,et al.Factors influencing the natural history of colorectal liver metastases[J].Lancet,1994;343(8910):1405
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[1]李连第,饶克勤,主编.1993-1997中国试点市、县恶性肿瘤的发病与死亡(第2卷)[M].北京:中国医药科技出版社2002:28-34.
[2]孙燕、汤钊猷主译.UICC临床肿瘤学手册[M].第8版北京:人民卫生出版社,2006:383.
[3]陈俊忠、徐嘉凤、叶红军,肝细胞生长因子及其受体与胃癌[J].医学综述,2005,11(7):613-614.
[4]Filigheddu N,Cutmpi S,Porporato PE,et al,Diacylglycerol kinase is required for HGF-induced invasiveness and anchorage-independent growth of MDA-MB-231breast cancer cells[J],Anticancer Res.2007 May-Jun;27(3B):1489-92
[5]Miki C,Inoue Y,Hiro J,et al,Combined measurement of hepatocyte growth factor and carcinoembryonic antigen as a prognostic marker for patients with dukes A and B colorectal cancer:results of a five-year study[J].Dis Colon Rectum.2006 Nov;49(11):1710-8.
[6]Takao Ide,Yoshihiko Kitajima,Atsushi Miyoshi,et al,The Hypoxic Environment in Tumor-Stromal Cells Accelerates Pancreatic Cancer Progression via the Activation of Paracrine Hepatocyte Growth Factor/c-Met Signaling[J].Ann Surg Oncol.2007Nov;14(9):2600-2607
[7]Jagadeeswaran R,Ma PC,Seiwert TY,et al,Functional analysis of c-Met/hepatocyte growth factor pathway in malignant pleural mesothelioma[J].Cancer Res.2006 Jan 1;66(1):352-61.
[8]Alexandrakis MG,Passam FH,Sfiridaki A,et al,Elevated serum concentration of hepatocyte growth factor in patients with multiple myeloma:correlation with markers of disease activity[J].Am J Hematol.2003 Apr;72(4):229-33.
[9]Kataoka H,Hamasuna R,ItohH,et al.Activation of hepatocyte growth factor in colorectal carcimoma[J].Cancer Res,2000,60:6148-6159.
[10]Tanaka K,Miki C,Wakuda R,etal.Circulating level of hepatocyte growth factor as a useful tumormarker in patients with early-stage carcinoma[J].Scand J Gastroenterol,2004,39(8):754-760.
[11]Eichbaum MH,de Rossi TM,Kaul S,et al,Serum levels of hepatocyte growth factor/scatter factor in patients with liver metastases from breast cancer.Tumour Biol.2007;28(1):36-44.
[12]尹家俊、张锦瑜、宋燕,等.血清肝细胞生长因子水平与乳腺癌转移的关系.中国肿瘤临床[J],2003,30(7):478-479.
2、夏振龙.大肠癌肝转移的发生率及临床特点[J].中国实用外科杂志,1999,19(10):579
3、李连第,饶克勤,主编.1993-1997中国试点市、县恶性肿瘤的发病与死亡(第二卷)[M]。北京:中国医药科技出版社2002.28-34
4、Stangl R,Altendorf Hofmann A,Charnly RM,et al.Factors influencing the natural history of colorectal liver metastases[J].Lancet,1994;343(8910):1405
5、Scheele J,Stangl R,Altendorf-Hofmarm A.Hepatic metastases from colorectal carcinoma:impact of surgical resection on the natural history[J].Br J Surg,1990;77:1241-1246
6、敖亚洲,胡建功,史丽民,等CEA mRNA和TA对诊断消化系统肿瘤远处转移的价值[J].中国肿瘤临床,2005,32(18):1061-1063
7、周立生,李大鹏,王斌,等.结直肠癌术后肝转移相关因素分析[J]。中国癌症杂志,2006,16(5):394-395
8、Ishida H,Yoshinage K,Gonda T,et al.Biliary carcinoem bryonic antigen levels can predict metachronous liver metastasis of col-orectal cancer[J].Anitcancer Res,2000,20(1B):523-526
9、Akashi,Arifumi;Komuta et al.Carcinoembryonic antigen mrna in the mesenteric vein is not a predictor of hepatic metastasis in patients with resectable colorectal cancer:a long-term study[J].Diseases of the Colon & Rectum.46(12):1653-1658,December 2003
10、曾益新肿瘤学(研究生教材)[M].北京:人民卫生出版社,2003年第二版.241-262
11、Filigheddu N,Cutrupi S,Porporato PE,et al,Diacylglycerol kinase is required for HGF-induced invasiveness and anthorage-independent growth of MDA-MB-231 breast cancer cells[J],Anticancer Res.2007 May-Jun;27(3B):1489-92
12、Nakamura T.Structure and function of hepatocyte growth factor[J].Prog Growth Factor Res,1991,3:67-85.
13、Michalopoulos GK,Zarnegar R.Hepatocyte growth factor[J].Hepatology,1992;15(1):149-155
14、Takao Ide,Yoshihiko Kitajima,Atsushi Miyoshi,et al,The Hypoxic environment in Tumor-Stromal Cells Accelerates Pancreatic Cancer Progression via the Activation of Paracrine Hepatocyte Growth Factor/c-Met Signaling[J].Ann Surg Oncol.2007 Nov;14(9):2600-2607
15、Jagadeeswaran R,Ma PC,Seiwert TY,et al,Functional analysis of c-Met/hepatocyte growth factor pathway in malignant pleural mesothelioma[J].Cancer Res.2006 Jan 1;66(1):352-61.
16、谢倩、刘康达等,c—met—SF/HGF基因表达对肝癌细胞转移能力的影响[J].实用癌症杂志.2001,16(2):117-120
17、罗运权、吴孟超,肝细胞生长因子及其受体基因在人肝癌和癌旁肝组织中的表达[J].第二军医大学学报.1998,19(4):316-318
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