• Archives of Pharmacal Research
• /
• v.27 no.2
• /
• pp.217-224
• /
• 2004

Previously, we reported that water-extracted Acanthopanax senticasus exhibited anti-meta-static activity by stimulating the immune system. In this study, we fractionated glycoproteins (EN-SP) from the soluble protein layer (GF-AS) of A. senticasus and determined their basic chemical properties. We also investigated the anti-tumor and immunostimulating activities of the fractionated glycoprotein, EN-SP. We found that intravenous (i.v.) administration of GF-AS dramatically inhibited metastasis of colon26-M3.1 carcinoma cells to the lung in a dose-dependent manner. In vitro analysis showed GF-AS to enhance the proliferation of splenocytes. GF-AS also stimulated peritoneal macrophage, which was followed by the production of various cytokines such as IL-1$\beta$, TNF-$\alpha$, IL-12 and IFN-${\gamma}$. Furthermore, the production of these cytokines was partially blocked when peritoneal macrophage was cultured with the polyclonal antibodies against GF-AS. The depletion of NK cells by rabbit anti-asialo GM1 serum partly abolished the inhibitory effect of GF-AS on lung metastasis of colon26-M3.1 cells. Using gel filtration, EN-SP, an active glycoprotein fraction, is isolated from GF-AS. While both GF-AS and EN-SP stimulated the proliferatation of splenocytes of normal mice, EN-SP showed higher anti-metastatic activity and more potently stimulated the proliferation of splenocytes compared to GF-AS. These results suggest the use of EN-SP, the fractionated glycoprotein from A. senticasus, can be used as a therapeutical reagent to prevent or inhibit tumor metastasis.

• Korean Journal of Pharmacognosy
• /
• v.36 no.4 s.143
• /
• pp.332-337
• /
• 2005

We here demonstrate the evidence of increased anti-tumor and immunostimulating activities of crude extracts (GAL) from Galium. aparine L. In experimental lung metastasis of colon26-M3.1 carcinoma or B16-BL6 melanoma cells, prophylactically intravenous (i.v) administration of GAL significantly inhibited lung metastasis in a dose-dependant manner. In an in vitro cytotoxicity analysis, GAL at the concentration up to $500\;{\mu}g/ml$ did not affect the growth of B16-BL6 melanoma cells. In contrast, GAL showed the enhancement of splenocyte proliferating activity in a dose-dependent manner. Peritoneal macrophages stimulated with GAL produced various cytokines such as $1L-1{\beta},\;TNF-{\alpha},\;IFN-{\gamma}$ and IL-12. These data suggest that GAL has an antitumor activity to inhibit tumor metastasis, and its antitumor effects is associated with activation of nonspecific immnune related cells.

• Toxicological Research
• /
• v.23 no.3
• /
• pp.197-205
• /
• 2007

Cancer metastasis is a major determinant of cancer patient mortality. Mounting evidence favors a strong positive role for $TGF-{\beta}$ in human cancer progression. The complex pattern on cross-talk of $TGF-{\beta}$ and the related other signaling pathways is an important area of investigation that will ultimately contribute to understanding of the bifunctional role of $TGF-{\beta}$ in cancer progression. This review summarizes some of the current understanding of $TGF-{\beta}$ signaling with a major focus in its contribution to the tumor cell invasion and metastasis. Five issues are addressed in this review: (1) $TGF-{\beta}$ signaling, (2) $TGF-{\beta}$ and EMT, (3) $TGF-{\beta}$ and MMP, (4) $TGF-{\beta}$ and Ras, and (5) Role of $TGF-{\beta}$ in invasion and metastasis. Due to the bifunctional cellular effects of $TGF-{\beta}$, as a tumor promoter and a tumor suppressor, more precisely defined $TGF-{\beta}$ signaling pathways need to be elucidated. According to the current literature, $TGF-{\beta}$ is clearly a major factor stimulating tumor progression through a complex spectrum of the interplay and cross-talk between various signaling molecules. Understanding the role of $TGF-{\beta}$ in invasion and metastasis will provide valuable information on establishing strategies to manipulate $TGF-{\beta}$ signaling which should be a high priority for the development of anti-metastatic therapeutics.

• Animal cells and systems
• /
• v.8 no.2
• /
• pp.117-123
• /
• 2004

The purpose of this study was to analyze inhibitory effects of anti-4-1BB monoclonal antibody on melanoma metastasis The 4-1BB (CD137) T cell molecule is a member of the TNF receptor family and its activation by either 4-1BB ligand or antibody induces T cell activation and growth. In the present study, administration of anti-4-1BB mAb induced inhibition of melanoma metastasis. Agonistic anti-4-1BB mAb induced not only CD$8^+$4-1BBT cells but also CD$8^+$IFN-${\gamma}$$^{+}$ T cell population. In the presence of anti-CD3 antibody, lymphocytes produced high levels of IFN-${\gamma}$ and low levels of IL-4 in anti-4-1BB mAb treated group. Exposure of melanoma cells to IFN-${\gamma}$ induced expression of MHC-I molecules. Thus, the increase in number of CD$8^+$T cells and enhanced MHC-I expression on B16F10 cells by augmented IFN-${\gamma}$ production in response to anti-4-1BB mAb may result in suppression of tumor growth and metastasis.s.

