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Abstract：
UNASSIGNED: The main objective of this study was to investigate the antitumor effect of a mouse anti-human glypican-1 (GPC1) monoclonal antibody (mAb) on non-small cell lung carcinoma (NSCLC) and associated molecular mechanisms.
UNASSIGNED: The anti-proliferative and anti-migratory activities of anti-GPC1 mAb were examined in A549 and H460 NSCLC cells and LL97A lung fibroblasts. The inhibitory effect of anti-GPC1 mAb on tumor growth was evaluated in an orthotopic lung tumor model.
UNASSIGNED: The in vitro study showed that anti-GPC1 mAb profoundly inhibited the anchorage-independent growth of A549 and H460 NSCLC cells and exhibited relatively high cytotoxic activities towards LL97A lung fibroblasts, A549/LL97A and H460/LL97A coculture spheroids. Moreover, anti-GPC1 mAb significantly decreased the expression of phospho-Src (p-Src; Tyr416), p-Akt (Ser473) and β-catenin in the co-cultured LL97A lung fibroblasts, and the expression of phospho-mitogen-activated protein kinase kinase (p-MEK; Ser217/221) and phospho-90 kDa ribosomal s6 kinase (p-p90RSK; Ser380) in co-cultured A549 cells. When anti-GPC1 mAb was administered to tumor-bearing mice, the inhibitory effect of anti-GPC1 mAb on the orthotopic lung tumor growth was not statistically significant. Nonetheless, results of Western blot analysis showed significant decrease in the phosphorylation of fibroblast growth factor receptor 1 (FGFR1) at Tyr766, Src at Tyr416, extracellular signal-regulated kinase (ERK) at Thr202/Tyr204, 90 kDa ribosomal S6 kinase (RSK) at Ser380, glycogen synthase kinases 3α (GSK3α) at Ser21 and GSK3β at Ser9 in tumor tissues. These data implicate that anti-GPC1 mAb treatment impairs the interaction between tumor cells and tumor associated fibroblasts by attenuating the paracrine FGFR signal transduction.
UNASSIGNED: The relatively potent cytotoxicity of anti-GPC1 mAb in lung fibroblasts and its potential inhibitory effect on the paracrine FGFR signal transduction warrant further studies on the combined use of this mAb with targeted therapeutics to improve therapeutic outcomes in lung cancer.
UNASSIGNED: The anti-proliferative and anti-migratory activities of anti-GPC1 mAb were examined in A549 and H460 NSCLC cells and LL97A lung fibroblasts. The inhibitory effect of anti-GPC1 mAb on tumor growth was evaluated in an orthotopic lung tumor model.
UNASSIGNED: The in vitro study showed that anti-GPC1 mAb profoundly inhibited the anchorage-independent growth of A549 and H460 NSCLC cells and exhibited relatively high cytotoxic activities towards LL97A lung fibroblasts, A549/LL97A and H460/LL97A coculture spheroids. Moreover, anti-GPC1 mAb significantly decreased the expression of phospho-Src (p-Src; Tyr416), p-Akt (Ser473) and β-catenin in the co-cultured LL97A lung fibroblasts, and the expression of phospho-mitogen-activated protein kinase kinase (p-MEK; Ser217/221) and phospho-90 kDa ribosomal s6 kinase (p-p90RSK; Ser380) in co-cultured A549 cells. When anti-GPC1 mAb was administered to tumor-bearing mice, the inhibitory effect of anti-GPC1 mAb on the orthotopic lung tumor growth was not statistically significant. Nonetheless, results of Western blot analysis showed significant decrease in the phosphorylation of fibroblast growth factor receptor 1 (FGFR1) at Tyr766, Src at Tyr416, extracellular signal-regulated kinase (ERK) at Thr202/Tyr204, 90 kDa ribosomal S6 kinase (RSK) at Ser380, glycogen synthase kinases 3α (GSK3α) at Ser21 and GSK3β at Ser9 in tumor tissues. These data implicate that anti-GPC1 mAb treatment impairs the interaction between tumor cells and tumor associated fibroblasts by attenuating the paracrine FGFR signal transduction.
