肝细胞生长因子及其受体c-met在人垂体瘤中的表达
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摘要
垂体瘤是神经外科病人中常见的肿瘤。其主要临床表现为肿瘤渐进性生长或瘤体急性出血挤压正常垂体,导致腺体激素分泌异常继而引起高催乳素血症、肢端肥大症、Cushing综合征、甲状腺功能亢进等,挤压视神经导致视力、视野改变,挤压、侵袭硬脑膜导致头痛等症状。垂体瘤的治疗包括手术切除、放疗、化疗等。垂体瘤手术后仍有可能会复发。对可能会复发的垂体瘤手术后可给予放疗、化疗。侵袭性垂体瘤是介于良性和恶性垂体瘤之间的肿瘤,其表现为生长突破其包膜并侵犯硬脑膜、视神经、骨质等毗邻结构。侵袭性垂体瘤因毗邻结构重要使手术不能完全切除,手术后易复发。
肝细胞生长因子(HGF)是具有促进肿瘤生长及血管生成作用的重要因子。其受体酪氨酸激酶受体c-met是HGF的已知唯一受体。HGF/c-met信号通路在促进肿瘤细胞增殖、迁徙、侵袭及肿瘤血管生成中具有重要的作用。针对HGF和c-met的治疗可以抑制肿瘤生长及血管生成,降低肿瘤HGF和c-met表达水平。HGF及c-met在胶质瘤、脑膜瘤、施万细胞瘤等脑肿瘤中高表达,且其表达水平高和患者恶性预后相关。HGF及c-met蛋白在垂体瘤中的表达情况及其作用还没有文献研究。
本实验研究目的是：通过免疫组织细胞化学观察HGF及c-met蛋白在人垂体瘤病理标本中的表达情况,研究HGF及c-met蛋白表达与微血管密度及细胞增生、肿瘤侵袭性等临床预后指标的相关性,探讨HGF及c-met蛋白在人垂体瘤发病中的机制及潜在的治疗价值。
目的
研究HGF及c-met蛋白在人垂体瘤病理标本中的表达情况,研究HGF及c-met蛋白表达与微血管密度及细胞增生、肿瘤侵袭性等临床预后指标的相关性。
材料与方法
收集人垂体瘤手术切除病理标本,行免疫组化染色,观察HGF及c-met蛋白在人垂体瘤病理标本中的表达情况,研究HGF及c-met蛋白表达与微血管密度及细胞增生、肿瘤侵袭性等临床预后指标的相关性。
1.材料
收集人垂体瘤手术切除病理标本65例及患者临床资料如患者年龄、性别、肿瘤组织类型、影像学资料等。
2.免疫组织化学染色
检测HGF和c-met蛋白表达是使用抗HGF和c-met抗体,通过链霉菌-亲和素-生物素复合物(SABC)方法染色。检测微血管密度是通过使用抗CD34抗体,检测细胞增殖指标是通过使用抗Ki-67抗体。
3.免疫组织化学结果分析
HGF和c-Met免疫组化结果记录为：一,无阳性细胞；+,小于30%的细胞阳性；++,30%-60%的细胞阳性；+++,大于60%的细胞阳性.Ki-67免疫组化结果记录为每个高倍镜(×400)下阳性细胞的数目,每个标本观察阳性细胞数目最多的5个视野,用平均数作为结果.微血管密度记录为高倍镜(×400)下CD34阳性的血管或细胞簇的数目,每个标本观察CD34阳性数目最多的5个视野,用平均数作为结果.
