血小板内在性VEGF-Aを分子標的とする新規大腸癌治療の臨床及び分子生物学的研究

以血小板固有VEGF-A为分子靶点的新型结直肠癌治疗的临床和分子生物学研究

• 批准号: 18F16420
• 负责人: 井本 浩
• 金额: $ 0.7万
• 依托单位: Kagoshima University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for JSPS Fellows
• 财政年份: 2018
• 资助国家: 日本
• 起止时间: 2018-04-25 至 2019-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18F16420/
• 关键词: VEGF; serotonin; HCC; CRC; VWF

Our project is 1) to examine the kinetics of intra-platelet VEGF-A in bevacizumab (Avastin) treated colorectal cancer (CRC) patients, and 2) to study dynamics of various intra-platelet growth factor in patients with Hepatocellular carcinoma (HCC). We also conducted in vitro and ex vivo experiments to investigate the bearing of bevacizumab on the intra-platelet VEGF-A. Following four major results were obtained from this grant.1. We observed a perioperative exhaustion (depletion) of intra-platelet serotonin concentrations in patients who developed early HCC recurrence and this was able to independently predict HCC recurrence [Aryal et. al, Journal of Cancer (2017)].2. Platelet-derived growth factor-BB (PDGF-BB) was significantly diminished in patients with cancer recurrence. [Aryal B, et al. Journal of Oncology (2019); article id 1925315].3. We observed a significant elevation of intra-platelet vWF during liver regeneration; moreover, patients who could not achieve marked rise in post-resection intra-platelet vWF concentration were found to have increased incidence of post-resection liver dysfunction [Aryal B, et al. Under Review (2019)].4. We performed experiments using an ex vivo and in vitro models to examine the effect of bevacizumab and pegaptanib on IP VEGF-A neutralization, suggesting that the intra-platelet VEGF-A could influence the impact of bevacizumab treatment, as platelets represent a major reservoir of VEGF.I appreciated this funding and would like to proceed more to accomplish this series of the project.

我们的项目是1）检查贝伐单抗（Avastin）治疗的结直肠癌（CRC）患者中血小板内VEGF-A的动力学，和2）研究肝细胞癌（HCC）患者中各种血小板内生长因子的动力学。我们还进行了体外和离体实验，以研究贝伐单抗对血小板内VEGF-A的影响。 本研究取得了以下四个主要成果：1.我们观察到早期HCC复发患者的围手术期血小板内5-羟色胺浓度耗竭，这能够独立预测HCC复发[Aryal et.等人，Journal of Cancer（2017）]。血小板衍生生长因子-BB（PDGF-BB）在癌症复发患者中显著减少。[Aryal B，et al. Journal of Oncology（2019）; article id 1925315]. 3.我们观察到肝再生过程中血小板内vWF显著升高;此外，发现无法实现切除术后血小板内vWF浓度显著升高的患者切除术后肝功能障碍的发生率增加[Aryal B，et al. Under Review（2019）]。4.我们使用离体和体外模型进行了实验，以检查贝伐单抗和哌加他尼对IP VEGF-A中和的影响，这表明血小板内VEGF-A可以影响贝伐单抗治疗的影响，因为血小板是VEGF的主要储存库。我感谢这笔资金，并希望继续完成这一系列项目。

项目成果

Perioperative Serum PDGF-BB Characterizes Patients with Post- Resection HCC Recurrence

围手术期血清 PDGF-BB 是切除后 HCC 复发患者的特征

• 发表时间: 2018
• 作者: Aryal Bibek;Yamakuchi Munekazu;Shimizu Toshiaki;Kadono Jun;Furoi Akira;Gejima Kentaro;Komokata Teruo;Hashiguchi Teruto;Imoto Yutaka;Bibek Aryal
• 通讯作者: Bibek Aryal

Exhaustion of Platelet Kinetics and its Implication in Post-resection HCC Recurrence

血小板动力学耗竭及其对切除后 HCC 复发的影响

• 发表时间: 2018
• 作者: Aryal Bibek;Yamakuchi Munekazu;Shimizu Toshiaki;Kadono Jun;Furoi Akira;Gejima Kentaro;Komokata Teruo;Hashiguchi Teruto;Imoto Yutaka;Bibek Aryal;Bibek Aryal
• 通讯作者: Bibek Aryal