Increased in vivo angiogenic effect of glioma stromal mesenchymal stem-like cells on glioma cancer stem cells from patients with glioblastoma

Abstract

The presence of glioma stromal mesenchymal stem‑like cells (GS-MSLCs) in tumors from glioma patients has been previously reported. The mechanisms through which these cells function as a part of the glioma microenvironment, however, remain incompletely understood. We investigated the biological effects of GS-MSLCs on glioma cancer stem cells (gCSCs), testing the hypothesis that GS-MSLCs alter the biological characteristics of gCSCs. GS-MSLCs and gCSCs were isolated from different glioblastoma (GBM) specimens obtained from patients. In in vitro experiments, gCSCs were cultured alone or co-cultured with GS-MSLCs, and gCSCs cell counts were compared between the two groups. In addition, two groups of orthotopic GBM xenografts in mice were created, one using gCSCs from the monoculture group and one using gCSCs isolated from the co-culture group, and tumor volume and survival were analyzed. Furthermore, in vivo proliferation, apoptosis and vessel formation were examined using immunohistochemical analyses. In vitro cell counts for gCSCs co-cultured with GS-MSLCs increased 3-fold compared to gCSCs cultured alone. In orthotopic xenograft experiments, mice injected with gCSCs isolated from the co-culture group had significantly larger tumor volume, measured on day 40 after injection, and their survival times were shorter. Immunohistochemical analysis showed increased tumor expression of CD31, indicative of enhanced microvessel formation in mice injected with gCSCs co-cultured with GS-MSLCs compared to mice injected with gCSCs cultured alone. However, proliferation (PCNA) and apoptosis (TUNEL) markers showed no significant difference between the two groups. In conclusion, GS-MSLCs may influence the biological properties of gCSCs, shifting them towards a more aggressive status; moreover, increased angiogenesis may be a critical component of this mechanism.

Glioma‐Associated Stem Cells: A Novel Class of Tumor‐Supporting Cells Able to Predict Prognosis of Human Low‐Grade Gliomas

“…These latter may arise from normal progenitors, in analogy with what occurs in Platelet‐Derived Growth Factor (PDGF)‐induced gliomas of the adult or neonatal rat, where a small population of neural stem cells are “recruited” into the glioma and are induced to proliferate . Accordingly, Kong's group has isolated from a single glioblastoma patient a stem cell line with some mesenchymal features (GS‐MSLC) that showed the ability to influence a GSC line by increasing, in vitro, its proliferation, and, in vivo, the size of the formed tumors via an incremented angiogenesis . Our article newly shows that normal stem cells with mesenchymal features and a wide differentiation potential can be isolated both from LGG and HGG, support tumor growth releasing exosomes, and can predict patient prognosis.…”

Paracrine effects of stem cells in wound healing and cancer progression

“…Concomitantly, the expression of pro-angiogenic factors, such as bFGF, platelet-derived growth factor-BB (PDGF-BB) and IGF-1, were reduced suggesting that MSCs inhibited the secretion of these factors by the glioma cells. However, another study using glioma stromal mesenchymal stem-like cells (GS-MSLCs), which are MSC-like cells residing in glioma, demonstrated that MSCs are also able to promote angiogenesis (93). Apparently, the source the MSCs are isolated from is an important factor that determines the effect of MSCs in glioma (94).…”

Doxorubicin alters the mitochondrial dynamics machinery and mitophagy in the liver of treated animals

“…To determine whether mitochondrial fission was coupled to enhanced cell division in response to Doxinduced injury, we assessed the content of PCNA. PCNA is expressed in early G1 and S phase of the cell cycle and functions in cell cycle progression, DNA replication, and DNA repair and has previously been used as a marker of cell proliferation [30,31]. There was no difference in PCNA content between groups (1644.00 AE 110.73 vs. 1543.89 AE 120.94, P = 0.562), indicating that Dox does not induce cell proliferation in livers of treated animals, at least 24 h post-treatment.…”