Macrophage inflammatory protein-3alpha promotes pancreatic cancer cell invasion.
BACKGROUND
Human CC chemokine Macrophage Inflammatory Protein-3alpha (MIP-3alpha) directs inflammatory cell migration through its binding to the transmembrane receptor CCR6. MIP-3alpha has recently been shown to promote tumor cell migration in pancreatic adenocarcinoma by up-regulation of matrix metalloproteinases (MMPs). We hypothesized that MIP-3alpha promotes pancreatic cancer invasion through the up-regulation of MMP-9, a Type 4 collagenase.


RESULTS
Immunohistochemistry and RT-PCR confirmed the presence of MIP-3alpha in PANC-1 cells, a human pancreatic adenocarcinoma cell line. MIP-3alpha stimulated the production of both latent and active forms of MMP-9 in PANC-1 by Western analysis. Tumor cell invasion was then evaluated using a modified Boyden chamber invasion assay. MIP-3alpha promoted a dose-dependent increase in pancreatic cancer cell invasion (P < 0.05) at 100 ng/ml. The activity at the putative MIP-3alpha receptor, CCR6, was demonstrated by receptor blockade. Anti-CCR6 antibody and anti-MMP-9 antibody inhibited MIP-3alpha-stimulated PANC-1 cell invasion of collagen to 37% and 35% of control, respectively (P < 0.05).


CONCLUSIONS
MIP-3alpha, through its CCR6 receptor, promotes tumor cell invasion by the up-regulation of MMP-9. Molecular based therapy aimed at the inhibition of MIP-3alpha activity through the CCR6 receptor may serve as a future target to prevent tumor cell invasion in pancreatic adenocarcinoma.
Campbell
Amy S
AS
Department of General Surgery, Section of Surgical Oncology, Medical College of Georgia, Augusta, Georgia 30912, USA.
Albo
Daniel
D
Kimsey
Troy F
TF
White
Stephanie L
SL
Wang
Thomas N
TN
D045744:Cell Line, Tumor; D054418:Chemokine CCL20; D019742:Chemokines, CC / Q000032:analysis / Q000502:physiology*; D003131:Combined Modality Therapy; D006801:Humans; D007150:Immunohistochemistry; D019402:Macrophage Inflammatory Proteins / Q000032:analysis / Q000502:physiology*; D020778:Matrix Metalloproteinase 2 / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000502:physiology; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000473:pathology* / Q000628:therapy; D054399:Receptors, CCR6; D019707:Receptors, Chemokine / Q000502:physiology
C108355:CCL20 protein, human; C106311:CCR6 protein, human; D054418:Chemokine CCL20; D019742:Chemokines, CC; D019402:Macrophage Inflammatory Proteins; D054399:Receptors, CCR6; D019707:Receptors, Chemokine; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9