Significance of perivascular tumour cells defined by CD109 expression in progression of glioma

Abstract

In the progression of glioma, tumour cells often exploit the perivascular microenvironment to promote their survival and resistance to conventional therapies. Some of these cells are considered to be brain tumour stem cells (BTSCs); however, the molecular nature of perivascular tumour cells has not been specifically clarified because of the complexity of glioma. Here, we identified CD109, a glycosylphosphatidylinositol-anchored protein and regulator of multiple signalling pathways, as a critical regulator of the progression of lower-grade glioma (World Health Organization grade II/III) by clinicopathological and whole-genome sequencing analysis of tissues from human glioma. The importance of CD109-positive perivascular tumour cells was confirmed not only in human lower-grade glioma tissues but also in a mouse model that recapitulated human glioma. Intriguingly, BTSCs isolated from mouse glioma expressed high levels of CD109. CD109-positive BTSCs exerted a proliferative effect on differentiated glioma cells treated with temozolomide. These data reveal the significance of tumour cells that populate perivascular regions during glioma progression, and indicate that CD109 is a potential therapeutic target for the disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Revealing the glioma cancer stem cell interactome, one niche at a time

“…Further work will be required to understand the degree to which these various CSC markers identify discrete and/or overlapping populations. These authors have also identified an interesting tumour‐promoting interaction between CSCs and adjacent NSTCs . We now add this interaction to the set of relationships that develop within GBM tumours that serve to resist our standard therapeutic interventions.…”

“…Shiraki et al conclude their study by describing a rare example of CSC and NSTC cooperative interaction by demonstrating that the conditioned medium from CD109 + CSCs induces proliferation of CD109 − NSTCs . This finding strongly suggests that the CSCs lining the vasculature of the brain signal outwardly to drive cell division within adjacent NSTC populations (Figure A ).…”

“…We also offer a brief synopsis of the landscape of interacting cell types within the GBM tumour microenvironment. This branch of GBM research has primarily focused on tumour cells interacting with non‐transformed neural cell populations, but we also touch on the few reported examples of tumour cell cooperative interactions such as that revealed by Shiraki et al . Numerous articles have helped to refine our understanding of the molecular identity of CSCs in various anatomical niches.…”

“…The landscape of interacting cell types within the glioma microenvironment. (A) Shiraki et al have revealed that CSCs expressing CD109 line blood vessels within the brains of glioma patients. Presentation of this CSC population is associated with progression from low‐grade to high‐grade glioma, and CD109 + CSCs stimulate the proliferation of adjacent NSTCs.…”

CD109: a multifunctional GPI‐anchored protein with key roles in tumor progression and physiological homeostasis

“…We previously reported that CD109‐deficient mice exhibit epidermal hyperplasia in skin and osteopenia in bone, suggesting possible CD109‐related physiological functions in vivo. Although previous studies report CD109 expression in various malignant tumors and correlation with prognosis in patients harboring a malignant tumor, such as a glioblastoma or lung adenocarcinoma, its roles in human disease remain largely unknown. In this review, we describe our views and perspectives on the significance of CD109 in malignant tumors and provide a description of our recent studies showing the involvement of CD109 in skin and bone‐tissue homeostasis in CD109‐deficient mice.…”