4.统计学分析
使用Spearman等级相关性分析方法研究HGF及c-met蛋白表达与微血管密度及细胞增生、肿瘤侵袭性等临床预后指标的相关性,SPSS17.0软件。
结果
HGF及c-met蛋白在人垂体瘤中高表达,HGF及c-met蛋白阳性表达率为98%及92%。HGF蛋白表达阳性细胞数和微血管密度(MVD)的相关性系数为0.31(P=0.01),和细胞增殖指标Ki-67的相关性系数为0.32(P=0.01)。c-met蛋白表达阳性细胞数和MVD的相关性系数为0.3(P=0.02),和Ki-67的相关性系数为0.38(P=0.00)。
结论
HGF及c-met蛋白在人垂体瘤中高表达,其表达程度和微血管密度及细胞增殖指标具有显著相关性,提示HGF及c-met在垂体瘤血管生成及细胞增殖中具有一定的作用,为研究垂体瘤的发病机制提供新的方向。抑制HGF及c-met表达可能会抑制垂体瘤的生长,为垂体瘤化疗提供新的手段。
Pituitary adenomas are common tumors in patients from Department of Neurosurgery. Progressive tumor growth or intratumoral hemorrhage can compress surrounding structures and cause clinical manifestations in patients. Compression of pituitary gland can result in disorder of hormone secretion and cause symptoms such as hyperprolactinoma, acromegaly, Cushing's disease and hyperthyroidism; compression of optic nerve can cause changes in vision and visual field; compression or invasion of cerebral dural matter will cause symptoms like headache. Treatments of pituitary adenomas include surgery, radiotherapy and chemotherapy. Tumors may recur after surgical resection. Radiotherapy or chemotherapy should be given for tumors that may recur after surgery. Invasiveness of pituitary adenomas refers to that tumors grow beyond its capsule and invade adjacent structures such as dural matter, optic nerve and skull. Invasive pituitary adenomas make complete surgical resection impossible because of adjacent impotant structures and prone to recur after surgery.
HGF is an important growth factor for tumor growth and angiogenesis. Its only known receptor c-met is a receptor tyrosine kinase. HGF/c-met pathway is important for tumor cell proliferation, migration, invasion and angiogenesis. Therapeutic approaches targeting HGF or c-met can decrease HGF and c-met expression levels and inhibit tumor growth and angiogenesis. HGF and c-met are ovexpressed in gliomas, meningiomas and schwannomas, and their expression levels correlates with patients'poor prognosis. However, HGF and c-met protein expression in pituitary adenomas has not been reported.
The aim of this study is as follows:to investigate HGF and c-met protein expression in human pituitary adenomas from patients; to analyze the correlation of HGF and c-met protein expression with prognostic markers such as microvessel density, proliferative marker and tumor invasiveness; to explore the mechanism of HGF and c-met protein expression in pathogenesis pituitary adenomas and their therapeutic potential.
Objective
To investigate HGF and c-met protein expression in human pituitary adenomas from patients; to analyze the correlation of HGF and c-met protein expression with prognostic markers such as microvessel density, proliferative marker and tumor invasiveness; to explore the mechanism of HGF and c-met protein expression in pathogenesis pituitary adenomas and their therapeutic potential.
Methods
Immunohistochemical staining was done to detect HGF and c-met protein expression in human pituitary adenomas. Statistical analysis was done to investigate the correlation of HGF and c-met protein expression with prognostic markers such as microvessel density, proliferative marker and tumor invasiveness.
1. Samples
65samples of pituitary adenomas and patients'clinical data such as patients'age, sex, tumor phenotypes on imaging and tumor histology types were collected.
2. Immunohistochemical staining
HGF and c-met protein expression, tumor angiogenesis and cell proliferation were detected by strepto-avidin-biotin complex method method using antibodies anti-HGF, anti-c-met, anti-CD34and anti-Ki-67.
3. Analysis of results
HGF and c-Met immunoreactivity was recorded as follows:-, no immunopositive cells;+,30%of tumor cells are immunopositive;++,30%-60%of tumor cells are immunopositive;+++,60%of tumor cells are immunopositive. Scores for Ki-67were recorded as the number of immunopositive cells per high-power microscope (X400). The number of immunopositive cells under5microscopes per slide with the highest cell counts was counted and the average was recorded. MVD was recorded as the number of vessels or clusters of cells immunopositive for CD34per high-power microscope (×400). Each immunostained cell or cell cluster that was clearly separated from adjacent micro vessels was considered as a single countable microvessel. MVD under5microscopes per slide with the highest vascular counts were counted and the average was recorded.
4. Statistical analysis
Statistical analysis of the correlation of HGF and c-met protein expression with prognostic markers such as microvessel density, proliferative marker and tumor invasiveness were done using Spearman rank correlation analysis (SPSS Version18.0). P<0.05is considered statistically significant.
Results
HGF and c-met protein are expressed in most pituitary tumors. HGF and c-met protein expression existed in98%and92%of pituitary adenomas respectively. HGF immunoreactivity has significant correlation with MVD (Spearman's correlation coefficient r=0.31, P=0.01) and has significant correlation with cell proliferation index Ki-67(r=0.32, P=0.01). c-met immunoreactivity has significant correlation with MVD (r=0.3, P=0.02) and has significant correlation with cell proliferation index Ki-67(r=0.38, P=0.00).
