Abstract LB-312: Egfl7 is expressed in a broad range of human tumors with apparent restriction to the endothelium

Abstract

Abstract EGFL7 is a secreted protein expressed by proliferating endothelial cells in growing vessels during normal organ development. Though expression is generally restricted to a small subset of vessels in the adult, elevated expression has been observed under physiological conditions requiring new blood vessel growth, such as wound healing, pregnancy and tumor growth. EGFL7 facilitates new blood vessel formation by supporting endothelial cell adhesion and migration. In addition, EGFL7 can protect endothelial cells from stress-induced apoptosis, such as hypoxia or potentially growth factor withdrawal. A blocking antibody to EGFL7 (anti-EGFL7) has demonstrated increased survival benefits in preclinical models when combined with a blocking antibody to the pro-angiogenic growth factor VEGFA. Anti-EGFL7 is currently being investigated in Phase II clinical trials in NSCLC and mCRC in combination with bevacizumab and chemotherapy. We present here a comprehensive assessment of Egfl7 expression in a broad range of human solid tumors using in situ hybridization (BC n=150, CRC n=134, RCC n=8, LC n=62, LN mets predom. BC n=27, OV n=25) and quantitative PCR (BC n=92 primary, n=20 LN mets synchronous collection, n=12 distant matched metastasis sequential collection; CRC n=85 primary, n=9 distant matched metastasis sequential collection; NSCLC n=77 primary, n=3 distant matched metastasis sequential collection). Egfl7 is expressed in all tumor types interrogated. With the methods utilized in this study, expression appears to be limited to endothelial cells, with no appreciable tumor cell expression. This data is supported by co-expression analysis in preclinical and clinical samples, showing correlation with vascular markers (n=91 xenograft models CD31 r=0.85, p<0.0001; human tumors CD34 BC r=0.54, p<0.0001; CRC r=0.5, p<0.0001; NSCLC r=0.39, p=0.0003). Comparison with pro-angiogenic growth factors suggests an indication-dependent pattern of co-expression, with strongest correlation being observed in CRC (VEGFA r=0.3, p=0.003; VEGFC r=0.74, p<0.0001; VEGFD r=0.38, p=0.0001). RNA expression in a cohort of archival samples from metastatic CRC, BC and NSCLC patients does not indicate a strong prognostic association between Egfl7 and overall survival. However, analysis of paired primary and metastasis samples indicate a significant upregulation of Egfl7 in distant metastasis of CRC tumors (average fold change 1.8, p=0.0079, n=9 matched pairs), despite little change in the total vascular content as measured by CD34 expression (average fold change 1.06, p=0.77, n=9 matched pairs). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-312. doi:1538-7445.AM2012-LB-312