title: Xenograft tumors vascularized with murine blood vessels may overestimate the effect of anti-tumor drugs: a pilot study.
abstract: Recent evidence demonstrated that endothelial cells initiate signaling events that enhance tumor cell survival, proliferation, invasion, and tumor recurrence. Under this new paradigm for cellular crosstalk within the tumor microenvironment, the origin of endothelial cells and tumor cells may have a direct impact on the pathobiology of cancer. The purpose of this pilot study was to evaluate the effect of endothelial cell species (i.e. murine or human) on xenograft tumor growth and response to therapy. Tumor xenografts vascularized either with human or with murine microvascular endothelial cells were engineered, side-by-side, subcutaneously in the dorsum of immunodefficient mice. When tumors reached 200 mm(3), mice were treated for 30 days with either 4 mg/kg cisplatin (i.p.) every 5 days or with 40 mg/kg sunitinib (p.o.) daily. Xenograft human tumors vascularized with human endothelial cells grow faster than xenograft tumors vascularized with mouse endothelial cells (P<0.05). Notably, human tumors vascularized with human endothelial cells exhibited nuclear translocation of p65 (indicative of high NF-kB activity), and were more resistant to treatment with cisplatin or sunitinib than the contralateral tumors vascularized with murine endothelial cells (P<0.05). Collectively, these studies suggest that the species of endothelial cells has a direct impact on xenograft tumor growth and response to treatment with the chemotherapeutic drug cisplatin or with the anti-angiogenic drug sunitinib.
authors.affiliation: Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, United States of America.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, United States of America.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Imai
authors.affiliation: Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, United States of America.
authors.forename: Sudha
authors.initials: S
authors.lastname: Krishnamurthy
authors.affiliation: Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, United States of America.
authors.forename: Zhaocheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, United States of America.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Zeitlin
authors.affiliation: Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, United States of America ; Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, Michigan, United States of America ; Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, Michigan, United States of America ; Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Jacques E
authors.initials: JE
authors.lastname: Nör
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000166:cytology*; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin; D042783:Endothelial Cells / Q000502:physiology*; D064593:Heterografts / Q000098:blood supply* / Q000187:drug effects; D006801:Humans; D007211:Indoles; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy; D010865:Pilot Projects; D011758:Pyrroles; D015398:Signal Transduction / Q000502:physiology*; D013045:Species Specificity; D000077210:Sunitinib; D023822:Tissue Engineering; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: D007211:Indoles; D011758:Pyrroles; D002945:Cisplatin; D000077210:Sunitinib