Cell Subpopulations Overexpressing p75NTR Have Tumor-initiating Properties in the C6 Glioma Cell Line.

Abstract

Glioma is the most common and lethal primary brain tumor. Even with the development of multidisciplinary treatment approaches, results are disappointing because of the unavoidable tumor recurrence, which may be caused by the existence of tumor-initiating cells. The p75 neurotrophin receptor (p75NTR), which belongs to the tumor necrosis factor receptor superfamily, is not only involved in various cellular functions but also related to tumor growth. This study is focused, on the possible role of p75NTR in glioma tumor initiation. C6 cells with high and low expression of p75NTR were sorted using flow cytometry. The neurosphere characteristics and properties of these two subpopulations were assessed and compared with those of parental cells. Radiation and chemotherapy sensitivity was also analyzed in these cell populations. Finally, in vivo tumorigenicity of cells was tested in a rat model. Cells overexpressing p75NTR (C6p75+++ cells) demonstrated greater ability of neurosphere formation, colony proliferation, and certain stem cell marker overexpression than cells with low p75NTR expression (C6p75+) and parental cells. In addition, following irradiation or temozolomide treatment, more viable C6p75+++ cells remained, and they proliferated into more colonies. In vivo, C6p75+++ cell implantation in Sprague Dawley rats reduced the survival time. Cells with p75NTR overexpression demonstrated certain unique characteristics of tumor-initiating cells, such as neurosphere formation, high colony proliferation, and resistance to radio- and chemotherapy. With regard to the heterogeneous composition of glioma cells, p75NTR can be used as an alternative marker to identify a glioma subpopulation with tumor-initiating properties.