胃肠道肿瘤仿真裸鼠移植瘤模型在新型抗VEGF靶向药物评价中的应用研究
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摘要
背景：肿瘤动物模型一直以来是抗肿瘤药物临床前疗效预测和可能的毒性评价的有效工具。如果不能为每一种肿瘤找到一个与临床密切相关的肿瘤模型,那么将大大妨碍为某种特定的肿瘤类型找到一种具有普遍疗效的抗肿瘤药物。同样,如果不能为每一个肿瘤患者找到一个最能反映其个体特征的肿瘤模型,也就妨碍了为特定患者找到个体化的治疗药物。建立用于体内评价的代表每一种肿瘤类型的实验性动物模型将大大加快筛选有效的抗肿瘤药物的速度。这些动物模型还可以有效降低药物开发的费用和减少所需的患者来源的肿瘤组织。同样,个体化的肿瘤模型还有利于为每个肿瘤患者选择最有效的个体化治疗药物。近年来,越来越多的研究小组开始使用患者新鲜肿瘤组织来源(patient-derived human tumor tissue, PDTT)的裸鼠移植瘤模型。这种PDTT模型比传统的细胞系模型更能反映人类肿瘤的生物学特征,在细胞增殖、组织形态学特征和分子特征与来源肿瘤组织具有高度的一致性。由于PDTT模型比细胞系模型更能反映体内状况,因此被有效地应用于潜在抗肿瘤药物的快速筛选。
PDTT模型具备四大应用前景：首先,这种模型可以作为抗肿瘤药物临床前筛选的工具。其次,这种模型可以用于评价、分析和筛选抗肿瘤治疗疗效和耐药的标志物。第三,PDTT模型的理想特征也为研究肿瘤原发瘤与转移瘤之间的异质性及这种异质性对抗肿瘤药物疗效的影响提供了一个有效的研究工具。第四,由于现有的个体化治疗方法的局限性,迫切需要一种新的方法来尽可能地实现肿瘤治疗的个体化。PDTT模型将是一个为每一位患者预测治疗药物疗效从而实现个体化治疗的理想工具。
血管生成是肿瘤多步骤发生发展过程中的八大标志之一。血管内皮生长因子(vascular endothelial growth factor, VEGF)是目前已知的唯一一个贯穿整个肿瘤生长周期的血管生长因子。因此,VEGF被认为是抗肿瘤血管生成药物开发的理想靶标。通过抗VEGF达到抗肿瘤血管生成进而实现抗肿瘤治疗的目的在实体瘤的治疗中具有广阔的应用前景。FP3是一个靶向VEGF的全人源化的可溶性受体蛋白。它的结构包括了VEGFR1(Flt-1)的第二个胞外区域和VEGFR2(Flk-1, KDR)的第三、四个胞外区域,将这些区域与人免疫球蛋白1(IgG1)的Fc片段基因融合构建融合蛋白。前期研究发现FP3对VEGF诱导的人脐静脉内皮细胞(HUVECs)具有明显抑制增殖和迁移的作用；对VEGF诱导的大鼠动脉环出芽具有明显抑制作用。研究还发现FP3具有明显抑制非小细胞肺癌(NSCLC, A549)移植瘤生长的作用。并且发现,FP3具有明显的体内抗血管生成作用。但是FP3的确切抗肿瘤血管生成作用的机制目前尚未明了。而且,FP3对胃肠道肿瘤的抗血管生成作用和抗肿瘤作用,以及FP3联合化疗和其他靶向治疗的协同治疗价值亦未明确。
第一部分：
目的：(1)本研究为了建立胃癌患者新鲜肿瘤组织来源的裸鼠移植瘤模型(PDTT模型)用于为肿瘤患者筛选个体化的治疗药物和评价一个新型的抗肿瘤靶向药物,FP3。(2)本研究主要采用胃癌PDTT模型评价FP3的抗肿瘤血管生成的作用机制。研究主要观察FP3对肿瘤血管血管内皮细胞和外膜细胞的影响。
方法：(1)胃癌患者新鲜肿瘤组织用于建立PDTT移植瘤模型。HE染色、免疫组织化学染色和蛋白质免疫印迹(Western blotting)等方法用于初步鉴定该模型在传代过程中的生物学稳定性。同时评价了该模型对西妥昔单抗、贝伐单抗和FP3的治疗敏感性。(2)应用胃癌PDTT模型采用荧光免疫组织化学方法评价了FP3对肿瘤血管细胞水平的作用。
结果：(1)成功建立了胃癌患者PDTT模型,该模型在组织形态、蛋白表达方面显示出与患者新鲜肿瘤组织高度的一致性。药物敏感性试验表明西妥昔单抗、贝伐单抗和FP3均显示出对该模型的疗效,而西妥昔单抗与贝伐单抗及西妥昔单抗与FP3联合应用较单药应用具有明显疗效上的优势。(2)FP3治疗后明显影响了PDTT模型的肿瘤血管的生成,成熟血管内皮和新生血管内皮均受到明显影响,而对外膜细胞的影响不如内皮细胞,肿瘤血管经FP3作用后显示出更为“正常”的特征。
结论：(1)本研究成功建立胃癌患者PDTT模型,并用于个体化抗肿瘤治疗药物的筛选。(2)本研究表明FP3对肿瘤血管的作用主要通过三个方面来实现,包括对成熟肿瘤血管的抑制作用、对新生肿瘤血管的抑制作用和对肿瘤血管的“正常化”作用。
第二部分：
目的：(1)本研究为了建立结肠癌患者新鲜肿瘤组织(结肠癌原发瘤、淋巴转移瘤和肝转移瘤)来源的裸鼠移植瘤模型(PDTT模型)用于评价一个新型的抗肿瘤靶向药物,FP3。(2)本研究为了评价FP3与卡培他滨联合治疗对结肠癌(结肠癌原发瘤、淋巴转移瘤和肝转移瘤)PDTT移植瘤模型的协同治疗价值。(3)本研究为了评价FP3与西妥昔单抗联合治疗对KRAS野生型结肠癌(结肠癌原发瘤、淋巴转移瘤和肝转移瘤)PDTT移植瘤模型的协同治疗价值。(4)本研究为了分析结肠癌原发瘤与转移瘤的异质性及这种异质性可能导致的抗VEGF和抗EGFR联合靶向治疗的疗效差异。
方法：(1)结肠癌患者新鲜肿瘤组织(结肠癌原发瘤、淋巴转移瘤和肝转移瘤)用于建立PDTT移植瘤模型。HE染色、免疫组织化学染色、和蛋白质免疫印迹(Western blotting)、基因组cDNA芯片基因表达分析、焦磷酸测序、实时荧光定量PCR (qRT-PCR)等方法用于鉴定该模型在传代过程中的生物学稳定性。同时评价了该模型对西妥昔单抗、贝伐单抗和FP3的治疗敏感性。(2)本研究评价了FP3联合卡培他滨对结肠癌患者新鲜肿瘤组织(结肠癌原发瘤、淋巴转移瘤和肝转移瘤)PDTT移植瘤模型的治疗价值,以及联合应用对肿瘤生长、增殖相关因子的影响。(3)本研究评价了FP3联合西妥昔单抗对KRAS野生型结肠癌患者新鲜肿瘤组织(结肠癌原发瘤、淋巴转移瘤和肝转移瘤)PDTT移植瘤模型的治疗价值,以及联合应用对肿瘤生长、增殖相关因子的影响。(4)本研究采用免疫组织化学染色、和蛋白质免疫印迹(Western blotting)、基因组cDNA芯片基因表达分析、焦磷酸测序等方法评价了结肠癌原发瘤与淋巴转移瘤和肝转移瘤的异质性,并采用药敏试验评价了这种异质性对贝伐单抗和西妥昔单抗联合靶向治疗疗效的影响。
