Abstract 1074: Tumor-associated microglia secrete paracrine factors that promote Nf1-deficient optic glial cell growth

Abstract

Abstract Previous studies have demonstrated that brain tumors are composed of heterogeneous mixtures of neoplastic and non-neoplastic (stromal) brain cells. However, current brain tumor therapies are primarily focused on inhibiting the growth of the cancerous cells, largely ignoring the contribution of the surrounding stromal elements. One of these stromal cell types is an immune system-like cell (microglia), which constitutes as many as half of the cells present in human brain tumors (gliomas). The tumor microenvironment is considered to play an important role in tumor formation and maintenance by providing signals that both negatively and positively influence tumor cell growth. Since children with the neurofibromatosis type 1 (NF1) inherited cancer syndrome are prone to the development of gliomas involving the optic nerve (optic gliomas), we have employed Nf1 genetically-engineered mice as an experimental model system to examine the role of microglia in optic glioma formation and maintenance. We leveraged RNA-sequencing data from FACS-isolated, mouse optic glioma-associated microglia to identify specific paracrine factors that are expressed in tumor-associated, but not normal, microglia. These factors were validated using RNA fluorescent in situ hybridization and investigated for their ability to increase the growth of Nf1-deficient optic nerve astroglial cells in vitro. Current studies are ongoing to determine whether (1) inhibition of microglia function in Nf1 genetically engineered mice reduces the expression of these paracrine factors and (2) inhibiting these factors attenuates optic glioma growth in vivo. Together, these studies identify a novel set of paracrine factors secreted by a key glioma-associated stromal cell type (microglia) relevant to the pathogenesis of NF1-associated tumors, raising the possibility that future therapies might be directed against tumor microenvironment paracrine factors. Citation Format: Anne C. Solga, Winnie W. Pong, Patrick J. Cimino, Keun Y. Kim, Jason Walker, Todd Wylie, Vincent Magrini, Joshua B. Rubin, David Piwnica-Worms, Mark H. Ellisman, Elaine R. Mardis, David H. Gutmann. Tumor-associated microglia secrete paracrine factors that promote Nf1-deficient optic glial cell growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1074. doi:10.1158/1538-7445.AM2014-1074