Conclusions
HGF and c-met protein are expressed in most pituitary tumors, and their expression levels significantly correlate with angiogenic and proliferative markers. The results indicate that HGF and c-met protein may have important roles in angiogenesis and cell proliferation in pituitary adenomas; and offer a new direction for investigating pituitary tumor pathogenesis. HGF and c-met can be new promising chemotherapeutic targets in pituitary adenomas as previous anti-HGF or anti-c-met approaches can inhibit tumor growth in other tumors.
肝细胞生长因子(HGF)是具有促进肿瘤生长及血管生成作用的重要因子。其受体酪氨酸激酶受体c-met是HGF的已知唯一受体。HGF/c-met信号通路在促进肿瘤细胞增殖、迁徙、侵袭及肿瘤血管生成中具有重要的作用。针对HGF和c-met的治疗可以抑制肿瘤生长及血管生成,降低肿瘤HGF和c-met表达水平。HGF及c-met在胶质瘤、脑膜瘤、施万细胞瘤等脑肿瘤中高表达,且其表达水平高和患者恶性预后相关。HGF及c-met蛋白在垂体瘤中的表达情况及其作用还没有文献研究。
本实验研究目的是：通过免疫组织细胞化学观察HGF及c-met蛋白在人垂体瘤病理标本中的表达情况,研究HGF及c-met蛋白表达与微血管密度及细胞增生、肿瘤侵袭性等临床预后指标的相关性,探讨HGF及c-met蛋白在人垂体瘤发病中的机制及潜在的治疗价值。
目的
研究HGF及c-met蛋白在人垂体瘤病理标本中的表达情况,研究HGF及c-met蛋白表达与微血管密度及细胞增生、肿瘤侵袭性等临床预后指标的相关性。
材料与方法
收集人垂体瘤手术切除病理标本,行免疫组化染色,观察HGF及c-met蛋白在人垂体瘤病理标本中的表达情况,研究HGF及c-met蛋白表达与微血管密度及细胞增生、肿瘤侵袭性等临床预后指标的相关性。
1.材料
收集人垂体瘤手术切除病理标本65例及患者临床资料如患者年龄、性别、肿瘤组织类型、影像学资料等。
2.免疫组织化学染色
检测HGF和c-met蛋白表达是使用抗HGF和c-met抗体,通过链霉菌-亲和素-生物素复合物(SABC)方法染色。检测微血管密度是通过使用抗CD34抗体,检测细胞增殖指标是通过使用抗Ki-67抗体。
3.免疫组织化学结果分析
HGF和c-Met免疫组化结果记录为：一,无阳性细胞；+,小于30%的细胞阳性；++,30%-60%的细胞阳性；+++,大于60%的细胞阳性.Ki-67免疫组化结果记录为每个高倍镜(×400)下阳性细胞的数目,每个标本观察阳性细胞数目最多的5个视野,用平均数作为结果.微血管密度记录为高倍镜(×400)下CD34阳性的血管或细胞簇的数目,每个标本观察CD34阳性数目最多的5个视野,用平均数作为结果.
4.统计学分析
使用Spearman等级相关性分析方法研究HGF及c-met蛋白表达与微血管密度及细胞增生、肿瘤侵袭性等临床预后指标的相关性,SPSS17.0软件。
结果
HGF及c-met蛋白在人垂体瘤中高表达,HGF及c-met蛋白阳性表达率为98%及92%。HGF蛋白表达阳性细胞数和微血管密度(MVD)的相关性系数为0.31(P=0.01),和细胞增殖指标Ki-67的相关性系数为0.32(P=0.01)。c-met蛋白表达阳性细胞数和MVD的相关性系数为0.3(P=0.02),和Ki-67的相关性系数为0.38(P=0.00)。
结论
HGF及c-met蛋白在人垂体瘤中高表达,其表达程度和微血管密度及细胞增殖指标具有显著相关性,提示HGF及c-met在垂体瘤血管生成及细胞增殖中具有一定的作用,为研究垂体瘤的发病机制提供新的方向。抑制HGF及c-met表达可能会抑制垂体瘤的生长,为垂体瘤化疗提供新的手段。
Pituitary adenomas are common tumors in patients from Department of Neurosurgery. Progressive tumor growth or intratumoral hemorrhage can compress surrounding structures and cause clinical manifestations in patients. Compression of pituitary gland can result in disorder of hormone secretion and cause symptoms such as hyperprolactinoma, acromegaly, Cushing's disease and hyperthyroidism; compression of optic nerve can cause changes in vision and visual field; compression or invasion of cerebral dural matter will cause symptoms like headache. Treatments of pituitary adenomas include surgery, radiotherapy and chemotherapy. Tumors may recur after surgical resection. Radiotherapy or chemotherapy should be given for tumors that may recur after surgery. Invasiveness of pituitary adenomas refers to that tumors grow beyond its capsule and invade adjacent structures such as dural matter, optic nerve and skull. Invasive pituitary adenomas make complete surgical resection impossible because of adjacent impotant structures and prone to recur after surgery.
