title: Endothelial cells enhance tumor cell invasion through a crosstalk mediated by CXC chemokine signaling.
abstract: Field cancerization involves the lateral spread of premalignant or malignant disease and contributes to the recurrence of head and neck tumors. The overall hypothesis underlying this work is that endothelial cells actively participate in tumor cell invasion by secreting chemokines and creating a chemotactic gradient for tumor cells. Here we demonstrate that conditioned medium from head and neck tumor cells enhance Bcl-2 expression in neovascular endothelial cells. Oral squamous cell carcinoma-3 (OSCC3) and Kaposi's sarcoma (SLK) show enhanced invasiveness when cocultured with pools of human dermal microvascular endothelial cells stably expressing Bcl-2 (HDMEC-Bcl-2), compared to cocultures with empty vector controls (HDMEC-LXSN). Xenografted OSCC3 tumors vascularized with HDMEC-Bcl-2 presented higher local invasion than OSCC3 tumors vascularized with control HDMEC-LXSN. CXCL1 and CXCL8 were upregulated in primary endothelial cells exposed to vascular endothelial growth factor (VEGF), as well as in HDMEC-Bcl-2. Notably, blockade of CXCR2 signaling, but not CXCR1, inhibited OSCC3 and SLK invasion toward endothelial cells. These data demonstrate that CXC chemokines secreted by endothelial cells induce tumor cell invasion and suggest that the process of lateral spread of tumor cells observed in field cancerization is guided by chemotactic signals that originated from endothelial cells.
authors.affiliation: Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, 48109-1078, USA.
authors.forename: Kristy A
authors.initials: KA
authors.lastname: Warner
authors.forename: Marta
authors.initials: M
authors.lastname: Miyazawa
authors.forename: Mabel M R
authors.initials: MM
authors.lastname: Cordeiro
authors.forename: William J
authors.initials: WJ
authors.lastname: Love
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Pinsky
authors.forename: Kathleen G
authors.initials: KG
authors.lastname: Neiva
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Spalding
authors.forename: Jacques E
authors.initials: JE
authors.lastname: Nör
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D054360:Chemokine CXCL1 / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D023063:Receptors, Interleukin-8B / 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; D023063:Receptors, Interleukin-8B