结果：(1)成功建立了结肠癌(原发瘤、淋巴转移瘤和肝转移瘤)PDTT移植瘤模型,该模型在组织形态、蛋白表达、基因突变和基因表达谱方面显示出与患者新鲜肿瘤组织高度的一致性。(2)FP3联合卡培他滨比单药治疗对结肠癌(原发瘤、淋巴转移瘤和肝转移瘤)PDTT移植瘤模型肿瘤生长的抑制作用具有明显优势。(3)FP3联合西妥昔单抗比单药治疗对KRAS野生型结肠癌(原发瘤、淋巴转移瘤和肝转移瘤)PDTT移植瘤模型肿瘤生长的抑制作用具有明显优势。(4)在EGFR、VEGF、 Akt/pAkt、ERK/pERK、MAPK/pMAPK和mTOR/pmTOR表达及基因表达方面,结肠癌原发瘤与淋巴转移瘤和肝转移瘤存在着明显的异质性。研究表明这种异质性可能导致来源于这些肿瘤组织的PDTT模型可能存在对抗EGFR和抗VEGF治疗疗效的差异。
结论：(1)本研究成功建立了结肠癌(原发瘤、淋巴转移瘤和肝转移瘤)PDTT移植瘤模型。该模型提供了一种评价新型抗肿瘤分子靶向药物的有效工具。(2)FP3与卡培他滨联合应用对结肠癌(原发瘤、淋巴转移瘤和肝转移瘤)PDTT移植瘤模型具有协同抗肿瘤作用。FP3和卡培他滨联合治疗可能是转移性结肠癌治疗的有效治疗方案。(3)FP3与西妥昔单抗联合应用对KRAS野生型结肠癌(原发瘤、淋巴转移瘤和肝转移瘤)PDTT移植瘤模型具有协同抗肿瘤作用。FP3和西妥昔单抗联合靶向治疗可能是KRAS野生型转移性结肠癌治疗的有效治疗方案。(4)结肠癌原发瘤与淋巴转移瘤和肝转移瘤存在明显的异质性,这种异质性可能影响其对抗VEGF和抗EGFR联合靶向治疗的疗效差异。
Background:Animal models have been used in "front-line" preclinical studies for predicting the efficacy and possible toxicities of anticancer drugs in cancer patients. The lack of general clinic-relevant tumor model for each kind of human cancer or model for a given cancer patient is a major impediment in seeking an general effective anticancer therapy for a certain kind of cancer or selecting the most appropriate therapy for an individual patient. Available in vivo experimental tumor models that are clinically representative of each major human cancer type would largely increase the success in identifying new active agents targetting sectionicular tumors. They can also accelerate the progress, reduce the cost and patient tumor tissue needed for anticancer drug development. Similarly, individualized models of human cancers would greatly facilitate selecting the best therapy for each individual patient as well. The increasingly used patient-derived human tumor tissue (PDTT) xenografts models implanted subcutaneously or in subrenal capsular in immunodeficient mice such as athymic nude mice or severe combined immune deficient (SCID) mice provided a more accurate reflection of human tumor biological characteristics than tumor cell lines. These xenografts models have become increasingly popular as evidence accrues that they are more accurately recapitulate features of patient tumors, such as maintaining the cell differentiation and morphology, the architecture, and molecular signatures of the original patient tumors. The unique feature of PDTT xenografts models is that the implanted tumor tissue still retains most of its normal architecture and function. This model more accurately reflects the in vivo situation than CCL thus could be functional for rapid screening of potential therapeutics.
