EGCG致人肺腺癌“血管正常化”及窗口期联合顺铂疗效评估
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摘要
背景：人肺腺癌作为一种实体肿瘤,肿瘤微血管与微环境对其增殖、侵袭、转移和进展起到了重要作用,同时也可被多种抗血管生成药物所影响。研究证明,合理运用抗血管生成治疗可使原来扭曲异常的肿瘤血管趋于正常,从而引起肿瘤血管和肿瘤微环境正常化,进而更有效地输送氧和药物到达肿瘤细胞,以提高化疗和放疗的疗效。正常化的过程是短暂而可逆的,因此会形成特定的正常化“时间窗"。它与使用的药物及肿瘤类型、部位相关,在该时间窗内联合放化疗可以起到协同作用。目前大量临床前和临床研究都证实,多种直接或间接的抗血管生成治疗能使肿瘤血管发生正常化。表没食子儿茶素没食子酸酯(Epigollatecatech in gallate, EGCG)是从绿茶中提取的主要天然成分,已被证明可以作用于多种血管生成因子,包括血管内皮生长因子(VEGF),血小板源性生长因子(PDGF)和血管生成素(Angs)。因此,我们假设EGCG能够引起人肺腺癌肿瘤微血管结构与功能的改变并诱发“血管正常化”现象,并推测在EGCG引起的肿瘤“血管正常化”窗口期联合化疗可以起到抗肿瘤的协同作用。为证明该假设,我们建立了A549人肺腺癌细胞株裸鼠移植瘤模型,检测经EGCG处理后模型肿瘤组织在不同时间点其微血管结构、功能以及微环境效应指标的变化,以及不同时间点联合化疗抗肿瘤疗效,以证明该假设。
方法与结果：建立A549人肺腺癌细胞株移植瘤模型,随机分成三组分别予以生理盐水、EGCG、贝伐单抗(阳性对照)处理,分别检测第0、2、4、6、9、12天6个时间点的以下指标。(1)血管结构改变指标：量子点双标免疫荧光标记CD31-a-SMA观察微血管结构,并计数CD31-MVD(微血管密度)、a-SMA-MVD,和计算周细胞覆盖率(MPI)；量子点双标免疫荧光标记CD31-CollagenIV观察血管基底膜;透射电镜评价内皮细胞、周细胞的形态与连接、基底膜的完整性以及肿瘤细胞与血管的关系；(2)血管功能改变指标：量子点双标免疫荧光标记CD31-lectin评价血管灌注功能；Evans blue灌注法评价血管渗透性；(3)肿瘤微环境效应改变指标：组织间液压(IFP)、组织氧分压(P02)测定;免疫组化法标记Pimonidazole检测肿瘤组织乏氧水平。以上结果显示EGCG及贝伐单抗处理A549荷瘤裸鼠后均可引起肿瘤组织CD31-MVD的持续下降,MPI逐渐上升,血管灌注功能及渗透性一过性升高,肿瘤组织IFP一过性下降、PO2一过性升高,但EGCG处理组微血管基底膜出现变薄且规律分布,而贝伐单抗组血管基底膜标记Collagen IV表达量仅出现下降趋势,无统计学意义(P>0.05)。根据以上改变可以明确观察到EGCG引起了人肺腺癌移植瘤肿瘤血管正常化,并且以上相应血管指标一过性改变的窗口约位于第4-9天,而贝伐单抗的窗口期约位于第2-6天。我们进一步检测予以不同EGCG联合顺铂给药方式时肿瘤组织内顺铂的浓度,分别分为d0(窗口期前)天予以全量顺铂(4mg/kg)单次腹腔注射给药(A组),d5(窗口期)予以半量顺铂(2mg/kg)单次腹腔注射给药(B组),d5(窗口期)予以全量顺铂(4mg/kg)单次腹腔注射给药(C组),以(石墨炉)原子吸收光谱法检测肿瘤组织中顺铂浓度。结果显示C组移植瘤组织内浓度明显高于另三组(1.8μg/gm组织,P<0.01),差异有统计学意义。B组所达顺铂组织浓度与A组近似(分别为1.0μg/gm组织,0.8μg/gm组织),差异无统计学意义(P>0.05)。为明确在以上窗口期联合化疗是否可以影响人肺腺癌肿瘤对化疗的敏感性并且产生协同抗肿瘤作用,我们将A549荷瘤裸鼠分别予以生理盐水(A组)、顺铂(B组)、EGCG溶液(C组)、EGCG+第0天联合顺铂(D1组)和EGCG+第5天(窗口期内)联合顺铂处理(D2组),通过记录各组瘤体长至1250mm3所需平均天数得出肿瘤生长延迟天数,并通过计算抑瘤率观察肿瘤生长速度。结果显示：(1).各组的肿瘤生长延迟天数分别为：6.3±1.51天,7.5±1.57天,83±1.79天,12.1±1.35天和15.4±1.99天,将A、B、C、D2四组肿瘤生长延迟天数进行统计学分析提示EGCG与顺铂抗肿瘤治疗有协同效应(P<0.01)；(2)联合治疗组(D1、D2)移植瘤生长速度较另三组明显较慢(抑瘤率分别为5.53%、12.82%、40.18%、56.88%,p<0.001),差异有统计学意义,且在窗口期联合化疗的D2组肿瘤生长速度明显缓于在窗口期前联合化疗的D1组(P<0.01)。
