Research Papers:

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

Yuan Pan, Laura J. Smithson, Yu Ma, Dolores Hambardzumyan and David H. Gutmann _

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Oncotarget. 2017; 8:32977-32989. https://doi.org/10.18632/oncotarget.16516

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Yuan Pan1, Laura J. Smithson1, Yu Ma1, Dolores Hambardzumyan2, David H. Gutmann1

1Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA

2Department of Oncology, Aflac Cancer and Blood Disorders Center, Emory University, GA, USA

Correspondence to:

David H. Gutmann, email: [email protected]

Keywords: chemokine, glioma, neurofibromin, mTOR, CD44

Received: October 24, 2016     Accepted: March 13, 2017     Published: March 23, 2017


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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