It is believed that PDTT xenografts models possess four general applications. Firstly, it can be used as an in vivo screening tool to test novel drugs with therapeutic potential in cancer treatment. Secondly, it can be used to evaluate key markers of response and resistance to drugs. The ideal characteristics of the PDTT xenograft model might also make it a candidate method to investigate heterogeneity in primary tumor and its corresponding metastases and to evaluate the effect of such heterogeneity on cancer therapy response. Finally, it can be applied to achieve individualized anticancer therapy regimens by preclinically assessing the sensitivity of tumors to registered anticancer agents in vivo. Because of the inherent limitations in the current approaches for personalized cancer therapy, the need for new techniques to realize this goal is urgent. PDTT xenograft model might be an ideal candidate method to help to predict tumor response to therapy and it can be applied to achieve personalized therapy regimens by pre-clinically assessing the therapy-sensitivity of tumors to registered anticancer agents in vivo.
Angiogenesis is one of the eight hallmarks of cancer acquired during the multistep development of human tumors. Vascular endothelial growth factor (VEGF) is well established as a central mediator in this process. Furthermore, VEGF is the only angiogenic factor known to be present throughout the entire tumor lifecycle. Based on these evidences, VEGF is considered as a rational target for antiangiogenic drug development. Because anti-VEGF approaches act by blocking tumor-associated angiogenesis, which appears to be widely required by many different types of tumors, these approaches have been proved to be generally useful against a wide assortment of solid tumors. FP3is an engineered protein which contains the extracellular domain2of VEGF receptor1(Flt-1) and extracellular domain3and4of VEGF receptor2(Flk-1, KDR) fused to the Fc portion of human immunoglobulin G1. Previous studies indicated that FP3had promise as a local antiangiogenic treatment of human CNV (choroidal neovascularization)-related AMD (age-related macular degeneration). In subsequent studies, it was demonstrated that FP3has an inhibitory efficacy in VEGF-mediated proliferation, migration and tube formation of human umbilical vein endothelial cells, and in VEGF-mediated vessel sprouting of rat aortic ring in vitro. It was also demonstrated that FP3has an antitumor effect in a non-small cell lung cancer cell line (A549) xenograft model in nude mice. However, little is known of the cellular effects of FP3on tumor vessels and its antitumor effects on gastrointestinal tumors.
Section I
Purpose:(1) It was the aim of our study to establish a patient-derived tumor tissue (PDTT) xenograft model of gastric carcinoma useful for personalized cancer therapeutic regimen selection as well as testing of novel molecularly targeted agents.(2) In the present studies, we examined the cellular effects of FP3on blood vessels, mainly focused on the endothelial cells and pericytes of tumor vessels in a PDTT xenograft model of gastric carcinoma using large tumors with established vasculature.
Methods:(1) A PDTT of primary gastric carcinoma was used to create the xenograft model. After11weeks, xenografts were harvested for serial transplantation. Hematoxylin and eosin staining, immunohistochemical staining and western blotting were used to determine the biological stability of the xenograft during serial transplantation compared with the original tumor tissue. Drug sensitivities of the xenograft to bevacizumab, FP3, and cetuximab were evaluated.(2) In this study, we further investigated the cellular effects of FP3on blood vessels in a PDTT xenograft model of gastric carcinoma using large tumors with established vasculature.
Results:(1) A PDTT xenograft model of primary gastric carcinoma was successfully established. Early passages of the PDTT xenograft model of gastric carcinoma revealed a high degree of similarity with the original clinical tumor sample with regard to histology, immunohistochemistry as well as proteins expression. The PDTT xenograft model responded to all the drugs tested, and a higher response rate was observed in bevacizumab in combination with cetuximab-treated group as well as FP3in combination with cetuximab-treated group.(2) Treatment with FP3caused robust and early changes in endothelial cells and pericytes of vessels in the PDTT xenograft model. Vascular density decreased and vascular sprouting was suppressed with treatment of FP3. Pericytes did not degenerate to the same extent as endothelial cells, and those on surviving tumor vessels acquired a more normal phenotype.
