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TGF-β受体抑制剂LY2109761在TACE术后靶向肝癌肿瘤微环境的作用机制及疗效

Mechanism of action and efficacy of LY2109761, a TGF-β receptor inhibitor, targeting tumor microenvironment in liver cancer after TACE.

作者信息

He Xiaojun, Guo Xiaopeng, Zhang Hongsen, Kong Xiangchuang, Yang Fan, Zheng Chuansheng

机构信息

Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Department of Radiology, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

出版信息

Oncotarget. 2017 Dec 11;9(1):1130-1142. doi: 10.18632/oncotarget.23193. eCollection 2018 Jan 2.

DOI:10.18632/oncotarget.23193
PMID:29416682
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5787425/
Abstract

TACE (transcatheter arterial chemoembolization) has been recognized as an effective palliative treatment option for patients with HCC, however, the medium-long term efficacy of it remains modest. LY2109761, a TGF-β receptor inhibitor, was confirmed to reduce tumor cell growth, intravasation, and metastatic dissemination of HCC cells through different molecular mechanisms. This study aims to investigate the treatment effect of combining TACE therapy with LY2109761- a TGF-β receptor I kinase inhibitor on suppressing tumor growth and metastasis in a rabbit VX2 tumor model. The molecular mechanisms underlying the biological activities of LY2109761 was also evaluated through an model. And we found that LY2109761 could inhibit cell proliferation by down-regulating the phosphorylation of Smad-2 as well as improved the therapeutic effect of TACE in a VX2 hepatocellular carcinoma model. And we further found that LY2109761 may play a modulating role in the process of T cell transformation. Hence, based on those obsevations in our research, we concluded that combing LY2109761 with TACE for the treatment of VX2 rabbit liver cancer can help inhibit tumor growth as well as increase the tumor cell necrosis after TACE.

摘要

经动脉化疗栓塞术（TACE）已被公认为是肝细胞癌（HCC）患者有效的姑息治疗选择，然而，其中长期疗效仍较为有限。LY2109761是一种转化生长因子-β（TGF-β）受体抑制剂，已证实可通过不同分子机制减少肝癌细胞的生长、血管内侵入及转移扩散。本研究旨在探讨TACE疗法联合LY2109761（一种TGF-β受体I激酶抑制剂）对兔VX2肿瘤模型中肿瘤生长和转移的抑制作用。还通过一种模型评估了LY2109761生物学活性的分子机制。并且我们发现，LY2109761可通过下调Smad-2的磷酸化来抑制细胞增殖，同时在VX2肝细胞癌模型中提高TACE的治疗效果。我们还进一步发现，LY2109761可能在T细胞转化过程中发挥调节作用。因此，基于我们研究中的这些观察结果，我们得出结论，LY2109761与TACE联合用于治疗兔VX2肝癌有助于抑制肿瘤生长，并增加TACE术后的肿瘤细胞坏死。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8617/5787425/fae8e249dc24/oncotarget-09-1130-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8617/5787425/113e6bf946c5/oncotarget-09-1130-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8617/5787425/6d830f0a716a/oncotarget-09-1130-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8617/5787425/78e449cdf80d/oncotarget-09-1130-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8617/5787425/67bf5c52e87e/oncotarget-09-1130-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8617/5787425/42629b5bc9d9/oncotarget-09-1130-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8617/5787425/99d61dd6c77b/oncotarget-09-1130-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8617/5787425/365f446a72bc/oncotarget-09-1130-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8617/5787425/3ded0f767f13/oncotarget-09-1130-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8617/5787425/fae8e249dc24/oncotarget-09-1130-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8617/5787425/113e6bf946c5/oncotarget-09-1130-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8617/5787425/6d830f0a716a/oncotarget-09-1130-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8617/5787425/78e449cdf80d/oncotarget-09-1130-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8617/5787425/67bf5c52e87e/oncotarget-09-1130-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8617/5787425/42629b5bc9d9/oncotarget-09-1130-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8617/5787425/99d61dd6c77b/oncotarget-09-1130-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8617/5787425/365f446a72bc/oncotarget-09-1130-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8617/5787425/3ded0f767f13/oncotarget-09-1130-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8617/5787425/fae8e249dc24/oncotarget-09-1130-g009.jpg

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