We have worked with a model that involves the generation of xenograft tumors by the co-transplantation of human endothelial cells and human tumor cells seeded into biodegradable scaffolds. This model allows for the establishment of human tumors vascularized with human Danshensu vessels in immunodefficient mice. Using this model, we observed that endothelial cells initiate signaling events that directly influence tumor cell survival, proliferation, invasion and tumor recurrence. During the course of these experiments, we noticed that drugs that had a very significant anti-tumor effect in traditional xenograft models were not nearly as effective in the xenograft model with humanized vasculature. We thus hypothesized that maximal resistance to anti-tumor therapies is achieved when both endothelial and tumor cells are human. Here, we report data that demonstrate that xenograft tumors with humanized vasculature grow faster than xenografts vascularized with mouse vasculature and are more resistant to therapy with Cisplatin or Sunitinib, used here as models of a traditional chemotherapeutic and an antiangiogenic drug. Several studies reported that the crosstalk between tumor cells and endothelial cells plays an important role in tumor angiogenesis and tumor growth. Wang and colleagues observed that the Notch ligand 20(S)-Notoginsenoside-R2 Jagged1 from head and neck squamous cell carcinoma cells triggered Notch activation in neighboring endothelial cells and promoted capillary-like sprout formation. Jagged1-expressing HNSCC cells significantly enhanced neovascularization and tumor growth in vivo. They concluded that the direct interplay between tumor cells and endothelial cells promotes tumor angiogenesis. We have reported that tumor cell-derived VEGF induces Bcl-2 expression in endothelial cells, and that the Bcl-2 expression levels in tumor endothelial cells correlate directly with the rate of tumor growth. Notably, Bcl-2 acts as a signaling molecule by activating the NF-kB signaling pathway and inducing expression of CXCL1 and CXCL8 that in turn enhance the invasive phenotype of neighboring tumor cells. We also observed that endothelial cell-derived interleukin-6 and epidermal growth factor induce the activity of the signal transducer and activator of transcription 3 and extracellular signal-regulated kinase in head and neck cancer cells, resulting in enhanced tumor cell proliferation and protection against anoikis. We speculate that the results reported here are mediated, at least in part, by the impact of species on the effectiveness of the molecular crosstalk between endothelial cells and tumor cells. An example of such 
differences might be the prominent role that CXCL8 has in the crosstalk between endothelial cells and tumor cells and the wellknown absence of this protein in murine cells. It is well known that chemokines are potent activators of NF-kB signaling. NF-kB signaling plays a major role in cancer progression and on response to therapy. Here, we observed that xenografts vascularized with humanized vessels express higher levels of nuclear p65, when compared to xenografts vascularized with murine vessels. This difference in NF-kB activity is likely due to species-specific factors that affect the crosstalk between endothelial cells and tumor cells. Indeed, it is possible that the absence of CXCL8 in murine endothelial cells might contribute to the lower level of NF-kB activity in xenografts vascularized with murine endothelial cells. We speculate that the high NF-kB activity observed in xenografts with humanized vasculature might contribute to the faster tumor growth and to the resistance to therapy observed in these experimental tumors.