Conclusions:(1) A PDTT xenograft model of gastric carcinoma has been established. It provides an appropriate model for personalized cancer therapeutic regimen selection as well as testing of novel molecularly targeted agents.(2) Our results revealed that FP3has a direct and rapid antiangiogenic effect in tumor vessels, which was achieved mainly via regression of tumor vasculature, inhibition of new and recurrent vessel growth, and normalization of existing tumor vasculature.
Section Ⅱ
Purpose:(1) It was the aim of our study to establish PDTT xenograft models of colon carcinoma with lymphatic and hepatic metastasis useful for testing of a novel molecularly targeted agent, FP3.(2) Combining inhibition of VEGF by FP3and chemotherapy by capecitabine might act additive or synergistically.(3) Combining inhibition of VEGF by FP3and EGF signaling by cetuximab might act additive or synergistically.(4) The aim of this study is to investigate whether the heterogeneity in primary tumor and related metastases exists and whether such heterogeneity would result in different response to anti-EGFR and anti-VEGF therapies.
Methods:(1) PDTT of primary colon carcinoma, lymphatic and hepatic metastases were used to create xenograft models. Hematoxylin and eosin staining, immunohistochemical staining, genome-wide gene expression analysis, pyrosequencing, qRT-PCR, and western blotting were used to determine the biological stability of the xenografts during serial transplantation compared with the original tumor tissues.(2) In this study, a series of PDTT xenograft models of primary colon carcinoma and lymphatic and hepatic metastases were established for assessment of the antitumor activity of FP3as a monotherapy and in combination with capecitabine. Tumorinoculated nude mice were treated with FP3, capecitabine, alone or in combination, after tumor growth was confirmed and volume and microvessel density in tumors were evaluated. Levels of VEGF, EGFR, and PCNA in the tumor were examined by immunohistonchamical staining, and levels of related cell signalling pathways proteins expression were examined by western blotting.(3) In this study, a series of PDTT xenograft models of primary colon carcinoma and lymphatic and hepatic metastases were established for assessment of the antitumor activity of FP3as a monotherapy and in combination with cetuximab. Tumorinoculated nude mice were treated with FP3, cetuximab, alone or in combination, after tumor growth was confirmed and volume and microvessel density in tumors were evaluated. Levels of VEGF, EGFR, and PCNA in the tumor were examined by immunohistonchamical staining, and levels of related cell signalling pathways proteins were examined by western blotting.(4) In this study, we compared the heterogeneity in primary colon cancer and its corresponding lymphatic and hepatic metastases, focusing on the cell signalling pathways proteins using the methods of immunohistochemical staining and western blotting, the gene status of KRAS using pyrosequencing, and genome-wide gene expression using GeneChip HGU133Plus2.0expression arrays. To investigate whether such heterogeneity would result in different response to anti-EGFR and anti-VEGF therapies, we further evaluate the therapy response of cetuximab in combination with bevacizumab in primary colon cancer and its corresponding lymphatic and hepatic metastases by establishing PDTT xenograft models based on the same tissue samples from above mentioned three tumor sites.
Results:(1) Early passages of the PDTT xenograft models of primary colon carcinoma, lymphatic and hepatic metastases revealed a high degree of similarity with the original clinical tumor samples with regard to histology, immunohistochemistry, genes expression, mutation status, mRNA expression as well as proteins expression.(2) FP3and FP3in combination with capecitabine showed significant antitumor activity as a monotherapy in three xenograft models (primary colon carcinoma, lymphatic metastasis, and hepatic metastasis). The microvessel density in tumor tissues treated with FP3and FP3in combination with capecitabine was lower than that of the control. Antitumor activity of FP3in combination with capecitabine was significantly higher than that of each agent alone in three xenograft models (primary colon carcinoma, lymphatic metastasis, and hepatic metastasis).(3) FP3and FP3in combination with cetuximab showed significant antitumor activity as a monotherapy in three xenograft models (primary colon carcinoma, lymphatic metastasis, and hepatic metastasis). The microvessel density in tumor tissues treated with FP3and FP3in combination with cetuximab was lower than that of the control. Antitumor activity of FP3in combination with cetuximab was significantly higher than that of each agent alone in three xenograft models (primary colon carcinoma, lymphatic metastasis, and hepatic metastasis).(4) The expressions of EGFR, VEGF, Akt/pAkt, ERK/pERK, MAPK/pMAPK, and mTOR/pmTOR and the genome-wide gene expression were different in primary colon cancer and matched lymphatic and hepatic metastases. Our results demonstrate that primary colon cancer and its corresponding lymphatic and hepatic metastases have different response rate to anti-EGFR and anti-VEGF therapies.
