title: Bcl-2 orchestrates a cross-talk between endothelial and tumor cells that promotes tumor growth.
abstract: The current understanding of the interaction between the endothelium and cancer cells is fundamentally based on the concept that endothelial cells are responsive to differentiation and survival signals originating from the tumor cells. Whereas the effect of tumor cell-secreted factors on angiogenesis is well established, little is known about the effect of factors secreted by endothelial cells on tumor cell gene expression and tumor progression. Here, we show that bcl-2 gene expression is significantly higher in the tumor-associated endothelial cells of patients with head and neck squamous cell carcinomas (HNSCC) as compared with endothelial cells from the normal oral mucosa. Bcl-2 induces vascular endothelial growth factor (VEGF) expression in neovascular endothelial cells through a signal transducer and activator of transcription 3 (STAT3)-mediated pathway. Endothelial cell-derived VEGF signals through VEGFR1 and induces expression of Bcl-2 and the proangiogenic chemokines CXCL1 and CXCL8 in HNSCC cells. Notably, inhibition of Bcl-2 expression in neovascular endothelial cells with RNA interference down-regulates expression of Bcl-2, CXCL8, and CXCL1 in HNSCC cells, and is sufficient to inhibit growth and decrease the microvessel density of xenografted HNSCC in immunodeficient mice. Together, these results show that Bcl-2 is the orchestrator of a cross-talk between neovascular endothelial cells and tumor cells, which has a direct effect on tumor growth. This work identifies a new function for Bcl-2 in cancer biology that is beyond its classic role in cell survival.
authors.affiliation: Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor 48109-1078, USA.
authors.forename: Tomoatsu
authors.initials: T
authors.lastname: Kaneko
authors.forename: Zhaocheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Maria G
authors.initials: MG
authors.lastname: Mantellini
authors.forename: Elisabeta
authors.initials: E
authors.lastname: Karl
authors.forename: Benjamin
authors.initials: B
authors.lastname: Zeitlin
authors.forename: Monique
authors.initials: M
authors.lastname: Verhaegen
authors.forename: María S
authors.initials: MS
authors.lastname: Soengas
authors.forename: Mark
authors.initials: M
authors.lastname: Lingen
authors.forename: Robert M
authors.initials: RM
authors.lastname: Strieter
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nunez
authors.forename: Jacques E
authors.initials: JE
authors.lastname: Nör
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D048708:Cell Growth Processes / Q000502:physiology; D054360:Chemokine CXCL1 / Q000096:biosynthesis; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D019254:Genes, bcl-2; D006258:Head and Neck Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D051379:Mice; D016513:Mice, SCID; D009061:Mouth Mucosa / Q000098:blood supply; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
chemical_list: C475829:CXCL1 protein, human; C508606:CXCL8 protein, human; D054360:Chemokine CXCL1; D016209:Interleukin-8; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1