1. Suppressing effects of dietary supplementation of soybean trypsin inhibitor on spontaneous, experimental and peritoneal disseminated metastasis in mouse model
- Author
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Toshihiko Terao, Hiroshi Kobayashi, Yasufumi Kanada, Naohiro Kanayama, Ryuji Yoshida, Nishiyama Setsuko, Mika Suzuki, and Yoichi Fukuda
- Subjects
Cancer Research ,Lung Neoplasms ,Diet therapy ,MAP Kinase Signaling System ,Trypsin inhibitor ,Biology ,Metastasis ,Transforming Growth Factor beta1 ,Carcinoma, Lewis Lung ,Mice ,Phosphatidylinositol 3-Kinases ,Transforming Growth Factor beta ,Cell Line, Tumor ,Granulocyte Colony-Stimulating Factor ,medicine ,Animals ,Humans ,Enzyme Inhibitors ,Phosphorylation ,Peritoneal Neoplasms ,Trypsin Inhibitor, Bowman-Birk Soybean ,Ovarian Neoplasms ,Kunitz STI protease inhibitor ,Intravasation ,Lewis lung carcinoma ,medicine.disease ,Urokinase-Type Plasminogen Activator ,Extravasation ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,Oncology ,Immunology ,Dietary Supplements ,Models, Animal ,Cancer research ,Female ,Trypsin Inhibitor, Kunitz Soybean ,Ovarian cancer ,Trypsin Inhibitors - Abstract
The modifying effects of a Kunitz trypsin inhibitor (KTI) and a Bowman-Birk trypsin inhibitor (BBI), purified from soybean trypsin inhibitor, as dietary supplements on experimental and spontaneous pulmonary metastasis of murine Lewis lung carcinoma 3LL cells as well as peritoneal disseminated metastasis model in human ovarian cancer HRA cells were investigated in i.v., s.c. and i.p. injection models in mice. Seven groups of female C57BL/6 or nude mice were fed a basal diet (control group) or the basal diet supplemented with KTI or BBI (5, 15, or 50 g/kg). Here we show that, in an in vivo spontaneous metastasis assay, the diet supplementation with KTI (15 and 50 g/kg), but not with BBI, for 28 days immediately after s.c. tumor cell inoculation significantly inhibited the formation of lung metastasis in C57BL/6 mice in a dose-dependent manner. The inhibition of lung metastasis was not due to direct antitumor effects of KTI. In an in vivo experimental metastasis assay, the diet supplementation with KTI or BBI for 21 days after i.v. tumor cell inoculation did not reduce the number of lung tumor colonies. In addition, KTI (15 or 50 g/kg) treatment in a peritoneal disseminated metastasis model of HRA cells resulted in a 40% reduction in total tumor burden when compared with control animals. Immunoblot analysis revealed that KTI specifically reduced expression of uPA protein as well as phosphorylation of MAP kinase and PI3 kinase proteins in the cells stimulated with agonists (G-CSF for 3LL cells or TGF-β1 for HRA cells). These results suggest that dietary supplementation of KTI more efficiently regulates the mechanism involved in the entry into vascular circulation of tumor cells (intravasation) than in extravasation during the metastatic process. KTI treatment may also be beneficial for ovarian cancer patients with or at risk for peritoneal disseminated metastasis; it greatly reduces tumor burden in part by inhibiting phosphorylation of MAP kinase and PI3 kinase, leading to suppression of uPA expression. © 2004 Wiley-Liss, Inc.
- Published
- 2004