**7. Vascular signals involved in tumor homing**

This issue was investigated by evaluating the expression of homing receptors on tumor vasculature. Confocal microscopy4 revealed that 30% of tumor vessels expressed high levels of VCAM-1 on the luminal surface (**Figure 2b-c**) (Jin et al., 2006), whereas SFD-1 was ubiquitously expressed on tumor vessels and tumor cells (**Figure 2e-f**). Thus, α4β1 integrins and the CXCR4 chemokine (De Raeve et al., 2004; Peled et al., 1999) seem to play a critical role in regulating intratumor homing of mTRAIL-expressing cells. To further investigate the functional relevance of SDF-1/CXCR4 and VCAM-1/VLA-4 pathways in mediating tumor homing of transduced cells, inhibitory experiments with an anti–VCAM-1 antibody and the CXCR4 antagonist AMD3100 were performed.5 As compared to controls, tumor homing of CD34-TRAIL+ cells was significantly reduced in mice administered with anti–VCAM-1 antibody [0.2 ± 0.03% vs 0.09 ± 0.01% (P = .001)] or the CXCR4 antagonist AMD3100 (Fricker et al., 2006) [0.2 ± 0.03% vs 0.05 ± 0.006% (P = .0003)]. Tumor vasculature was also analyzed for the expression of TRAIL-R2 receptor. Indeed, confocal microscopy revealed that approximately 8 - 12% of tumor endothelial cells expressed TRAIL-R2 receptor on their luminal surface (**Figure 2h-i**), suggesting that mechanisms other than SDF-1/CXCR4 and VCAM-1/VLA-4, such as the mTRAIL/TRAIL-R2 interactions, might be involved in regulating intratumor homing as well as functional activity of CD34-TRAIL+ cells (Lavazza et al., 2010).
