Abstract

Simple SummaryCancer cells with a stem-like phenotype that are thought to be highly tumorigenic are commonly described in glioblastoma, the most common primary adult brain cancer. This phenotype comprises high self-renewal capacity and resistance against chemotherapy and radiation therapy, thereby promoting tumor progression and disease relapse. Here, we show that calcitriol, the hormonally active form of the “sun hormone” vitamin D3, effectively suppresses stemness properties in glioblastoma stem-like cells (GSCs), supporting the hypothesis that calcitriol sensitizes them to additional chemotherapy. Indeed, a physiological organotypic brain slice model was used to monitor tumor growth of GSCs, and the effectiveness of combined treatment with temozolomide, the current standard-of-care, and calcitriol was proven. These findings indicate that further research on applying calcitriol, a well-known and safe drug, as a potential adjuvant therapy for glioblastoma is both justified and necessary.Glioblastoma (GBM) is the most common and most aggressive primary brain tumor, with a very high rate of recurrence and a median survival of 15 months after diagnosis. Abundant evidence suggests that a certain sub-population of cancer cells harbors a stem-like phenotype and is likely responsible for disease recurrence, treatment resistance and potentially even for the infiltrative growth of GBM. GBM incidence has been negatively correlated with the serum levels of 25-hydroxy-vitamin D3, while the low pH within tumors has been shown to promote the expression of the vitamin D3-degrading enzyme 24-hydroxylase, encoded by the CYP24A1 gene. Therefore, we hypothesized that calcitriol can specifically target stem-like glioblastoma cells and induce their differentiation. Here, we show, using in vitro limiting dilution assays, quantitative real-time PCR, quantitative proteomics and ex vivo adult organotypic brain slice transplantation cultures, that therapeutic doses of calcitriol, the hormonally active form of vitamin D3, reduce stemness to varying extents in a panel of investigated GSC lines, and that it effectively hinders tumor growth of responding GSCs ex vivo. We further show that calcitriol synergizes with Temozolomide ex vivo to completely eliminate some GSC tumors. These findings indicate that calcitriol carries potential as an adjuvant therapy for a subgroup of GBM patients and should be analyzed in more detail in follow-up studies.

Highlights

  • Gliomas are tumors of the central nervous system, of which the highest grade, glioblastoma (GBM, WHO grade IV glioma), is the most common and the most aggressive form [1].These tumors are resistant towards conventional chemotherapy, currently consisting of Temozolomide (TMZ)-based radiochemotherapy, with the recent addition of tumor-treating fields (TTF) [2,3,4,5]

  • The anti-cancer and differentiation-promoting activity of Vitamin D3 (VitD3) and calcitriol has been known for some time, and it has been shown in numerous studies that intake of VitD3, a safe and well-studied drug, can prevent cancer occurrence [15,22,49]

  • Based on these two paradigms, i.e., its known ability to target the cancer stem-like phenotype and its anti-tumorigenic activity, we decided to apply therapeutic doses of calcitriol, the hormonally active form of VitD3, in an aim to reduce the stem-like phenotype of GSCs and thereby increase its sensitivity to chemotherapy

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Summary

Introduction

Gliomas are tumors of the central nervous system, of which the highest grade, glioblastoma (GBM, WHO grade IV glioma), is the most common and the most aggressive form [1] These tumors are resistant towards conventional chemotherapy, currently consisting of Temozolomide (TMZ)-based radiochemotherapy, with the recent addition of tumor-treating fields (TTF) [2,3,4,5]. A surgical resection of GBM is often not entirely possible due to highly infiltrative and diffuse growth of these tumors, which routinely leaves some undetectable tumor cells that cause frequent recurrences. All of those factors cause a devastatingly low 5-year survival-rate of less than 5% and a median survival of 15 months after diagnosis [7]. Key characteristics of the cells are that they have a higher differentiation potential, express various marker proteins associated with stemness such as SOX2, SOX9, OLIG2 and are considered more tumorigenic upon transplantation into rodents compared to their differentiated counterparts (reviewed in [8])

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