Pericytes/vessel-associated mural cells (VAMCs) are the major source of key epithelial-mesenchymal transition (EMT) factors SLUG and TWIST in human glioma

Abstract

Epithelial-to-mesenchymal transition (EMT) is supposed to be responsible for increased invasion and metastases in epithelial cancer cells. The activation of EMT genes has further been proposed to be important in the process of malignant transformation of primary CNS tumors. Since the cellular source and clinical impact of EMT factors in primary CNS tumors still remain unclear, we aimed at deciphering their distribution in vivo and clinico-pathological relevance in human gliomas.We investigated 350 glioma patients for the expression of the key EMT factors SLUG and TWIST by immunohistochemistry and immunofluorescence related to morpho-genetic alterations such as EGFR-amplification, IDH-1 (R132H) mutation and 1p/19q LOH. Furthermore, transcriptional cluster and survival analyses were performed.Our data illustrate that SLUG and TWIST are overexpressed in gliomas showing vascular proliferation such as pilocytic astrocytomas and glioblastomas. EMT factors are exclusively expressed by non-neoplastic pericytes/vessel-associated mural cells (VAMCs). They are not associated with patient survival but correlate with pericytic/VAMC genes in glioblastoma cluster analysis.In summary, the upregulation of EMT genes in pilocytic astrocytomas and glioblastomas reflects the level of activation of pericytes/VAMCs in newly formed blood vessels. Our results underscore that the negative prognostic potential of the EMT signature in the group of diffuse gliomas of WHO grade II-IV does most likely not derive from glioma cells but rather reflects the degree of proliferating mural cells thereby constituting a potential target for future alternative treatment approaches.

Pericyte‐secreted IGF2 promotes breast cancer brain metastasis formation

“…Besides enhancing adhesion to the substrate, pericytes inhibit intercellular adhesions and expression of E-cadherin, conferring breast cancer cells a migratory, invasive phenotype, characteristic of cells undergoing epithelial-to-mesenchymal transition (EMT) [36]. In line with these results, pericytes have been shown to be major sources of EMT factors in glioma [37]. We have also found that pericytes have a prompt effect on the proliferation of TNBC, but not of melanoma cells.…”

TGF‐β activates pericytes via induction of the epithelial‐to‐mesenchymal transition protein SLUG in glioblastoma

“…[5–10] Previous analysis of different mRNA signatures of GBM led to the proposition of a new stratification of GBM subgroups, in which the mesenchymal mRNA signature profile has been associated with more frequent recurrences and higher malignancy. [11] More recent studies showed that the rather more benign pilocytic astrocytoma (World Health Organization, WHO grade I) also displayed a mesenchymal signature,[12] which at least partly contradicts the hypothesis that, in glioma, the mesenchymal signature is associated with increased malignancy. [13] A possible reason for the correlation of the mesenchymal signature with a poor prognosis might be that the EMT factor expression in glioma was analysed at the mRNA level [14] instead of determining protein levels and identifying the cell type that expresses specific EMT proteins.…”

Overexpressed P75CUX1 promotes EMT in glioma infiltration by activating β-catenin

“…The specific phenomenon that P75CUX1 significantly regulated the migration and invasion but not the proliferation of glioma cells facilitated us to reveal novel mechanisms of rapid infiltrating progression in glioma. The mechanism of correlation of CUX1 and EMT was the breakthrough finding because EMT is a well-recognized mechanism in glioma diffuse infiltration 12 – 14 . In our study, when P75CUX1 was knocked down, E-cadherin, ZO-1, and Claudin were significantly augmented while N-cadherin, β-catenin, Slug, Snail, MMP2, and MMP9 were reduced in vitro and in vivo, indicating a more epithelial phenotype under P75CUX1 inhibition.…”

“…In glioma, epithelial–mesenchymal transition (EMT) has an essential role in diffuse infiltrating phenotype and frequently associated with glioma recurrence and malignant development 5 , 6 , 12 – 14 . EMT is an important biological process for epithelial-derived malignant tumor cells to acquire the ability to migrate and invade 15 .…”

“…It provides tumor cells the infiltrating phenotype characterized by cadherins regulation, cytoskeleton reorganization, special transcription factors (TFs) overexpression, and metabolic change 16 . Accumulating evidences have suggested that a highly sensitive molecular regulator of EMT can be the promising marker of diffuse infiltrating glioma 6 , 12 – 14 .…”