Disruption of intracerebral progression of rat C6 glioblastoma by in vivo treatment with anti-CD44 monoclonal antibody

Breyer, Roger; Hussein, S.; Radu, D; Pütz, Klaus-Martin; Gunia, Sven; Hecker, Hartmut; Samii, Madjid; Walter, G. F.; Stan, Alexandru C.

doi:10.3171/jns.2000.92.1.0140

Cited by 48 publications

(29 citation statements)

References 38 publications

(43 reference statements)

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“…CD44 expression is increased in GBM compared to low-grade gliomas and high levels of CD44 are associated with worse survival of GBM patients [37]. Inhibiting CD44 function using monoclonal antibodies or RNA silencing reduced GBM growth in vivo and prolonged mouse survival [38, 39]. The interaction between CD44 and its ligands (e.g., hyaluronic acid and osteopontin) modulates multiple aspects of glioma biology.…”

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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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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“…Binding of CD44 to its natural ligands (vitronectin, chondroitin sulfate, laminin, fibronectin and collagen), and addition of HA, a major component of the brain extracellular matrix, promotes glioma invasion. Intracerebral tumor progression of C6 cells is also disrupted after in vivo treatment with an anti-CD44 monoclonal antibody (Breyer et al 2000). In contrast, immunological staining of CD44 shows that its presence is restricted to isolated cells at the invasion border, indicating that its expression may be regulated by the cell cycle and/or the microenvironment of single cells (Pilkington et al 1993;Khoshyomn et al 1997).…”

Section: Adhesion Processesmentioning

confidence: 90%

Rat C6 glioma as experimental model system for the study of glioblastoma growth and invasion

Grobben

Deyn

Slegers

2002

Cell and Tissue Research

312

247

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Infiltration of the central nervous system by neoplastic cells in patients with glioblastoma multiforme (GBM) leads to neurological dysfunction and eventually to death. The elucidation of the mechanisms underlying the aggressive nature of GBM aims at improving radio-, chemo- and gene therapy. This review is focused on the use of rat C6 glioma as an experimental model system for GBM and provides an overview of the experimental data published in the literature using this cell line in elucidating the mechanism of tumor growth, angiogenesis and invasion, and in the design and evaluation of anticancer therapies. Understanding the stages of malignant brain tumor progression requires a series of experimental approaches with a varying degree of complexity. Implantation of malignant cells into animal brain tissue closely resembles in vivo tumor growth and has the advantage over simplified models that inflammatory and vascular mechanisms are activated. However, the complexity of these models makes it difficult to identify the individual processes involved in sustained tumor growth, angiogenesis and invasion. In cell culture models, the effect of growth factors, extracellular matrix components, proteases and adhesion molecules can be investigated. The secretion of tumor-derived factors into the medium can also be analyzed when simplified models are used. This review is a compilation of experimental data focused on the characterization of tumor-related processes and on the evaluation of new therapies for the treatment of malignant glial neoplasms using rat C6 glioma as a model system.

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“…Anti-CD44 monoclonal antibodies induced differentiation and apoptosis of human myeloid leukemia cells [308, 309]. Anti-CD44 monoclonal antibodies inhibited human melanoma growth and metastasis in mice in vivo [310], and disrupted intracerebral progression of rat glioblastoma in rats in vivo [311]. Blocking CD44v6 with humanized anti-CD44v6 monoclonal antibody U36 has been tested in patients with head and neck cancer [51].…”

Section: Ha As Therapeuticmentioning

confidence: 99%

Hyaluronan as a therapeutic target in human diseases

Liang

Jiang

Noble

2016

Advanced Drug Delivery Reviews

178

117

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Accumulation and turnover of extracellular matrix is a hallmark of tissue injury, repair and remodeling in human diseases. Hyaluronan is a major component of the extracellular matrix and plays an important role in regulating tissue injury and repair, and controlling disease outcomes. The function of hyaluronan depends on its size, location, and interactions with binding partners. While fragmented hyaluronan stimulates the expression of an array of genes by a variety of cell types regulating inflammatory responses and tissue repair, cell surface hyaluronan provides protection against tissue damage from the environment and promotes regeneration and repair. The interactions of hyaluronan and its binding proteins participate in the pathogenesis of many human diseases. Thus, targeting hyaluronan and its interactions with cells and proteins may provide new approaches to developing therapeutics for inflammatory and fibrosing diseases. This review focuses on the role of hyaluronan in biological and pathological processes, and as a potential therapeutic target in human diseases.

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Disruption of intracerebral progression of rat C6 glioblastoma by in vivo treatment with anti-CD44 monoclonal antibody

Abstract: The authors conclude that CD44s-targeted treatment with specific mAb may represent an effective means for preventing progression of highly invasive GBMs.

Cited by 48 publications

References 38 publications

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

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

Rat C6 glioma as experimental model system for the study of glioblastoma growth and invasion

Hyaluronan as a therapeutic target in human diseases

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