Conclusions:(1) In this study, PDTT xenograft models of colon carcinoma with lymphatic and hepatic metastasis have been successfully established. They provide appropriate models for testing of novel molecularly targeted agents.(2) This study indicated that addition of FP3to capecitabine significantly improved tumor growth inhibition in a series of PDTT xenograft models of primary colon carcinoma and lymphatic and hepatic metastases.(3) This study indicated that addition of FP3to cetuximab significantly improved tumor growth inhibition in a series of PDTT xenograft models of primary colon carcinoma and lymphatic and hepatic metastases with wide-type KRAS gene status. Combination anti-VEGF and anti-EGFR therapy may represent a novel therapeutic strategy for the management of colon carcinoma.(4) Our results indicate that the heterogeneity in primary colon cancer and its corresponding lymphatic and hepatic metastases would result in difference in response to double-inhibition of EGFR and VEGF. PDTT xenograft model could be an ideal in vivo tool to clear whether the primary tumors and corresponding metastases have different response to the same anticancer drugs.
PDTT模型具备四大应用前景：首先,这种模型可以作为抗肿瘤药物临床前筛选的工具。其次,这种模型可以用于评价、分析和筛选抗肿瘤治疗疗效和耐药的标志物。第三,PDTT模型的理想特征也为研究肿瘤原发瘤与转移瘤之间的异质性及这种异质性对抗肿瘤药物疗效的影响提供了一个有效的研究工具。第四,由于现有的个体化治疗方法的局限性,迫切需要一种新的方法来尽可能地实现肿瘤治疗的个体化。PDTT模型将是一个为每一位患者预测治疗药物疗效从而实现个体化治疗的理想工具。
血管生成是肿瘤多步骤发生发展过程中的八大标志之一。血管内皮生长因子(vascular endothelial growth factor, VEGF)是目前已知的唯一一个贯穿整个肿瘤生长周期的血管生长因子。因此,VEGF被认为是抗肿瘤血管生成药物开发的理想靶标。通过抗VEGF达到抗肿瘤血管生成进而实现抗肿瘤治疗的目的在实体瘤的治疗中具有广阔的应用前景。FP3是一个靶向VEGF的全人源化的可溶性受体蛋白。它的结构包括了VEGFR1(Flt-1)的第二个胞外区域和VEGFR2(Flk-1, KDR)的第三、四个胞外区域,将这些区域与人免疫球蛋白1(IgG1)的Fc片段基因融合构建融合蛋白。前期研究发现FP3对VEGF诱导的人脐静脉内皮细胞(HUVECs)具有明显抑制增殖和迁移的作用；对VEGF诱导的大鼠动脉环出芽具有明显抑制作用。研究还发现FP3具有明显抑制非小细胞肺癌(NSCLC, A549)移植瘤生长的作用。并且发现,FP3具有明显的体内抗血管生成作用。但是FP3的确切抗肿瘤血管生成作用的机制目前尚未明了。而且,FP3对胃肠道肿瘤的抗血管生成作用和抗肿瘤作用,以及FP3联合化疗和其他靶向治疗的协同治疗价值亦未明确。
第一部分：
目的：(1)本研究为了建立胃癌患者新鲜肿瘤组织来源的裸鼠移植瘤模型(PDTT模型)用于为肿瘤患者筛选个体化的治疗药物和评价一个新型的抗肿瘤靶向药物,FP3。(2)本研究主要采用胃癌PDTT模型评价FP3的抗肿瘤血管生成的作用机制。研究主要观察FP3对肿瘤血管血管内皮细胞和外膜细胞的影响。
方法：(1)胃癌患者新鲜肿瘤组织用于建立PDTT移植瘤模型。HE染色、免疫组织化学染色和蛋白质免疫印迹(Western blotting)等方法用于初步鉴定该模型在传代过程中的生物学稳定性。同时评价了该模型对西妥昔单抗、贝伐单抗和FP3的治疗敏感性。(2)应用胃癌PDTT模型采用荧光免疫组织化学方法评价了FP3对肿瘤血管细胞水平的作用。
结果：(1)成功建立了胃癌患者PDTT模型,该模型在组织形态、蛋白表达方面显示出与患者新鲜肿瘤组织高度的一致性。药物敏感性试验表明西妥昔单抗、贝伐单抗和FP3均显示出对该模型的疗效,而西妥昔单抗与贝伐单抗及西妥昔单抗与FP3联合应用较单药应用具有明显疗效上的优势。(2)FP3治疗后明显影响了PDTT模型的肿瘤血管的生成,成熟血管内皮和新生血管内皮均受到明显影响,而对外膜细胞的影响不如内皮细胞,肿瘤血管经FP3作用后显示出更为“正常”的特征。
结论：(1)本研究成功建立胃癌患者PDTT模型,并用于个体化抗肿瘤治疗药物的筛选。(2)本研究表明FP3对肿瘤血管的作用主要通过三个方面来实现,包括对成熟肿瘤血管的抑制作用、对新生肿瘤血管的抑制作用和对肿瘤血管的“正常化”作用。
第二部分：
目的：(1)本研究为了建立结肠癌患者新鲜肿瘤组织(结肠癌原发瘤、淋巴转移瘤和肝转移瘤)来源的裸鼠移植瘤模型(PDTT模型)用于评价一个新型的抗肿瘤靶向药物,FP3。(2)本研究为了评价FP3与卡培他滨联合治疗对结肠癌(结肠癌原发瘤、淋巴转移瘤和肝转移瘤)PDTT移植瘤模型的协同治疗价值。(3)本研究为了评价FP3与西妥昔单抗联合治疗对KRAS野生型结肠癌(结肠癌原发瘤、淋巴转移瘤和肝转移瘤)PDTT移植瘤模型的协同治疗价值。(4)本研究为了分析结肠癌原发瘤与转移瘤的异质性及这种异质性可能导致的抗VEGF和抗EGFR联合靶向治疗的疗效差异。