结论：EGCG可以引起人肺腺癌移植瘤肿瘤血管正常化,其正常化窗口期约位于第4-9天,在该窗口期内联合化疗可以使肿瘤组织局部化疗浓度升高,并与化疗抗肿瘤治疗产生协同效应,为EGCG作为辅助化疗药物提供了新的应用策略。
Background:Microvasculature and microenvironment play important roles of proliferation, invasion, metastasis and prognosis in human lung adenocarcinoma, and can be affected by various anti-angiogenic drugs. It has been demonstrated that appropriate anti-angiogenesis treatment tends to normalize previously torturous and malformed vessels, thus normalizing microvasculature and microenvir-onment, which, then translates to delivering oxygen and drugs to tumor cells in a more effective way, and consequently improving the treatment efficacy of both chemotherapy and radiotherapy. The priod of normalization is transient and reversible, so a specific normalization time window can be formed according to the applied drugs, as well as the types and location of the tumor. In this time window, combined chemotherapy can reach a synergistic effect.Currently a large scale of pre-clinical or clinical researches synergistic effect. Epigallocatechin-3-gallate (EGCG), a nature anti-angiogenesis agent refined from green tea, is defined to have multiple effects on angiogenesis factors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and angiopoietins(ANGs). So, we suppose that ECGC can alter human lung adenocarcinoma tumor microvasculature and microenvironment and cause "vessel normalization"phenomenon, and in addition combined chemotherapy exert a synergistic effect in the tumor vessel normalization window caused by EGCG treatment.To demonstrate this assumption, we built a nude mice xenograft tumor model in the cell line of A549human lung adenocarcinoma, examine the structure and function of microvasculature, microenvironment index changes, as well as the efficacy of combined chemotherapy at different time points after treating the model with EGCG.