UNASSIGNED: The relatively potent cytotoxicity of anti-GPC1 mAb in lung fibroblasts and its potential inhibitory effect on the paracrine FGFR signal transduction warrant further studies on the combined use of this mAb with targeted therapeutics to improve therapeutic outcomes in lung cancer.
摘要：
■本研究的主要目的是研究小鼠抗人磷脂酰肌醇蛋白聚糖-1（GPC1）单克隆抗体（mAb）对非小细胞肺癌（NSCLC）的抗肿瘤作用及其相关分子机制。
■在A549和H460NSCLC细胞和LL97A肺成纤维细胞中检测了抗GPC1mAb的抗增殖和抗迁移活性。在原位肺肿瘤模型中评价抗GPC1mAb对肿瘤生长的抑制作用。
■体外研究表明，抗GPC1mAb对A549和H460NSCLC细胞的锚定非依赖性生长有明显的抑制作用，对LL97A肺成纤维细胞表现出相对较高的细胞毒活性，A549/LL97A和H460/LL97A共培养球体。此外，抗GPC1单克隆抗体显著降低磷酸化Src(p-Src;Tyr416)的表达,p-Akt（Ser473）和β-catenin在共培养的LL97A肺成纤维细胞中，以及共培养的A549细胞中磷酸丝裂原活化蛋白激酶激酶（p-MEK;Ser217/221）和磷酸90kDa核糖体s6激酶（p-p90RSK;Ser380）的表达。当对荷瘤小鼠施用抗GPC1mAb时，抗GPC1mAb对原位肺癌生长的抑制作用无统计学意义。尽管如此，Westernblot分析结果表明，肿瘤组织中Tyr766的成纤维细胞生长因子受体1（FGFR1），Tyr416的Src，Thr202/Tyr204的细胞外信号调节激酶（ERK），90kDa核糖体S6激酶（RSK）的磷酸化显着降低Ser380，Ser21的糖原合酶激酶3α（GSK3α）和Ser9的GSK3β。这些数据暗示抗GPC1mAb治疗通过减弱旁分泌FGFR信号转导来削弱肿瘤细胞和肿瘤相关成纤维细胞之间的相互作用。
■抗GPC1mAb在肺成纤维细胞中的相对有效的细胞毒性及其对旁分泌FGFR信号转导的潜在抑制作用，需要进一步研究该mAb与靶向疗法的组合使用以改善肺癌的治疗结果。
■在A549和H460NSCLC细胞和LL97A肺成纤维细胞中检测了抗GPC1mAb的抗增殖和抗迁移活性。在原位肺肿瘤模型中评价抗GPC1mAb对肿瘤生长的抑制作用。
■体外研究表明，抗GPC1mAb对A549和H460NSCLC细胞的锚定非依赖性生长有明显的抑制作用，对LL97A肺成纤维细胞表现出相对较高的细胞毒活性，A549/LL97A和H460/LL97A共培养球体。此外，抗GPC1单克隆抗体显著降低磷酸化Src(p-Src;Tyr416)的表达,p-Akt（Ser473）和β-catenin在共培养的LL97A肺成纤维细胞中，以及共培养的A549细胞中磷酸丝裂原活化蛋白激酶激酶（p-MEK;Ser217/221）和磷酸90kDa核糖体s6激酶（p-p90RSK;Ser380）的表达。当对荷瘤小鼠施用抗GPC1mAb时，抗GPC1mAb对原位肺癌生长的抑制作用无统计学意义。尽管如此，Westernblot分析结果表明，肿瘤组织中Tyr766的成纤维细胞生长因子受体1（FGFR1），Tyr416的Src，Thr202/Tyr204的细胞外信号调节激酶（ERK），90kDa核糖体S6激酶（RSK）的磷酸化显着降低Ser380，Ser21的糖原合酶激酶3α（GSK3α）和Ser9的GSK3β。这些数据暗示抗GPC1mAb治疗通过减弱旁分泌FGFR信号转导来削弱肿瘤细胞和肿瘤相关成纤维细胞之间的相互作用。
■抗GPC1mAb在肺成纤维细胞中的相对有效的细胞毒性及其对旁分泌FGFR信号转导的潜在抑制作用，需要进一步研究该mAb与靶向疗法的组合使用以改善肺癌的治疗结果。
