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一种利用工程化干细胞的潜在疗法在细胞和异种移植小鼠模型中预防了恶性黑色素瘤。

A Potential Therapy Using Engineered Stem Cells Prevented Malignant Melanoma in Cellular and Xenograft Mouse Models.

机构信息

Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Korea.

Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.

出版信息

Cancer Res Treat. 2019 Apr;51(2):797-811. doi: 10.4143/crt.2018.364. Epub 2018 Sep 14.

DOI:10.4143/crt.2018.364
PMID:30213181
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6473263/
Abstract

PURPOSE

In the present study, human neural stem cells (hNSCs) with tumor-tropic behavior were used as drug delivery vehicle to selectively target melanoma. A hNSC line (HB1.F3) was transduced into two types: one expressed only the cytosine deaminase (CD) gene (HB1.F3. CD) and the other expressed both CD and human interferon-β (IFN-β) genes (HB1.F3.CD. IFN-β).

MATERIALS AND METHODS

This study verified the tumor-tropic migratory competence of engineered hNSCs on melanoma (A375SM) using a modified Boyden chamber assay in vitro and CM-DiI staining in vivo. The antitumor effect of HB1.F3.CD and HB1.F3.CD.IFN-β on melanoma was also confirmed using an MTT assay in vitro and xenograft mouse models.

RESULTS

A secreted form of IFN-β from the HB1.F3.CD.IFN-β cells modified the epithelial-mesenchymal transition (EMT) process and metastasis of melanoma. 5-Fluorouracil treatment also accelerated the expression of the pro-apoptotic protein BAX and decelerated the expression of the anti-apoptotic protein Bcl-xL on melanoma cell line.

CONCLUSION

Our results illustrate that engineered hNSCs prevented malignant melanoma cells from proliferating in the presence of the prodrug, and the form that secreted IFN-β intervened in the EMT process and melanoma metastasis. Hence, neural stem cell-directed enzyme/prodrug therapy is a plausible treatment for malignant melanoma.

摘要

目的

在本研究中，具有肿瘤趋向性的人神经干细胞（hNSCs）被用作药物输送载体，以选择性靶向黑色素瘤。转导了一条 hNSC 系（HB1.F3），使其表达两种基因：一种仅表达胞嘧啶脱氨酶（CD）基因（HB1.F3.CD），另一种同时表达 CD 和人干扰素-β（IFN-β）基因（HB1.F3.CD.IFN-β）。

材料和方法

本研究通过体外改良 Boyden 室测定和体内 CM-DiI 染色，验证了工程化 hNSC 对黑色素瘤（A375SM）的肿瘤趋向性迁移能力。还通过体外 MTT 测定和异种移植小鼠模型，证实了 HB1.F3.CD 和 HB1.F3.CD.IFN-β 对黑色素瘤的抗肿瘤作用。

结果

HB1.F3.CD.IFN-β 细胞分泌的 IFN-β 改变了黑色素瘤的上皮-间质转化（EMT）过程和转移。5-氟尿嘧啶治疗还加速了促凋亡蛋白 BAX 的表达，减缓了抗凋亡蛋白 Bcl-xL 在黑色素瘤细胞系中的表达。

结论

我们的结果表明，工程化 hNSC 在前药存在的情况下阻止了恶性黑色素瘤细胞的增殖，分泌 IFN-β 的形式干预了 EMT 过程和黑色素瘤转移。因此，神经干细胞定向酶/前药疗法是恶性黑色素瘤的一种合理治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d76/6473263/02f244da1524/crt-2018-364f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d76/6473263/196b7a201471/crt-2018-364f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d76/6473263/e4d94f32f72c/crt-2018-364f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d76/6473263/1b89a680059c/crt-2018-364f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d76/6473263/0671645a8f51/crt-2018-364f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d76/6473263/2960690a9953/crt-2018-364f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d76/6473263/4b733d7ff694/crt-2018-364f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d76/6473263/3d1dd6d2807a/crt-2018-364f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d76/6473263/02f244da1524/crt-2018-364f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d76/6473263/196b7a201471/crt-2018-364f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d76/6473263/e4d94f32f72c/crt-2018-364f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d76/6473263/1b89a680059c/crt-2018-364f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d76/6473263/0671645a8f51/crt-2018-364f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d76/6473263/2960690a9953/crt-2018-364f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d76/6473263/4b733d7ff694/crt-2018-364f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d76/6473263/3d1dd6d2807a/crt-2018-364f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d76/6473263/02f244da1524/crt-2018-364f8.jpg

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