Methods and results:Build a nude mice xenograft tumor model in the cell line of A549human lung adenocarcinoma. Randomly divide the mice into three groups and treat each one with saline, EGCG, bevacizumab, and respectively test the following indexes at the time points of0,2,4,6,9,12day.(1)Vessel structure change index:quantum dots double-lable immunofluorescence assessment of CD31-a-SMA to observe microvasculature, counting CD31-MVD, a-SMA-MVD, and MPI; quantum dots double-lable immunofluorescence assessment of CD31-Collagen IV to observe vessel GBM; Transmission electron microscope to assess endothelial cells, the form and connection of pericytes, the integrity of GBM and the association between tumor cells and vessels.(2)Vessel functional change indexes:quantum dots double-lable immunofluorescence assessment of CD31-lectin to assess vessel perfusion function. Evans blue perfusion to assess vessel permeability.(3)Microenvironment effect change indexes:IFP, PO2. Immunohistochmical label of Pimonidazole to test hypoxia level in the tumor tissue. EGCG treatment of A549cells in mice bearing xenografts in vivo led to a persisting decrease of CD31-MVD, and a gradual decrease of MPI, a transient alevation of vessel perfusion function and permeability and PO2, transient decrease of IFP in tumor tissue. Yet EGCG treated group had a thinner microvasculature GBM which was regularly distributed, but bevacizumab group had simply a tendency of decreased Collage IV expression without significancy (P>0.05). Accordingly, it can be concluded that EGCG caused the vessel normalization of NSCLC xenografts tumor. Additionally, vessel indexes mentioned above had a transient change window in day4to9, yet bevacizumab's time window was in day2to6. We test cisplatin concentration in tumor tissues when administrated with different combined chemotherapy of EGCG and cisplatin. Full-dose cisplatin (4mg/kg) at dO (pre-window period) in single intraperitoneal administration (Group A), half-dose cisplatin (2mg/kg) at d5(window period) in single intraperitoneal administration (Group B), full-dose cisplatin (4mg/kg) at d5in single intraperitoneal administration(Group C), and use graphite furnace atomic absorption spectrometry to test cisplatin concentration in tumor tissue. Results showed that Group C had a concentration significantly higher than other three groups (1.8μg/gm tissue, p<0.001), and Group B had the assembling concentration as Group A (respectively1.0μg/gm tissue and0.8μg/gm tissue) without significancy (p>0.05). To specify whether combined therapy can affect human lung adenocarcinoma tumor's sensitivity to chemotherapy and have synergistic effect in the window periods mentioned above, we treated xenograft tumor nude mice with saline (Group A), cisplatin (Group B), EGCG (Group C), EGCG+combining cisplatin on dO (Group D1) and EGCG+combining cisplatin on d5(Group D2). Recorded the time for each tumor to reach the approximately volume of1250mm3then calculate number of tumor growth delay, and calculate tumor suppressing rate to observe tumor growth rate. Results showed that each group had a tumor growth delay of6.3±1.51days,7.5±1.57days,8.3+1.79days,12.1±1.35days and15.4±1.99days. Analysis of tumor growth delay of Group A, B, C, D2suggested that EGCG and cisplatin had synergistic effect as a combined anti-tumor chemotherapy (P<0.01). In addition, this result also revealed that combined treatment groups (D1, D2) had significantly lower xenograft tumor growth rates than other three groups (tumor inhibition rate were respectively5.53%、12.82%、40.18%、 56.88%, p<0.001), and tumor growth rate in D2was significantly lower than D1(P<0.01).
Conclusion:EGCG causes vessel normalization in NSCLC xenograft tumor, the window period of with is between Day4to Day9. Combined therapy in this window period can escalate drug concentration in local tumor tissue, and leads to anti-tumor synergistic effect, providing a new strategy for EGCG applying as a complementary chemotherapy drug.
