Abstract 1436: TNF-alpha-dependent tumor reprogramming and promotion by microenvironment: Potential involvement of endothelial cells.

Abstract

Abstract Interactions of tumor clones with the host microenvironment have profound effects on tumor growth, response to radio/chemotherapy and formation of metastases. TNFα is a potent factor driving and orchestrating such interactions. We used mice with disrupted TNFα receptor I/II signaling to investigate phenotypic and genomic changes induced in tumors by TNFα-deficient or wild type (WT) host microenvironment. At the basal level, disruption of host stromal TNFα signaling resulted in the over-expression of tumor genes involved in extracellular matrix remodeling and angiogenesis. Phenotypically, these tumors exhibited a reduced vascular density, which induced the expression of oxidative stress signaling pathways and increased levels of tissue hypoxia and necrosis. These alterations were paralleled by the suppression of genes involved in chromosomal stability and key effectors of the ATM-dependent/ non-homologous end-joining pathways, which resulted in greater DNA double-strand breaks and caspase 3 activation following IR treatment. We further investigated tumor-associated endothelial cells (TAEC) obtained from tumors grown in WT and TNFα RI/II-/- animals. Differentially expressed genes (DEGs) primarily represented TNFα/Type I IFN-signaling. These genes significantly separated cohorts of patients with chronic inflammation (RA, IBD and liver cirrhosis) from normal samples. We trained these genes in human cancer datasets and defined a six-gene inflammatory signature that predicted significantly reduced overall survival in breast cancer, colon cancer, lung cancer, and glioma. Consistent with these findings, conditioned culture media from human endothelial cells stimulated by pro-inflammatory cytokines accelerated the growth of human colon and breast tumors in immunodeficient mice as compared with conditioned media from untreated endothelial cells. Based on these studies we came to two important conclusions. First, the host stroma may determine phenotypic and transcriptomic properties of tumor cells, and TNFα might be an important component of such microenvironment-dependent tumor reprogramming (MDTR). Second, endothelial cells may be an important cellular component of MDTR and tumor promotion. Citation Format: Nikolai N. Khodarev, Sean P. Pitroda, Ralph R. Weichselbaum. TNF-alpha-dependent tumor reprogramming and promotion by microenvironment: Potential involvement of endothelial cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1436. doi:10.1158/1538-7445.AM2013-1436