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Tumor-stromal cell interaction under hypoxia increases the invasiveness of pancreatic cancer cells through the hepatocyte growth factor/c-Met pathway.
- Source :
-
International journal of cancer [Int J Cancer] 2006 Dec 15; Vol. 119 (12), pp. 2750-9. - Publication Year :
- 2006
-
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.<br /> (Copyright 2006 Wiley-Liss, Inc.)
- Subjects :
- Blotting, Western
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 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 metabolism
RNA, Messenger genetics
RNA, Messenger metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction drug effects
Signal Transduction physiology
Stromal Cells cytology
Time Factors
Tissue Inhibitor of Metalloproteinases genetics
Tissue Inhibitor of Metalloproteinases metabolism
Cell Communication physiology
Hepatocyte Growth Factor genetics
Proto-Oncogene Proteins c-met genetics
Stromal Cells metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0020-7136
- Volume :
- 119
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- International journal of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 16998831
- Full Text :
- https://doi.org/10.1002/ijc.22178