Role of thymidine phosphorylase on invasiveness and metastasis in lung adenocarcinoma.
Thymidine phosphorylase (TP) is expressed at higher levels in a variety of human cancers than in adjacent normal tissue. It is reported that the higher expression is associated with an increase of intratumoral microvessel density and a poor prognosis. We investigated the role of TP in human non small cell lung cancers (NSCLCs). The concentrations of TP in the tumors and the adjacent normal tissue from surgically resected specimens of 54 cases of NSCLCs were measured by using an enzyme-linked immunosorbent assay. Tumor specimens were also examined immunohistochemically. TP concentrations in the tumors were 169 +/- 18 units/mg protein (mean +/- SD), whereas those in normal tissue were 43 +/- 4 units/mg protein (mean +/- SD), consistent with TP staining patterns. There was no correlation between TP expression and microvessel density. Among clinicopathologic factors examined, the concentrations of TP but not TP immunoreactivity correlated with tumor differentiation in lung adenocarcinoma. Although a specific TP inhibitor (TPI) and overexpression of TP did not affect the growth of A549 lung adenocarcinoma cells, Matrigel invasion assay showed that A549 transfected with TP had higher invasive potential than mock transfectant, and such enhanced invasive activity was markedly diminished by treatment with TPI. Furthermore, administration of TPI suppressed lung metastasis of TP-overexpressing A549 cells in nude mice. These results demonstrate that TP may play an important role in tumor differentiation, invasiveness and metastasis in lung adenocarcinoma, and suggest that TP could be a novel target for treatment of TP-overexpressing lung adenocarcinoma.
Sato
Jun
J
First Department of Internal Medicine, Yamagata University School of Medicine, Yamagata, Japan.
Sata
Makoto
M
Nakamura
Hidenori
H
Inoue
Sumito
S
Wada
Toshihiro
T
Takabatake
Noriaki
N
Otake
Kazuhisa
K
Tomoike
Hitonobu
H
Kubota
Isao
I
D000368:Aged; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000556:secondary*; D002454:Cell Differentiation; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007797:Laminin / Q000737:chemistry; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology*; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins; D009389:Neovascularization, Pathologic / Q000201:enzymology; D011509:Proteoglycans / Q000737:chemistry; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007797:Laminin; D009363:Neoplasm Proteins; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen; D013939:Thymidine Phosphorylase