Up-regulation of matrix metalloproteinase 9 by thrombospondin 1 in gastric cancer.
BACKGROUND
Matrix metalloproteinase 9 (MMP-9) plays a key role in tumor cell invasion. It was recently reported that plasma levels of MMP-9 in patients with gastric cancer correlate with the tumors' metastatic potential. We previously demonstrated that thrombospondin 1 (TSP-1) up-regulates MMP-9 expression by endothelial cells and promotes tumor cell invasion. We hypothesized that TSP-1 plays a role in the up-regulation of MMP-9 in gastric cancer.


METHODS
MMP-9, TSP-1, and CSVTCG-specific TSP-1 receptor expression were measured by immunohistochemical staining in 31 consecutive gastric adenocarcinomas from patients who did not undergo neoadjuvant chemotherapy or radiation therapy. Additionally, we measured TSP-1, CSVTCG-specific TSP-1 receptor, and MMP-9 expression by Western blotting, zymography, and immunohistochemical staining in AGS gastric adenocarcinoma cells. We also investigated the effect of TSP-1 on MMP-9 expression by AGS cells.


RESULTS
TSP-1 localized to the tumor-associated extracellular matrix. CSVTCG-specific TSP-1 receptor and MMP-9 colocalized to tumor cells, fibroblasts, and tumor-associated microvessels. Intense staining for TSP-1, CSVTCG-specific TSP-1 receptor, and MMP-9 correlated with markers of aggressive tumor behavior. AGS gastric adenocarcinoma cells expressed high levels of CSVTCG-specific TSP-1 receptor but not TSP-1. TSP-1 up-regulated MMP-9 expression by AGS cells.


CONCLUSIONS
We conclude that TSP-1 plays a role in the up-regulation of MMP-9 expression in gastric cancer. Our data also suggest a correlation between expression of TSP-1, CSVTCG-specific TSP-1 receptor, and MMP-9 and the acquisition of an aggressive tumor phenotype.
Albo
Daniel
D
Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA. albo@mdanderson.org
Shinohara
Tetsuo
T
Tuszynski
George P
GP
D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology; D000918:Antibody Specificity; D018955:CD36 Antigens / Q000276:immunology / Q000378:metabolism; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000473:pathology; D019700:Thrombospondin 1 / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
D018955:CD36 Antigens; D019700:Thrombospondin 1; D020780:Matrix Metalloproteinase 9