Stromal cell‐derived factor‐1 stimulates vasculogenesis and enhances Ewing's sarcoma tumor growth in the absence of vascular endothelial growth factor

Abstract

Stromal cell-derived Factor-1a (SDF-1a) stimulates the migration of bone marrow (BM) cells, similar to vascular endothelial growth factor (VEGF). We previously demonstrated that inhibition of VEGF 165 by small interfering RNA inhibited Ewing's sarcoma tumor growth, tumor vessel formation and recruitment of BM cells to the tumor. To determine the importance of BM cells in tumor vessel development, we investigated the effects of SDF-1a on VEGF-inhibited TC/siVEGF 7-1 Ewing's tumor neovasculature formation and growth. The effect of SDF-1a on CD34 1 progenitor cell chemotaxis was determined in vivo. Using a BM transplantation model with GFP 1 transgenic mice as BM donors and nude mice as recipients, we evaluated the effect of SDF-1a on the recruitment of BM-derived cells to VEGF 165 -inhibited TC/ siVEGF 7-1 tumors, as well as its effect on neovasculature development, vessel morphology and tumor growth. SDF-1a stimulated the migration of CD34 1 progenitor cells to Matrigel plugs in vivo and promoted the retainment of BM-derived pericytes in close association with perfused, functional tumor vessels. Intratumor inoculation of Ad-SDF-1a into TC/siVEGF 7-1 tumors resulted in increased SDF-1 and PDGF-BB expression, augmented tumor growth, an increase in the number of large, lumen-bearing vascular structures, and enhanced vessel pericyte coverage, with no change in VEGF 165 . SDF-1a stimulates BM cell chemotaxis and the association of these cells with functional tumor vessels. Furthermore, SDF-1a enhances tumor neovascularization and growth with no alteration in VEGF 165 . Our work suggests that SDF-1-mediated vasculogenesis may represent an alternate pathway that could potentially be utilized by tumors to sustain growth and neovasculature expansion after anti-VEGF therapy. '

Delta-like ligand 4–Notch signaling regulates bone marrow–derived pericyte/vascular smooth muscle cell formation

“…Our findings indicate a critical role for Notch signaling in pericyte/vSMC development, which is in keeping with data from other investigators, which include a role for Notch1 in SMC proliferation after vascular injury, a correlation between the expression of Notch3 and the expression of RGS5 in pericytes of developing teeth, and the presence of Notch3 ϩ BM-derived cells in thickened neointima of mice after femoral artery injury. 24,25 While the importance of functional Notch receptors for pericyte/vSMC development has been well documented, we are the first to demonstrate the critical role of DLL4 specifically in inducing expression of pericyte/vSMC markers. Our demonstration of a role for DLL4-Notch signaling in pericyte/vSMC marker regulation in vitro may be applicable to pericytes/vSMCs from non-BM origins.…”

“…We previously demonstrated that BM cells contribute to the expansion of the tumor vascular network by migrating to the tumor and differentiating into both endothelial cells and pericytes/vSMCs. 5,16,17,[23][24][25] The tumor blood vessels were surrounded by thick layers of BMderived pericytes/vSMCs. We also previously demonstrated that these BM-derived cells were essential for tumor growth using MEKK3-knockout BM cells, which cannot participate in vessel formation.…”

Critical signaling pathways in bone sarcoma: Candidates for therapeutic interventions

“…VEGF drives new blood vessel formation in Ewing sarcoma, because there is a positive correlation between VEGF and microvessel density (MVD) [45]. Blockade of VEGF production with an siRNA inhibited the growth of Ewing sarcoma xenografts, and production of VEGF in Ewing sarcoma also recruits CD34 + cells, precursors to pericytes, to the growing vasculature [46,47]. Anti-VEGF also inhibited the growth of Ewing sarcoma xenografts [47].…”

“…Anti-VEGF also inhibited the growth of Ewing sarcoma xenografts [47]. Unfortunately, VEGF-mediated vascularization is not the only signal promoting a blood supply in Ewing sarcoma because stromal cell-derived factor-1α (SDF-1α)-enhanced tumor neovascularization and growth in the absence of VEGF expression [46]. Therefore, SDF-1 signaling may be an alternate pathway that could mediate resistance to anti-VEGF therapy by Ewing sarcoma following therapy.…”

3D tissue-engineered model of Ewing's sarcoma

“…or soluble growth factors. In an attempt to overcome those limitations, 3D models of ES have integrated naturally occurring substrates derived from human tumors, elements of the basement membrane, and/or gels rich in collagen or laminin [21, 95-98]. By adding back key elements of the surrounding ECM, one can also invoke membrane-bound integrin signaling and, thereby, activate a diverse array of downstream signaling cascades including those responsible for angiogenesis [95, 96, 99], cancer cell motility [97, 100], and drug sensitivity [101, 102].…”