方法：(1)结肠癌患者新鲜肿瘤组织(结肠癌原发瘤、淋巴转移瘤和肝转移瘤)用于建立PDTT移植瘤模型。HE染色、免疫组织化学染色、和蛋白质免疫印迹(Western blotting)、基因组cDNA芯片基因表达分析、焦磷酸测序、实时荧光定量PCR (qRT-PCR)等方法用于鉴定该模型在传代过程中的生物学稳定性。同时评价了该模型对西妥昔单抗、贝伐单抗和FP3的治疗敏感性。(2)本研究评价了FP3联合卡培他滨对结肠癌患者新鲜肿瘤组织(结肠癌原发瘤、淋巴转移瘤和肝转移瘤)PDTT移植瘤模型的治疗价值,以及联合应用对肿瘤生长、增殖相关因子的影响。(3)本研究评价了FP3联合西妥昔单抗对KRAS野生型结肠癌患者新鲜肿瘤组织(结肠癌原发瘤、淋巴转移瘤和肝转移瘤)PDTT移植瘤模型的治疗价值,以及联合应用对肿瘤生长、增殖相关因子的影响。(4)本研究采用免疫组织化学染色、和蛋白质免疫印迹(Western blotting)、基因组cDNA芯片基因表达分析、焦磷酸测序等方法评价了结肠癌原发瘤与淋巴转移瘤和肝转移瘤的异质性,并采用药敏试验评价了这种异质性对贝伐单抗和西妥昔单抗联合靶向治疗疗效的影响。
结果：(1)成功建立了结肠癌(原发瘤、淋巴转移瘤和肝转移瘤)PDTT移植瘤模型,该模型在组织形态、蛋白表达、基因突变和基因表达谱方面显示出与患者新鲜肿瘤组织高度的一致性。(2)FP3联合卡培他滨比单药治疗对结肠癌(原发瘤、淋巴转移瘤和肝转移瘤)PDTT移植瘤模型肿瘤生长的抑制作用具有明显优势。(3)FP3联合西妥昔单抗比单药治疗对KRAS野生型结肠癌(原发瘤、淋巴转移瘤和肝转移瘤)PDTT移植瘤模型肿瘤生长的抑制作用具有明显优势。(4)在EGFR、VEGF、 Akt/pAkt、ERK/pERK、MAPK/pMAPK和mTOR/pmTOR表达及基因表达方面,结肠癌原发瘤与淋巴转移瘤和肝转移瘤存在着明显的异质性。研究表明这种异质性可能导致来源于这些肿瘤组织的PDTT模型可能存在对抗EGFR和抗VEGF治疗疗效的差异。
结论：(1)本研究成功建立了结肠癌(原发瘤、淋巴转移瘤和肝转移瘤)PDTT移植瘤模型。该模型提供了一种评价新型抗肿瘤分子靶向药物的有效工具。(2)FP3与卡培他滨联合应用对结肠癌(原发瘤、淋巴转移瘤和肝转移瘤)PDTT移植瘤模型具有协同抗肿瘤作用。FP3和卡培他滨联合治疗可能是转移性结肠癌治疗的有效治疗方案。(3)FP3与西妥昔单抗联合应用对KRAS野生型结肠癌(原发瘤、淋巴转移瘤和肝转移瘤)PDTT移植瘤模型具有协同抗肿瘤作用。FP3和西妥昔单抗联合靶向治疗可能是KRAS野生型转移性结肠癌治疗的有效治疗方案。(4)结肠癌原发瘤与淋巴转移瘤和肝转移瘤存在明显的异质性,这种异质性可能影响其对抗VEGF和抗EGFR联合靶向治疗的疗效差异。
Background:Animal models have been used in "front-line" preclinical studies for predicting the efficacy and possible toxicities of anticancer drugs in cancer patients. The lack of general clinic-relevant tumor model for each kind of human cancer or model for a given cancer patient is a major impediment in seeking an general effective anticancer therapy for a certain kind of cancer or selecting the most appropriate therapy for an individual patient. Available in vivo experimental tumor models that are clinically representative of each major human cancer type would largely increase the success in identifying new active agents targetting sectionicular tumors. They can also accelerate the progress, reduce the cost and patient tumor tissue needed for anticancer drug development. Similarly, individualized models of human cancers would greatly facilitate selecting the best therapy for each individual patient as well. The increasingly used patient-derived human tumor tissue (PDTT) xenografts models implanted subcutaneously or in subrenal capsular in immunodeficient mice such as athymic nude mice or severe combined immune deficient (SCID) mice provided a more accurate reflection of human tumor biological characteristics than tumor cell lines. These xenografts models have become increasingly popular as evidence accrues that they are more accurately recapitulate features of patient tumors, such as maintaining the cell differentiation and morphology, the architecture, and molecular signatures of the original patient tumors. The unique feature of PDTT xenografts models is that the implanted tumor tissue still retains most of its normal architecture and function. This model more accurately reflects the in vivo situation than CCL thus could be functional for rapid screening of potential therapeutics.
