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CXCL8/IL‐8 and CXCL12/SDF‐1α co‐operatively promote invasiveness and angiogenesis in pancreatic cancer
Author(s) -
Matsuo Yoichi,
Ochi Nobuo,
Sawai Hirozumi,
Yasuda Akira,
Takahashi Hiroki,
Funahashi Hitoshi,
Takeyama Hiromitsu,
Tong Zhimin,
Guha Sushovan
Publication year - 2008
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24040
Subject(s) - angiogenesis , interleukin 8 , stromal cell , chemokine , matrigel , cancer research , cxc chemokine receptors , biology , fibroblast , receptor , microbiology and biotechnology , chemistry , chemokine receptor , cytokine , immunology , in vitro , biochemistry
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. © 2008 Wiley‐Liss, Inc.