Abstract
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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal cancer, with a dismal 5-year survival rate of 8% [1]
We further investigated the effects of Vitamin E delta-tocotrienol (VEDT) on self-renewal of pancreatic cancer stem-like cells (CSCs) L3.6pl CD24+CD44+CD133+ isolated from the pancreatic cancer cell line L3.6pl using flow cytometry and the commercially available patient-derived human pancreatic CSCs CD24+CD44+CD133+ ESA+ grown in three-dimensional ultra-low non-adherent culture plates containing stem cell medium (Figure 1D and 1E)
In addition to the depletion of Matrix metallopeptidase 9 (MMP9) in cells and in the tumor tissue of mice treated with VEDT compared with vehicle shown in Figures 4 and 5, together, these results indicate that VEDT can suppress the tumorigenesis and metastasis of pancreatic cancer cells in vitro and in vivo
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal cancer, with a dismal 5-year survival rate of 8% [1]. The prognosis of these patients remains poor, with a 5-year overall survival rate of only 28.9% [2, 3]. Pancreatic CSCs express the cell surface markers CD44, CD24, and ESA. They make up 0.2% to 0.8% of human PDAC tumors [8]. These CSCs have the capacity to self-renew, to generate differentiated progeny, are highly tumorigenic and metastatic, and are resistant to chemotherapies used to prevent PDAC relapse [9]. A new strategy targeting these CSCs may lead to prevention or delay in PDAC relapse
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