Critical roles of chemokine receptor CCR5 in regulating glioblastoma proliferation and invasion

Zhao, Lanfu; Wang, Yuan; Xue, Yong; Liu, Wenhai; Zhang, Yufu; He, Shiming

doi:10.1093/abbs/gmv095

Cited by 37 publications

(44 citation statements)

References 52 publications

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“…As shown in Figure 1A, the levels of several cytokines including CX3CL1, RANTES, and CCL11 were upregulated in GBM tumors. Since previous studies had shown that RANTES [15] and CX3CL1 [16] expression were correlated with the development of GBM, we focused on elucidating the role of CCL11. Real-time quantitative PCR demonstrated that CCL11 was overexpressed in 8 freshly collected GBM samples compared with paired adjacent tissue from the same subject (Figure 1B, left panel).…”

Section: Resultsmentioning

confidence: 99%

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Expression and prognostic significance of CCL11/CCR3 in glioblastoma

Tian

Chen

et al. 2016

Oncotarget

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Glioblastoma (GBM) is the most lethal primary nervous system cancer, but due to its rarity and complexity, its pathogenesis is poorly understood. To identify potential tumorigenic factors in GBM, we screened antibody-based cytokine arrays and found that CCL11 was upregulated. We then demonstrated in vitro that both CCL11 and its receptor, CCR3, were overexpressed and promoted the proliferation, migration and invasion of cancer cells. To examine the clinical significance of CCL11/CCR3, 458 GBM samples were divided into a training cohort with 225 cases and a test cohort containing 233 cases. In the training set, immunohistochemical analysis showed overexpression of CCL11 and CCR3 were correlated with unfavorable overall survival (OS). We further developed a prognostic classifier combining CCL11 and CCR3 expression and Karnofsky performance status (KPS) for predicting one-year survival in GBM patients. Receiver operating characteristic (ROC) analysis demonstrated that this predictor achieved 90.7% sensitivity and 73.4% specificity. These results were validated with the test sample set. Our findings suggest that CCL11-CCR3 binding is involved in the progression of GBM and may prompt a novel therapeutic approach. In addition, CCL11 and CCR3 expression, combined with KPS, may be used as an accurate predictor of one-year survival in GBM patients.

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Section: Resultsmentioning

confidence: 99%

“…Previous studies have shown that several chemokines and their receptors including CXCL12 [21], CXCL8 [22], CCL2 [23], RANTES [15], CX3CL1 [16], CCR4 [24], CXCR4 [25] and CX3CR1 [26] participate in tumorigenesis. In particular, CCR2 [27], CCR3 [16], and CCR5 [16, 28], three known CCL11 receptors, were all markedly upregulated in GBM.…”

Section: Discussionmentioning

confidence: 99%

Expression and prognostic significance of CCL11/CCR3 in glioblastoma

Tian

Chen

et al. 2016

Oncotarget

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“…However, while CCL5 function in glioma has not been fully elucidated, several reports have suggested that it might be an important chemokine in this setting. First, one of the main CCL5 receptors, CCR5, is expressed in U87 and U251 glioblastoma cell lines, such that its knockdown inhibits U87 growth in nude mice [35]. Second, CCL5 mRNA and protein expression are elevated in both tumor tissue and serum from patients with high-grade glioma [36].…”

Section: Discussionmentioning

confidence: 99%

Ccl5 establishes an autocrine high-grade glioma growth regulatory circuit critical for mesenchymal glioblastoma survival

Pan

Smithson

et al. 2017

Oncotarget

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Glioblastoma (GBM) is the most common malignant brain tumor in adults, with a median survival of 15 months. These poor clinical outcomes have prompted the development of drugs that block neoplastic cancer cell growth; however, non-neoplastic cell-derived signals (chemokines and cytokines) in the tumor microenvironment may also represent viable treatment targets. One such chemokine, Ccl5, produced by low-grade tumor-associated microglia, is responsible for maintaining neurofibromatosis type 1 (NF1) mouse optic glioma growth in vivo. Since malignant gliomas may achieve partial independence from growth regulatory factors produced by non-neoplastic cells in the tumor microenvironment by producing the same cytokines secreted by the stromal cells in their low-grade counterparts, we tested the hypothesis that CCL5/CCL5-receptor signaling in glioblastoma creates an autocrine circuit important for high-grade glioma growth. Herein, we demonstrate that increased CCL5 expression was restricted to both human and mouse mesenchymal GBM (M-GBM), a molecular subtype characterized by NF1 loss. We further show that the NF1 protein, neurofibromin, negatively regulates Ccl5 expression through suppression of AKT/mTOR signaling. Consistent with its role as a glioblastoma growth regulator, Ccl5 knockdown in M-GBM cells reduces M-GBM cell survival in vitro, and increases mouse glioblastoma survival in vivo. Finally, we demonstrate that Ccl5 operates through an unconventional CCL5 receptor, CD44, to inhibit M-GBM apoptosis. Collectively, these findings reveal an NF1-dependent CCL5-mediated pathway that regulates M-GBM cell survival, and support the concept that paracrine factors important for low-grade glioma growth can be usurped by high-grade tumors to create autocrine regulatory circuits that maintain malignant glioma survival.

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“…The axis of chemokines and chemokine receptors has been demonstrated as important regulators in the invasion and metastasis process of cancer cells. CCR5, whose ligands include CCL3 (MIP-1α), CCL4 (MIP-1β) and CCL5 (RANTES), was reported to be highly expressed in GBM tissue (24,25). A recent study showed that the overexpression of CCR5 was associated with poor prognosis of GBM patients, and activation of CCR5 signaling promoted the invasion of u87 and u251 cell lines in vitro by upregulating MMP-9 expression (24).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia and macrophages promote glioblastoma invasion by the CCL4-CCR5 axis

et al. 2016

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Glioblastoma (GBM) is a highly malignant brain tumor characterized by invasion tendency. Macrophage infiltration is associated with GBM invasion, but the mechanisms remain unclear. Hypoxia is an outstanding characteristic of GBM tissue. Hypoxia microenvironment modulates the biological behaviors of both tumor cells and infiltrated immune cells, including macrophages. In the present study, we analyzed the effects of hypoxia and macrophages on invasion of GBM cells and its potential mechanisms. We found that both hypoxia and macrophage supernatant promoted GBM cells invasion and matrix metalloproteinase (MMP)-9 expression, and hypoxia modulated the invasive activity of GBM cells by upregulating their CCR5 expression. The supernatant of hypoxic macrophages also showed greater pro-invasion effect than normoxic macrophages through the elevated secretion of CCL4. Moreover, we found that interferon regulatory factor-8 (IRF-8) was possibly involved in hypoxia-modulated CCL4 expression of macrophages. Taken together, the present study found that macrophages promoted GBM invasion by the CCL4-CCR5 axis, and hypoxia enhanced the interaction between these two types of cells by upregulating both CCL4 and CCR5 expression, respectively. The results of the present study suggested that hypoxia would be a potential target for the development of immune therapies of GBM.

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Critical roles of chemokine receptor CCR5 in regulating glioblastoma proliferation and invasion

Cited by 37 publications

References 52 publications

Expression and prognostic significance of CCL11/CCR3 in glioblastoma

Expression and prognostic significance of CCL11/CCR3 in glioblastoma

Ccl5 establishes an autocrine high-grade glioma growth regulatory circuit critical for mesenchymal glioblastoma survival

Hypoxia and macrophages promote glioblastoma invasion by the CCL4-CCR5 axis

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