It is believed that PDTT xenografts models possess four general applications. Firstly, it can be used as an in vivo screening tool to test novel drugs with therapeutic potential in cancer treatment. Secondly, it can be used to evaluate key markers of response and resistance to drugs. The ideal characteristics of the PDTT xenograft model might also make it a candidate method to investigate heterogeneity in primary tumor and its corresponding metastases and to evaluate the effect of such heterogeneity on cancer therapy response. Finally, it can be applied to achieve individualized anticancer therapy regimens by preclinically assessing the sensitivity of tumors to registered anticancer agents in vivo. Because of the inherent limitations in the current approaches for personalized cancer therapy, the need for new techniques to realize this goal is urgent. PDTT xenograft model might be an ideal candidate method to help to predict tumor response to therapy and it can be applied to achieve personalized therapy regimens by pre-clinically assessing the therapy-sensitivity of tumors to registered anticancer agents in vivo.
Angiogenesis is one of the eight hallmarks of cancer acquired during the multistep development of human tumors. Vascular endothelial growth factor (VEGF) is well established as a central mediator in this process. Furthermore, VEGF is the only angiogenic factor known to be present throughout the entire tumor lifecycle. Based on these evidences, VEGF is considered as a rational target for antiangiogenic drug development. Because anti-VEGF approaches act by blocking tumor-associated angiogenesis, which appears to be widely required by many different types of tumors, these approaches have been proved to be generally useful against a wide assortment of solid tumors. FP3is an engineered protein which contains the extracellular domain2of VEGF receptor1(Flt-1) and extracellular domain3and4of VEGF receptor2(Flk-1, KDR) fused to the Fc portion of human immunoglobulin G1. Previous studies indicated that FP3had promise as a local antiangiogenic treatment of human CNV (choroidal neovascularization)-related AMD (age-related macular degeneration). In subsequent studies, it was demonstrated that FP3has an inhibitory efficacy in VEGF-mediated proliferation, migration and tube formation of human umbilical vein endothelial cells, and in VEGF-mediated vessel sprouting of rat aortic ring in vitro. It was also demonstrated that FP3has an antitumor effect in a non-small cell lung cancer cell line (A549) xenograft model in nude mice. However, little is known of the cellular effects of FP3on tumor vessels and its antitumor effects on gastrointestinal tumors.
Section I
Purpose:(1) It was the aim of our study to establish a patient-derived tumor tissue (PDTT) xenograft model of gastric carcinoma useful for personalized cancer therapeutic regimen selection as well as testing of novel molecularly targeted agents.(2) In the present studies, we examined the cellular effects of FP3on blood vessels, mainly focused on the endothelial cells and pericytes of tumor vessels in a PDTT xenograft model of gastric carcinoma using large tumors with established vasculature.
Methods:(1) A PDTT of primary gastric carcinoma was used to create the xenograft model. After11weeks, xenografts were harvested for serial transplantation. Hematoxylin and eosin staining, immunohistochemical staining and western blotting were used to determine the biological stability of the xenograft during serial transplantation compared with the original tumor tissue. Drug sensitivities of the xenograft to bevacizumab, FP3, and cetuximab were evaluated.(2) In this study, we further investigated the cellular effects of FP3on blood vessels in a PDTT xenograft model of gastric carcinoma using large tumors with established vasculature.
Results:(1) A PDTT xenograft model of primary gastric carcinoma was successfully established. Early passages of the PDTT xenograft model of gastric carcinoma revealed a high degree of similarity with the original clinical tumor sample with regard to histology, immunohistochemistry as well as proteins expression. The PDTT xenograft model responded to all the drugs tested, and a higher response rate was observed in bevacizumab in combination with cetuximab-treated group as well as FP3in combination with cetuximab-treated group.(2) Treatment with FP3caused robust and early changes in endothelial cells and pericytes of vessels in the PDTT xenograft model. Vascular density decreased and vascular sprouting was suppressed with treatment of FP3. Pericytes did not degenerate to the same extent as endothelial cells, and those on surviving tumor vessels acquired a more normal phenotype.
Conclusions:(1) A PDTT xenograft model of gastric carcinoma has been established. It provides an appropriate model for personalized cancer therapeutic regimen selection as well as testing of novel molecularly targeted agents.(2) Our results revealed that FP3has a direct and rapid antiangiogenic effect in tumor vessels, which was achieved mainly via regression of tumor vasculature, inhibition of new and recurrent vessel growth, and normalization of existing tumor vasculature.
