CXCL8/IL‐8 and CXCL12/SDF‐1α 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 fibroblastderived 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.

CXC‐chemokine/CXCR2 biological axis promotes angiogenesis in vitro and in vivo in pancreatic cancer

“…23 Further, our recent data showed that ELR 1 -CXC-chemokine production from PaCa cells was increased by co-culturing them with stromal cells. 24 Given the fact that the network of ELR 1 -CXC-chemokines is modulated by the interaction between the tumor and its microenvironment, it is crucial to investigate the role of the ELR 1 -CXC-chemokines/CXCR2 biological axis in an orthotopic metastatic PaCa model.…”

Influence of Donor Age and Passage Number on Angiogenic Activity in Human Adipose-Derived Stem Cell-Conditioned Media

“…These findings imply that other factors may play a role in the passage number-dependent angiogenic activity in ASC-CM. Chemokines such as CXCL8 [49] and proteolytic enzymes such as matrix metalloproteinases 3 and 9 [7] stimulate tube formation in HUVECs. Further studies are needed to determine the concentrations of these chemokines/enzymes in ASC-CM and the relationship with passage number.…”

IL-8 mRNA expression in the mouse mammary glands during pregnancy and lactation

“…However, IL-8 has biological functions in addition to and distinct from its roles in regulating inflammatory responses. IL-8 has recently been suggested to be closely related to the tumorigenesis, angiogenesis, adhesion, invasion, and metastasis of cancer (Kitadai et al, 1999;Matsuo et al, 2009;Song et al, 2010;Ning et al, 2011;Ju et al, 2012).…”