CXCL12 secreted from glioma stem cells regulates their proliferation

et al. 2016

Sci Rep

Although the chemotactic cytokine CXCL3 is thought to play an important role in tumor initiation and invasion, little is known about its function in hepatocellular carcinoma (HCC). In our previous study, we found that Ikaros inhibited CD133 expression via the MAPK pathway in HCC. Here, we showed that Ikaros may indirectly down-regulate CXCL3 expression in HCC cells, which leads to better outcomes in patients with CD133+ cancer stem cell (CSC) populations. CD133 overexpression induced CXCL3 expression, and silencing of CD133 down-regulated CXCL3 in HCC cells. Knockdown of CXCL3 inhibited CD133+ HCC CSCs’ self-renewal and tumorigenesis. The serum CXCL3 level was higher in HCC patients’ samples than that in healthy individual. HCC patients with higher CXCL3 expression displayed a poor prognosis, and a high level of CXCL3 was significantly associated with vascular invasion and tumor capsule formation. Exogenous CXCL3 induced Erk1/2 and ETS1 phosphorylation and promoted CD133 expression, indicating a positive feedback loop between CXCL3 and CD133 gene expression in HCC cells via Erk1/2 activation. Together, our findings indicated that CXCL3 might be a potent therapeutic target for HCC.

Section: Discussionmentioning

confidence: 99%

CXCL3 contributes to CD133+ CSCs maintenance and forms a positive feedback regulation loop with CD133 in HCC via Erk1/2 phosphorylation

et al. 2016

Sci Rep

“…In vitro, GBM CSC proliferation was induced either by treatment with exogenous CXCL12 (Liu et al, 2013) or by the receptor activation induced by CXCL12 secreted by CSCs in an autocrine fashion (Uemae et al, 2014). This effect was mainly mediated by CXCR4, since it was reversed in the presence of the CXCR4 antagonist AMD3100 (Schulte et al, 2011; Gatti et al, 2013).…”

Section: Cxcl12 Cxcr4–cxcr7 Activity In Human Glioblastoma Stem-likementioning

confidence: 99%

“…In particular, knocking down CXCR4 using RNAi or inhibiting CXCR4 function by AMD3100 in CSCs, impairs proliferation in vivo , effectively reducing tumor growth in two different xenograft models (Ping et al, 2011; Lee et al, 2013); similarly shRNA CXCL12 knock-down in CSCs inhibited tumor growth in vivo (Uemae et al, 2014). …”

Section: Cxcl12 Cxcr4–cxcr7 Activity In Human Glioblastoma Stem-likementioning

confidence: 99%

“…Discordant findings have been reported using murine GBM stem-like cells, in which endothelial-like differentiation was associated with CXCL12 expression but CXCL12/CXCR4 blockade did not affect either in vitro tube formation or in vivo angiogenesis. Thus autocrine/paracrine CXCL12 regulates GBM murine stem cell proliferation but probably not angiogenesis (Uemae et al, 2014). …”

Section: Cxcl12 Cxcr4–cxcr7 Activity In Human Glioblastoma Stem-likementioning

confidence: 99%

See 1 more Smart Citation

CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem-like cells and regulation of the tumor microenvironment

Würth

Bajetto

Harrison

et al. 2014

Front. Cell. Neurosci.

115

128

Chemokines are crucial autocrine and paracrine players in tumor development. In particular, CXCL12, through its receptors CXCR4 and CXCR7, affects tumor progression by controlling cancer cell survival, proliferation and migration, and, indirectly, via angiogenesis or recruiting immune cells. Glioblastoma (GBM) is the most prevalent primary malignant brain tumor in adults and despite current multimodal therapies it remains almost incurable. The aggressive and recurrent phenotype of GBM is ascribed to high growth rate, invasiveness to normal brain, marked angiogenesis, ability to escape the immune system and resistance to standard of care therapies. Tumor molecular and cellular heterogeneity severely hinders GBM therapeutic improvement. In particular, a subpopulation of chemo- and radio-therapy resistant tumorigenic cancer stem–like cells (CSCs) is believed to be the main responsible for tumor cell dissemination to the brain. GBM cells display heterogeneous expression levels of CXCR4 and CXCR7 that are overexpressed in CSCs, representing a molecular correlate for the invasive potential of GBM. The microenvironment contribution in GBM development is increasingly emphasized. An interplay exists between CSCs, differentiated GBM cells, and the microenvironment, mainly through secreted chemokines (e.g., CXCL12) causing recruitment of fibroblasts, endothelial, mesenchymal and inflammatory cells to the tumor, via specific receptors such as CXCR4. This review covers recent developments on the role of CXCL12/CXCR4–CXCR7 networks in GBM progression and the potential translational impact of their targeting. The biological and molecular understanding of the heterogeneous GBM cell behavior, phenotype and signaling is still limited. Progress in the identification of chemokine-dependent mechanisms that affect GBM cell survival, trafficking and chemo-attractive functions, opens new perspectives for development of more specific therapeutic approaches that include chemokine-based drugs.

“…It was reported that killer cell lectin-like receptor subfamily C, member 2 (KLRC2), a transmembrane activating receptor of natural killer cells, expressed higher in glioma-initiating cells compared with neural stem cell lines and normal adult brain tissue [36]. Emerging evidence suggests that the chemokine (C-X-C motif) ligand 12 (CXCL12), which is secreted from glioma stem cells (GSCs), plays a vital role in tumorigenesis and proliferation [37]. Additionally, many of the selected 26 functional pathways are related to the immune microenvironment, such as regulation of immune effector process, positive regulation of cytokine production, and cell chemotaxis.…”

Section: Discussionmentioning

confidence: 99%

Development and validation of an immune-related gene pairs signature in lower-grade glioma

Shuai

et al. 2020

Preprint

Background Lower-grade gliomas (LGG) are the prevalent primary intracerebral malignancy tumor. Increasing evidence indicated an association between immune signature and LGG prognosis. Thus, we aim to develop an immune-related gene pairs (IRGPs) signature that can predict prognosis for LGG. Method: Gene expression levels and clinical information of LGG patients (LGGs) were collected from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. The two databases were divided into training cohort (n = 515) and an independent validation cohort (n = 604). IGRPs significantly associated with prognosis were selected by Cox regression. Gene set enrichment analysis and filtration were performed on IGRPs. Results Within 1991 immune genes, an 8 IRGPs signature including 15 unique genes was constructed, which had a significant association with survival. In the validation dataset, the IRGPs signature significantly stratified LGGs into low- and high-risk groups (P < 0.001), and it remained an independent prognostic factor in univariate and multivariate analyses (P < 0.001). Additionally, 26 functional pathways were filtrated through the intersection of Gene set enrichment analysis (GSEA) and gene ontology (GO) enrichment analysis. Conclusion The IGRPs signature demonstrated good prognostic value in lower-grade glioma, which may provide new insights into individual treatment for glioma patients. And the IGRPs might take effect through these filtrated 26 functional pathways.