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

• Type of Material: Article
• Authors: Yuan Pan, Washington University; Laura J. Smithson, Washington University; Yu Ma, Washington University; Dolores Hambardzumyan, Emory University; David H. Gutmann, Washington University
• Language: English
• Date: 2017-05-16
• Publisher: Impact Journals
• Publication Version: Final Published Version
• Copyright Statement: © Pan et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.18632/oncotarget.16516
• Title of Journal or Parent Work: Oncotarget
• ISSN: 1949-2553
• Volume: 8
• Issue: 20
• Start Page: 32977
• End Page: 32989
• Grant/Funding Information: This work was supported by funding from the National Cancer Institute (U01-CA160882-01 to D.H. and D.H.G.).; Y.P. was supported by a McDonnell Center for Cellular and Molecular Neurobiology Postdoctoral Fellowship.
• Keywords: Life Sciences & Biomedicine; PROLIFERATION; Oncology; MAMMALIAN TARGET; CANCER; CHEMOKINE RECEPTOR; CELLS; glioma; Cell Biology; Science & Technology; neurofibromin; chemokine; INVASION IN-VITRO; INHIBITION; CD44; ACTIVATION; mTOR; UNITED-STATES
• Research Categories: Biology, Neuroscience; Health Sciences, Oncology

Abstract

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 lowgrade 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.