Section Ⅱ
Purpose:(1) It was the aim of our study to establish PDTT xenograft models of colon carcinoma with lymphatic and hepatic metastasis useful for testing of a novel molecularly targeted agent, FP3.(2) Combining inhibition of VEGF by FP3and chemotherapy by capecitabine might act additive or synergistically.(3) Combining inhibition of VEGF by FP3and EGF signaling by cetuximab might act additive or synergistically.(4) The aim of this study is to investigate whether the heterogeneity in primary tumor and related metastases exists and whether such heterogeneity would result in different response to anti-EGFR and anti-VEGF therapies.
Methods:(1) PDTT of primary colon carcinoma, lymphatic and hepatic metastases were used to create xenograft models. Hematoxylin and eosin staining, immunohistochemical staining, genome-wide gene expression analysis, pyrosequencing, qRT-PCR, and western blotting were used to determine the biological stability of the xenografts during serial transplantation compared with the original tumor tissues.(2) In this study, a series of PDTT xenograft models of primary colon carcinoma and lymphatic and hepatic metastases were established for assessment of the antitumor activity of FP3as a monotherapy and in combination with capecitabine. Tumorinoculated nude mice were treated with FP3, capecitabine, alone or in combination, after tumor growth was confirmed and volume and microvessel density in tumors were evaluated. Levels of VEGF, EGFR, and PCNA in the tumor were examined by immunohistonchamical staining, and levels of related cell signalling pathways proteins expression were examined by western blotting.(3) In this study, a series of PDTT xenograft models of primary colon carcinoma and lymphatic and hepatic metastases were established for assessment of the antitumor activity of FP3as a monotherapy and in combination with cetuximab. Tumorinoculated nude mice were treated with FP3, cetuximab, alone or in combination, after tumor growth was confirmed and volume and microvessel density in tumors were evaluated. Levels of VEGF, EGFR, and PCNA in the tumor were examined by immunohistonchamical staining, and levels of related cell signalling pathways proteins were examined by western blotting.(4) In this study, we compared the heterogeneity in primary colon cancer and its corresponding lymphatic and hepatic metastases, focusing on the cell signalling pathways proteins using the methods of immunohistochemical staining and western blotting, the gene status of KRAS using pyrosequencing, and genome-wide gene expression using GeneChip HGU133Plus2.0expression arrays. To investigate whether such heterogeneity would result in different response to anti-EGFR and anti-VEGF therapies, we further evaluate the therapy response of cetuximab in combination with bevacizumab in primary colon cancer and its corresponding lymphatic and hepatic metastases by establishing PDTT xenograft models based on the same tissue samples from above mentioned three tumor sites.
Results:(1) Early passages of the PDTT xenograft models of primary colon carcinoma, lymphatic and hepatic metastases revealed a high degree of similarity with the original clinical tumor samples with regard to histology, immunohistochemistry, genes expression, mutation status, mRNA expression as well as proteins expression.(2) FP3and FP3in combination with capecitabine showed significant antitumor activity as a monotherapy in three xenograft models (primary colon carcinoma, lymphatic metastasis, and hepatic metastasis). The microvessel density in tumor tissues treated with FP3and FP3in combination with capecitabine was lower than that of the control. Antitumor activity of FP3in combination with capecitabine was significantly higher than that of each agent alone in three xenograft models (primary colon carcinoma, lymphatic metastasis, and hepatic metastasis).(3) FP3and FP3in combination with cetuximab showed significant antitumor activity as a monotherapy in three xenograft models (primary colon carcinoma, lymphatic metastasis, and hepatic metastasis). The microvessel density in tumor tissues treated with FP3and FP3in combination with cetuximab was lower than that of the control. Antitumor activity of FP3in combination with cetuximab was significantly higher than that of each agent alone in three xenograft models (primary colon carcinoma, lymphatic metastasis, and hepatic metastasis).(4) The expressions of EGFR, VEGF, Akt/pAkt, ERK/pERK, MAPK/pMAPK, and mTOR/pmTOR and the genome-wide gene expression were different in primary colon cancer and matched lymphatic and hepatic metastases. Our results demonstrate that primary colon cancer and its corresponding lymphatic and hepatic metastases have different response rate to anti-EGFR and anti-VEGF therapies.
Conclusions:(1) In this study, PDTT xenograft models of colon carcinoma with lymphatic and hepatic metastasis have been successfully established. They provide appropriate models for testing of novel molecularly targeted agents.(2) This study indicated that addition of FP3to capecitabine significantly improved tumor growth inhibition in a series of PDTT xenograft models of primary colon carcinoma and lymphatic and hepatic metastases.(3) This study indicated that addition of FP3to cetuximab significantly improved tumor growth inhibition in a series of PDTT xenograft models of primary colon carcinoma and lymphatic and hepatic metastases with wide-type KRAS gene status. Combination anti-VEGF and anti-EGFR therapy may represent a novel therapeutic strategy for the management of colon carcinoma.(4) Our results indicate that the heterogeneity in primary colon cancer and its corresponding lymphatic and hepatic metastases would result in difference in response to double-inhibition of EGFR and VEGF. PDTT xenograft model could be an ideal in vivo tool to clear whether the primary tumors and corresponding metastases have different response to the same anticancer drugs.
引文
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