title: CXCL8/IL-8 and CXCL12/SDF-1alpha co-operatively promote invasiveness and angiogenesis in pancreatic cancer.
abstract: CXC-chemokines are involved in the chemotaxis of neutrophils, lymphocytes and monocytes. However, role of these chemokines in tumorigenesis, especially with regard to interaction between tumor and its microenvironment, has not been clearly elucidated. The purpose of this study was to analyze the co-operative role of CXCL8 and CXCL12 in the tumor-stromal interaction in pancreatic cancer (PaCa). Using enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR), we initially confirmed the expression of ligands and receptors, respectively, of CXC-chemokines in PaCa and stromal cells. We examined the co-operative role of CXCL8 and CXCL12 in proliferation/invasion of PaCa and human umbilical vein endothelial cells (HUVECs), and in HUVEC tube-formations through tumor-stromal interaction by MTS, Matrigel invasion, and angiogenesis assays, respectively. We detected expression of CXCR4, but not CXCR2, in all PaCa cells and fibroblasts. PaCa cells secreted CXCL8, and fibroblast cells secreted CXCL12. CXCL8 production in PaCa was significantly enhanced by CXCL12, and CXCL12 production in fibroblasts was significantly enhanced by co-culturing with PaCa. CXCL8 enhanced proliferation/invasion of HUVECs but did not promote proliferation/invasion of PaCa. Both recombinant and PaCa-derived CXCL8 enhanced tube formation of HUVECs that were co-cultured with fibroblast cells. CXCL12 enhanced the proliferation/invasion of HUVECs and the invasion of PaCa cells but had no effect on tube formation of HUVEC. We showed that PaCa-derived CXCL8 and fibroblast-derived CXCL12 cooperatively induced angiogenesis in vitro by promoting HUVEC proliferation, invasion, and tube formation. Thus, corresponding receptors CXCR2 and CXCR4 are potential antiangiogenic and antimetastatic therapeutic targets in PaCa.
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsuo
authors.forename: Nobuo
authors.initials: N
authors.lastname: Ochi
authors.forename: Hirozumi
authors.initials: H
authors.lastname: Sawai
authors.forename: Akira
authors.initials: A
authors.lastname: Yasuda
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takahashi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Funahashi
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Takeyama
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Tong
authors.forename: Sushovan
authors.initials: S
authors.lastname: Guha
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000096:biosynthesis* / Q000378:metabolism; D018920:Coculture Techniques; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry; D014471:Umbilical Veins / Q000473:pathology
chemical_list: C515255:CXCL12 protein, human; C508606:CXCL8 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D016209:Interleukin-8; D019718:Receptors, CXCR4; D023063:Receptors, Interleukin-8B; D011994:Recombinant Proteins