δ-Tocotrienol, a natural form of vitamin E, inhibits pancreatic cancer stem-like cells and prevents pancreatic cancer metastasis.
δ-Tocotrienol, a natural form of vitamin E, inhibits pancreatic cancer stem-like cells and prevents pancreatic cancer metastasis.
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DOI：
10.18632/oncotarget.15767
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发表时间：
2017-05-09
期刊：
影响因子：
--
通讯作者：
Malafa MP
中科院分区：
文献类型：
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作者：
Husain K;Centeno BA;Coppola D;Trevino J;Sebti SM;Malafa MP
胰腺导管腺癌 (PDAC) 的生长、转移和化疗耐药的特点是远处器官中具有干细胞样特性的肿瘤起始细胞的激活和生长。因此，抑制这些细胞的生长可以防止 PDAC 生长和转移。我们已经证明，δ-生育三烯酚是维生素 E (VEDT) 的天然形式，在 PDAC 转基因小鼠模型中具有抗癌生物活性、延缓进展并预防转移。在本报告中，我们首次提供了 VEDT 选择性抑制 PDAC 干细胞样细胞的证据。 VEDT 抑制 3 种 PDAC 干细胞样细胞模型中的活力、存活、自我更新以及 Oct4 和 Sox2 转录因子的表达。此外，VEDT 还能抑制 PDAC 细胞和肿瘤中的迁移、侵袭以及上皮间质转化和血管生成的多种生物标志物。这些过程对于肿瘤转移至关重要。此外，在 PDAC 转移的 L3.6pl 原位模型中，VEDT 显着抑制这些细胞的生长和转移。最后，在人 PDAC 干细胞样细胞的原位异种移植模型中，我们发现 VEDT 显着延缓了吉西他滨耐药的 PDAC 人干细胞样细胞的生长和转移。由于 VEDT 已被证明是安全的，并且在人体中达到生物活性水平，因此这项工作支持研究 VEDT 用于化学预防 PDAC 转移。
The growth, metastasis, and chemotherapy resistance of pancreatic ductal adenocarcinoma (PDAC) is characterized by the activation and growth of tumor-initiating cells in distant organs that have stem-like properties. Thus, inhibiting growth of these cells may prevent PDAC growth and metastases. We have demonstrated that δ-tocotrienol, a natural form of vitamin E (VEDT), is bioactive against cancer, delays progression, and prevents metastases in transgenic mouse models of PDAC. In this report, we provide the first evidence that VEDT selectively inhibits PDAC stem-like cells. VEDT inhibited the viability, survival, self-renewal, and expression of Oct4 and Sox2 transcription factors in 3 models of PDAC stem-like cells. In addition, VEDT inhibited the migration, invasion, and several biomarkers of epithelial-to-mesenchymal transition and angiogenesis in PDAC cells and tumors. These processes are critical for tumor metastases. Furthermore, in the L3.6pl orthotopic model of PDAC metastases, VEDT significantly inhibited growth and metastases of these cells. Finally, in an orthotopic xenograft model of human PDAC stem-like cells, we showed that VEDT significantly retarded the growth and metastases of gemcitabine-resistant PDAC human stem-like cells. Because VEDT has been shown to be safe and to reach bioactive levels in humans, this work supports investigating VEDT for chemoprevention of PDAC metastases.