RRC ID 42766
Author Ide T, Kitajima Y, Miyoshi A, Ohtsuka T, Mitsuno M, Ohtaka K, Koga Y, Miyazaki K.
Title Tumor-stromal cell interaction under hypoxia increases the invasiveness of pancreatic cancer cells through the hepatocyte growth factor/c-Met pathway.
Journal Int J Cancer
Abstract The hypoxic environment in tumor is reported to play an important role in pancreatic cancer progression. The interaction between stromal and cancer cells also contributes to the malignant behavior of pancreatic cancer. In the present study, we investigated whether hypoxic stimulation affects stromal as well as pancreatic cancer cells. Our findings demonstrated that hypoxia remarkably elevated the HIF-1alpha expression in both pancreatic cancer (PK8) and fibroblast cells (MRC5). Hypoxic stimulation accelerated the invasive activity of PK8 cells, and invasiveness was thus further accelerated when the hypoxic PK8 cells were cultured with conditioned medium prepared from hypoxic MRC5 cells (hypoxic conditioned medium). MMP-2, MMP-7, MT1-MMP and c-Met expressions were increased in PK8 cells under hypoxia. Hypoxic stimulation also increased the hepatocyte growth factor (HGF) secretion from MRC5 cells, which led to an elevation of c-Met phosphorylation in PK8 cells. Conversely, the elevated cancer invasion, MMP activity and c-Met phosphorylation of PK8 cells were reduced by the removal of HGF from hypoxic conditioned medium. In immunohistochemical study, the HIF-1alpha expression was observed in surrounding stromal as well as pancreatic cancer cells, thus indicating hypoxia exists in both of cancer and stromal cells. Moreover, the stromal HGF expression was found to significantly correlate with not only the stromal HIF-1alpha expression but also the c-Met expression in cancer cells. These results indicate that the hypoxic environment within stromal as well as cancer cells activates the HGF/c-Met system, thereby contributing to the aggressive invasive features of pancreatic cancer.
Volume 119(12)
Pages 2750-9
Published 2006-12-15
DOI 10.1002/ijc.22178
PMID 16998831
MeSH Blotting, Western Cell Communication / physiology* Cell Hypoxia / physiology Cell Line, Tumor Cell Movement / drug effects Cell Movement / physiology Cell Proliferation / drug effects Culture Media, Conditioned / pharmacology Fibroblasts / cytology Fibroblasts / drug effects Fibroblasts / metabolism Hepatocyte Growth Factor / genetics* Hepatocyte Growth Factor / metabolism Humans Hypoxia-Inducible Factor 1, alpha Subunit / metabolism Matrix Metalloproteinase 2 / genetics Matrix Metalloproteinase 2 / metabolism Matrix Metalloproteinases / genetics Matrix Metalloproteinases / metabolism Neoplasm Invasiveness Pancreatic Neoplasms / genetics Pancreatic Neoplasms / metabolism Pancreatic Neoplasms / pathology Proto-Oncogene Proteins c-met / genetics* Proto-Oncogene Proteins c-met / metabolism RNA, Messenger / genetics RNA, Messenger / metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction / drug effects Signal Transduction / physiology Stromal Cells / cytology Stromal Cells / metabolism* Time Factors Tissue Inhibitor of Metalloproteinases / genetics Tissue Inhibitor of Metalloproteinases / metabolism
IF 4.982
Times Cited 90
Human and Animal Cells