HGF is an important growth factor for tumor growth and angiogenesis. Its only known receptor c-met is a receptor tyrosine kinase. HGF/c-met pathway is important for tumor cell proliferation, migration, invasion and angiogenesis. Therapeutic approaches targeting HGF or c-met can decrease HGF and c-met expression levels and inhibit tumor growth and angiogenesis. HGF and c-met are ovexpressed in gliomas, meningiomas and schwannomas, and their expression levels correlates with patients'poor prognosis. However, HGF and c-met protein expression in pituitary adenomas has not been reported.
The aim of this study is as follows:to investigate HGF and c-met protein expression in human pituitary adenomas from patients; to analyze the correlation of HGF and c-met protein expression with prognostic markers such as microvessel density, proliferative marker and tumor invasiveness; to explore the mechanism of HGF and c-met protein expression in pathogenesis pituitary adenomas and their therapeutic potential.
Objective
To investigate HGF and c-met protein expression in human pituitary adenomas from patients; to analyze the correlation of HGF and c-met protein expression with prognostic markers such as microvessel density, proliferative marker and tumor invasiveness; to explore the mechanism of HGF and c-met protein expression in pathogenesis pituitary adenomas and their therapeutic potential.
Methods
Immunohistochemical staining was done to detect HGF and c-met protein expression in human pituitary adenomas. Statistical analysis was done to investigate the correlation of HGF and c-met protein expression with prognostic markers such as microvessel density, proliferative marker and tumor invasiveness.
1. Samples
65samples of pituitary adenomas and patients'clinical data such as patients'age, sex, tumor phenotypes on imaging and tumor histology types were collected.
2. Immunohistochemical staining
HGF and c-met protein expression, tumor angiogenesis and cell proliferation were detected by strepto-avidin-biotin complex method method using antibodies anti-HGF, anti-c-met, anti-CD34and anti-Ki-67.
3. Analysis of results
HGF and c-Met immunoreactivity was recorded as follows:-, no immunopositive cells;+,30%of tumor cells are immunopositive;++,30%-60%of tumor cells are immunopositive;+++,60%of tumor cells are immunopositive. Scores for Ki-67were recorded as the number of immunopositive cells per high-power microscope (X400). The number of immunopositive cells under5microscopes per slide with the highest cell counts was counted and the average was recorded. MVD was recorded as the number of vessels or clusters of cells immunopositive for CD34per high-power microscope (×400). Each immunostained cell or cell cluster that was clearly separated from adjacent micro vessels was considered as a single countable microvessel. MVD under5microscopes per slide with the highest vascular counts were counted and the average was recorded.
4. Statistical analysis
Statistical analysis of the correlation of HGF and c-met protein expression with prognostic markers such as microvessel density, proliferative marker and tumor invasiveness were done using Spearman rank correlation analysis (SPSS Version18.0). P<0.05is considered statistically significant.
Results
HGF and c-met protein are expressed in most pituitary tumors. HGF and c-met protein expression existed in98%and92%of pituitary adenomas respectively. HGF immunoreactivity has significant correlation with MVD (Spearman's correlation coefficient r=0.31, P=0.01) and has significant correlation with cell proliferation index Ki-67(r=0.32, P=0.01). c-met immunoreactivity has significant correlation with MVD (r=0.3, P=0.02) and has significant correlation with cell proliferation index Ki-67(r=0.38, P=0.00).
Conclusions
HGF and c-met protein are expressed in most pituitary tumors, and their expression levels significantly correlate with angiogenic and proliferative markers. The results indicate that HGF and c-met protein may have important roles in angiogenesis and cell proliferation in pituitary adenomas; and offer a new direction for investigating pituitary tumor pathogenesis. HGF and c-met can be new promising chemotherapeutic targets in pituitary adenomas as previous anti-HGF or anti-c-met approaches can inhibit tumor growth in other tumors.
引文
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