Regulation Of Bone Marrow Angiogenesis By Cxcl12 In The Leukemia Tumor Microenvironment

Abstract While it is well established that angiogenesis is essential for the progression of solid tumors, its role in hematological tumors is more recently becoming fully appreciated. In the current study we have investigated the potential role of leukemic cells in regulating local angiogenesis as well as the modulation of tumor cell CXCL12 expression subsequent to interaction with bone marrow derived osteoblasts as one mechanism by which local vascular rich niches may be created. Human REH acute lymphoblastic leukemia (ALL; ATCC #CRL-8286) increased vessel density when placed on the chorioallantoic membrane (CAM) assay. Conditioned media from these same tumor cells increased human brain microvessel endothelial cell (HBMEC) motility and tube formation suggesting leukemia cell influence on surrounding vasculature. Strikingly, while REH cells express negligible CXCL12 at baseline, the chemokine is consistently induced to easily detectable levels upon co-culture with human osteoblasts indicating one mechanism by which tumor cells within the bone marrow microenvironment may be poised to enhance vascular cell recruitment even more robustly than leukemic cells alone. Preliminary evaluation of primary, patient-derived ALL leukophoresis samples demonstrated a comparable increase in tumor cell CXCL12 indicating this modulation is not limited to an established tumor cell line. Increased expression of CXCL12 by REH leukemic cells was consistent with enhanced chemotaxis of HUVECs toward the co-culture of tumor and osteoblasts when compared to either cell type alone. The inclusion of 5-Aza-deoxycytidine (Aza-C) to REH cells alone resulted in expression of CXCL12 in the absence of osteoblast co-culture, suggesting methylation may play a regulatory role in the suppression of this chemokine. As a site in which metastatic disease is often refractory to standard therapy, in addition to the anatomical niche in which hematopoietic malignancies initiate and most frequently relapse, regulation of local angiogenesis in the bone marrow microenvironment requires further investigation. Our preliminary observations suggest CXCL12 may play an important role in regulating leukemic cell niche angiogenesis, and targeting it could potentially represent a novel application of antagonists currently in clinical trials in an effort to treat refractory leukemia. 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 1525. doi:1538-7445.AM2012-1525