方法与结果：建立A549人肺腺癌细胞株移植瘤模型,随机分成三组分别予以生理盐水、EGCG、贝伐单抗(阳性对照)处理,分别检测第0、2、4、6、9、12天6个时间点的以下指标。(1)血管结构改变指标：量子点双标免疫荧光标记CD31-a-SMA观察微血管结构,并计数CD31-MVD(微血管密度)、a-SMA-MVD,和计算周细胞覆盖率(MPI)；量子点双标免疫荧光标记CD31-CollagenIV观察血管基底膜;透射电镜评价内皮细胞、周细胞的形态与连接、基底膜的完整性以及肿瘤细胞与血管的关系；(2)血管功能改变指标：量子点双标免疫荧光标记CD31-lectin评价血管灌注功能；Evans blue灌注法评价血管渗透性；(3)肿瘤微环境效应改变指标：组织间液压(IFP)、组织氧分压(P02)测定;免疫组化法标记Pimonidazole检测肿瘤组织乏氧水平。以上结果显示EGCG及贝伐单抗处理A549荷瘤裸鼠后均可引起肿瘤组织CD31-MVD的持续下降,MPI逐渐上升,血管灌注功能及渗透性一过性升高,肿瘤组织IFP一过性下降、PO2一过性升高,但EGCG处理组微血管基底膜出现变薄且规律分布,而贝伐单抗组血管基底膜标记Collagen IV表达量仅出现下降趋势,无统计学意义(P>0.05)。根据以上改变可以明确观察到EGCG引起了人肺腺癌移植瘤肿瘤血管正常化,并且以上相应血管指标一过性改变的窗口约位于第4-9天,而贝伐单抗的窗口期约位于第2-6天。我们进一步检测予以不同EGCG联合顺铂给药方式时肿瘤组织内顺铂的浓度,分别分为d0(窗口期前)天予以全量顺铂(4mg/kg)单次腹腔注射给药(A组),d5(窗口期)予以半量顺铂(2mg/kg)单次腹腔注射给药(B组),d5(窗口期)予以全量顺铂(4mg/kg)单次腹腔注射给药(C组),以(石墨炉)原子吸收光谱法检测肿瘤组织中顺铂浓度。结果显示C组移植瘤组织内浓度明显高于另三组(1.8μg/gm组织,P<0.01),差异有统计学意义。B组所达顺铂组织浓度与A组近似(分别为1.0μg/gm组织,0.8μg/gm组织),差异无统计学意义(P>0.05)。为明确在以上窗口期联合化疗是否可以影响人肺腺癌肿瘤对化疗的敏感性并且产生协同抗肿瘤作用,我们将A549荷瘤裸鼠分别予以生理盐水(A组)、顺铂(B组)、EGCG溶液(C组)、EGCG+第0天联合顺铂(D1组)和EGCG+第5天(窗口期内)联合顺铂处理(D2组),通过记录各组瘤体长至1250mm3所需平均天数得出肿瘤生长延迟天数,并通过计算抑瘤率观察肿瘤生长速度。结果显示：(1).各组的肿瘤生长延迟天数分别为：6.3±1.51天,7.5±1.57天,83±1.79天,12.1±1.35天和15.4±1.99天,将A、B、C、D2四组肿瘤生长延迟天数进行统计学分析提示EGCG与顺铂抗肿瘤治疗有协同效应(P<0.01)；(2)联合治疗组(D1、D2)移植瘤生长速度较另三组明显较慢(抑瘤率分别为5.53%、12.82%、40.18%、56.88%,p<0.001),差异有统计学意义,且在窗口期联合化疗的D2组肿瘤生长速度明显缓于在窗口期前联合化疗的D1组(P<0.01)。
结论：EGCG可以引起人肺腺癌移植瘤肿瘤血管正常化,其正常化窗口期约位于第4-9天,在该窗口期内联合化疗可以使肿瘤组织局部化疗浓度升高,并与化疗抗肿瘤治疗产生协同效应,为EGCG作为辅助化疗药物提供了新的应用策略。
Background:Microvasculature and microenvironment play important roles of proliferation, invasion, metastasis and prognosis in human lung adenocarcinoma, and can be affected by various anti-angiogenic drugs. It has been demonstrated that appropriate anti-angiogenesis treatment tends to normalize previously torturous and malformed vessels, thus normalizing microvasculature and microenvir-onment, which, then translates to delivering oxygen and drugs to tumor cells in a more effective way, and consequently improving the treatment efficacy of both chemotherapy and radiotherapy. The priod of normalization is transient and reversible, so a specific normalization time window can be formed according to the applied drugs, as well as the types and location of the tumor. In this time window, combined chemotherapy can reach a synergistic effect.Currently a large scale of pre-clinical or clinical researches synergistic effect. Epigallocatechin-3-gallate (EGCG), a nature anti-angiogenesis agent refined from green tea, is defined to have multiple effects on angiogenesis factors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and angiopoietins(ANGs). So, we suppose that ECGC can alter human lung adenocarcinoma tumor microvasculature and microenvironment and cause "vessel normalization"phenomenon, and in addition combined chemotherapy exert a synergistic effect in the tumor vessel normalization window caused by EGCG treatment.To demonstrate this assumption, we built a nude mice xenograft tumor model in the cell line of A549human lung adenocarcinoma, examine the structure and function of microvasculature, microenvironment index changes, as well as the efficacy of combined chemotherapy at different time points after treating the model with EGCG.
