Glioma stem cells involved in tumor tissue remodeling in a xenograft model

Abstract

Object Although tissue remodeling plays a crucial role in the tumorigenesis and progression of human gliomas, its mechanisms remain largely uncertain. In the current study, the authors investigated the potential role of human glioma stem cells (hGSCs) in the tissue remodeling of gliomas. Methods Transgenic nude mice with ubiquitous green fluorescent protein (GFP) expression were obtained by crossing nontransgenic NC athymic nude mice with the GFP transgenic C57BL/6J mice. As a result, GFP was expressed in essentially all tissues in the offspring. Human glioma stem cells were then orthotopically implanted into the GFP nude mice in an effort to assess the hGSC–host brain interactions and thereby elucidate the roles of tissue remodeling during tumorigenesis and progression of human gliomas. Results All of the essential tissues in the GFP transgenic nude mice, including the brain, fluoresced green under an excitation light; therefore, tumor remodeling by hGSCs can be unambiguously distinguished from a bright green background composed of adjacent host GFP-expressing components. This technique enabled the authors to address the following concerns: 1) hGSCs were involved in the invasiveness of gliomas and adjacent stroma degradation of the host. 2) An in vivo study demonstrated that cell fusion occurred between hGSCs and host cells. 3) Vasculogenic mimicry—the formation of patterned, tubular networks of vascular channels by transdifferentiated hGSCs—could be observed. 4) Differentiation mimicry—namely, the differentiation direction of hGSCs bearing multidifferentiation potentials—seemed to be decided by the local host cellular microenviroment. Conclusions The results of this study indicated that the GFP transgenic nude mice model with GFP expression in essentially all tissues could be obtained by crossing nontransgenic athymic nude mice with transgenic GFP mice. This model should greatly expand our knowledge of glioma-host interactions. The data indicated that hGSCs might play a decisive role in tissue remodeling of gliomas as well.