Angiogenesis promotes tumor progression and enables metastatsis. Previous studies focused on the function of tumor signals that activate endothelial cell responses. However, the function of endothelial cell signals that directly elicit tumor cell responses remain uncharacterized. The goal of this proposal is to identify and characterize novel, endothelial-derived molecular regulators of tumor cell growth and invasion. Our preliminary studies showed that conditioned media from wild-type, but not EphA2-deficient, endothelial cells promotes tumor cell growth and motility in culture. Co-transplanted wild-type, but not EphA2-deficient, endothelial cells enhanced tumor cell proliferation in the absence of blood flow in vivo. Microarray analysis of wild-type and EphA2-deficient endothelial cells revealed that mRNA encoding slit2 is elevated in EphA2-deficient endothelial cells. Slit2 is a secreted ligand for the roundabout (Robo) receptor family that functions in neural development, and was more recently shown to negatively regulate angiogenesis and tumor progression. In addition we observed the absence of slit2 protein in EphA2-positive blood tumor vessels within a significant number of human breast cancer samples, and also found that ephA2 correlates negatively, while slit2 correlates positively, with overall survival in human breast cancer patients. This led us to hypothesize that EphA2 downregulates slit2 ligand to facilitate endothelial cell-induced tumor cell proliferation, migration, and progression, as well as angiogenesis. This research will enhance our understanding of how seemingly normal tissue in the microenvironment, such as endothelium, that surrounds the tumor facilitates growth, invasion, and metastasis, an NCI priority for FY2010 and beyond. Investigation will be completed at Vanderbilt University School of Medicine in the context of the Vanderbilt-Ingram Comprehensive Cancer Center facilities, which supports a host-tumor interaction focused research environment ideally suited for the molecular, biochemical, genetic, and imaging analyses involved in this research.
Our research objective is to investigate the novel concept that signals derived from host endothelial cells directly stimulate tumor cell growth and invasion, facilitating metastastic spread that ultimately leads to cancer death. Identifying and characterizing these signals will provide the foundation for molecularly targeted therapies designed to inhibit these signals and more effectively treat malignant cancer.
|Song, W; Hwang, Y; Youngblood, V M et al. (2017) Targeting EphA2 impairs cell cycle progression and growth of basal-like/triple-negative breast cancers. Oncogene 36:5620-5630|
|Youngblood, Victoria M; Kim, Laura C; Edwards, Deanna N et al. (2016) The Ephrin-A1/EPHA2 Signaling Axis Regulates Glutamine Metabolism in HER2-Positive Breast Cancer. Cancer Res 76:1825-36|
|Wang, Shan; Amato, Katherine R; Song, Wenqiang et al. (2015) Regulation of endothelial cell proliferation and vascular assembly through distinct mTORC2 signaling pathways. Mol Cell Biol 35:1299-313|
|Morrison, Meghan M; Young, Christian D; Wang, Shan et al. (2015) mTOR Directs Breast Morphogenesis through the PKC-alpha-Rac1 Signaling Axis. PLoS Genet 11:e1005291|
|Youngblood, Victoria; Wang, Shan; Song, Wenqiang et al. (2015) Elevated Slit2 Activity Impairs VEGF-Induced Angiogenesis and Tumor Neovascularization in EphA2-Deficient Endothelium. Mol Cancer Res 13:524-37|
|Amato, Katherine R; Wang, Shan; Hastings, Andrew K et al. (2014) Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC. J Clin Invest 124:2037-49|
|Song, Wenqiang; Ma, Yufang; Wang, Jialiang et al. (2014) JNK signaling mediates EPHA2-dependent tumor cell proliferation, motility, and cancer stem cell-like properties in non-small cell lung cancer. Cancer Res 74:2444-54|
|Stanford, Jamie C; Young, Christian; Hicks, Donna et al. (2014) Efferocytosis produces a prometastatic landscape during postpartum mammary gland involution. J Clin Invest 124:4737-52|
|Brantley-Sieders, Dana M; Fan, Kang-Hsien; Deming-Halverson, Sandra L et al. (2012) Local breast cancer spatial patterning: a tool for community health resource allocation to address local disparities in breast cancer mortality. PLoS One 7:e45238|
|Brantley-Sieders, Dana M (2012) Clinical relevance of Ephs and ephrins in cancer: lessons from breast, colorectal, and lung cancer profiling. Semin Cell Dev Biol 23:102-8|
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