Methods and results:Build a nude mice xenograft tumor model in the cell line of A549human lung adenocarcinoma. Randomly divide the mice into three groups and treat each one with saline, EGCG, bevacizumab, and respectively test the following indexes at the time points of0,2,4,6,9,12day.(1)Vessel structure change index:quantum dots double-lable immunofluorescence assessment of CD31-a-SMA to observe microvasculature, counting CD31-MVD, a-SMA-MVD, and MPI; quantum dots double-lable immunofluorescence assessment of CD31-Collagen IV to observe vessel GBM; Transmission electron microscope to assess endothelial cells, the form and connection of pericytes, the integrity of GBM and the association between tumor cells and vessels.(2)Vessel functional change indexes:quantum dots double-lable immunofluorescence assessment of CD31-lectin to assess vessel perfusion function. Evans blue perfusion to assess vessel permeability.(3)Microenvironment effect change indexes:IFP, PO2. Immunohistochmical label of Pimonidazole to test hypoxia level in the tumor tissue. EGCG treatment of A549cells in mice bearing xenografts in vivo led to a persisting decrease of CD31-MVD, and a gradual decrease of MPI, a transient alevation of vessel perfusion function and permeability and PO2, transient decrease of IFP in tumor tissue. Yet EGCG treated group had a thinner microvasculature GBM which was regularly distributed, but bevacizumab group had simply a tendency of decreased Collage IV expression without significancy (P>0.05). Accordingly, it can be concluded that EGCG caused the vessel normalization of NSCLC xenografts tumor. Additionally, vessel indexes mentioned above had a transient change window in day4to9, yet bevacizumab's time window was in day2to6. We test cisplatin concentration in tumor tissues when administrated with different combined chemotherapy of EGCG and cisplatin. Full-dose cisplatin (4mg/kg) at dO (pre-window period) in single intraperitoneal administration (Group A), half-dose cisplatin (2mg/kg) at d5(window period) in single intraperitoneal administration (Group B), full-dose cisplatin (4mg/kg) at d5in single intraperitoneal administration(Group C), and use graphite furnace atomic absorption spectrometry to test cisplatin concentration in tumor tissue. Results showed that Group C had a concentration significantly higher than other three groups (1.8μg/gm tissue, p<0.001), and Group B had the assembling concentration as Group A (respectively1.0μg/gm tissue and0.8μg/gm tissue) without significancy (p>0.05). To specify whether combined therapy can affect human lung adenocarcinoma tumor's sensitivity to chemotherapy and have synergistic effect in the window periods mentioned above, we treated xenograft tumor nude mice with saline (Group A), cisplatin (Group B), EGCG (Group C), EGCG+combining cisplatin on dO (Group D1) and EGCG+combining cisplatin on d5(Group D2). Recorded the time for each tumor to reach the approximately volume of1250mm3then calculate number of tumor growth delay, and calculate tumor suppressing rate to observe tumor growth rate. Results showed that each group had a tumor growth delay of6.3±1.51days,7.5±1.57days,8.3+1.79days,12.1±1.35days and15.4±1.99days. Analysis of tumor growth delay of Group A, B, C, D2suggested that EGCG and cisplatin had synergistic effect as a combined anti-tumor chemotherapy (P<0.01). In addition, this result also revealed that combined treatment groups (D1, D2) had significantly lower xenograft tumor growth rates than other three groups (tumor inhibition rate were respectively5.53%、12.82%、40.18%、 56.88%, p<0.001), and tumor growth rate in D2was significantly lower than D1(P<0.01).
Conclusion:EGCG causes vessel normalization in NSCLC xenograft tumor, the window period of with is between Day4to Day9. Combined therapy in this window period can escalate drug concentration in local tumor tissue, and leads to anti-tumor synergistic effect, providing a new strategy for EGCG applying as a complementary chemotherapy drug.
引文
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