• Proceedings of the Korean Society of Toxicology Conference
• /
• 2001.10a
• /
• pp.139-140
• /
• 2001

Ginseng saponins (ginsenosides) have been regarded as principal components responsible for the majority of pharmacological activities exerted by ginseng. IH-901, an intestinal bacterial metabolite derived from the protopanaxadiol saponin of Panax ginseng C.A. Meyer, has been reported to have anti-tumor effects including inhibition of angiogenesis, invasion and metastasis, as well as induction of tumor cell apoptosis. (omitted)

• BMB Reports
• /
• v.48 no.3
• /
• pp.127-128
• /
• 2015

Tumor metastasis involves circulating and tumor-initiating capacities of metastatic cancer cells. Hepatic TM4SF5 promotes EMT for malignant growth and migration. Hepatocellular carcinoma (HCC) biomarkers remain unexplored for metastatic potential throughout metastasis. Here, novel TM4SF5/CD44 interaction-mediated self-renewal and circulating tumor cell (CTC) capacities were mechanistically explored. TM4SF5-dependent sphere growth was correlated with $CD133^+$, $CD24^-$, ALDH activity, and a physical association between CD44 and TM4SF5. The TM4SF5/CD44 interaction activated c-Src/STAT3/ Twist1/ B mi1 signaling for spheroid formation, while disturbing the interaction, expression, or activity of any component in this signaling pathway inhibited spheroid formation. In serial xenografts of less than 5,000 cells/injection, TM4SF5-positive tumors exhibited locally-increased CD44 expression, suggesting tumor cell differentiation. TM4SF5-positive cells were identified circulating in blood 4 to 6 weeks after orthotopic liver-injection. Anti-TM4SF reagents blocked their metastasis to distal intestinal organs. Altogether, our results provide evidence that TM4SF5 promotes self-renewal and CTC properties supported by $CD133^+/TM4SF5^+/CD44^+^{(TM4SF5-bound)}/ALDH^+/CD24^-$ markers during HCC metastasis.

• The Korean Journal of Food And Nutrition
• /
• v.20 no.3
• /
• pp.253-258
• /
• 2007

In experimental lung metastasis of colon26-M3.1 carcinoma cells, we found that the prophylactic or therapeutic admini-stration of Inonotus obliquus extracts significantly inhibited lung metastasis. In an in vitro cytotoxicity analysis, the extracts did not affect colon26-M3.1 cell growth at concentrations up to 1000 ${\mu}g/m{\ell}$. Peritoneal macrophages that were stimulated with the extracts produced $TNF-{\alpha}$. These data suggest that Inonotus obliquus extract has antitumor activity to inhibit tumor metastasis, and its antitumor effects are partially associated with macrophages activation.

• THE JOURNAL OF KOREAN ORIENTAL ONCOLOGY
• /
• v.9 no.1
• /
• pp.65-73
• /
• 2003

The researches for tumor and the developments for new anti-tumor medicine are being continuously developed in the oriental as well as the west. The principles therapy of anti-tumor activity was based on knowledge of the method of support the healthy energy and strengthen the body resistance, promote blood circulation to remove blood stasis, clear away heat and toxic materials, dissipate phlegm and disperse the accumulation of evils. But the major clinical features of tumor was to be considered in developing a treatment plan include (1) distinguish between clinical and pathologic staging - acute and chronic, (2) classification of pathologic pattern, and (3) distinction of body situation : for examples asthenia - sthenia etc. It was most important to distinguish between supporting the healthy and eliminating the evil factors and to treat differently at the root and the branch cause of a neoplasm. In clinical study and experimental study, the effects of oriental medicine could be summarized as three that were decreasing toxicity of chemo-therapy, directly suppressing and killing cancerous cell and increasing chemo-effect through preventing metastasis. Improving organic immunity with oriental medicine could be summarized as five that were promoting phagocytosis of macrophage, inducing interferon, promoting formation of immnoglobulin, increasing number of T-cell and promoting transformation of lymphocyte. It is suggested that effective use of immune activating herbs inhibited metastasis and decreased recurrence and then we were able to expect increasing survival rate and improving clinical symptoms and quality of life(QOL) of tumor patients.

• Maxillofacial Plastic and Reconstructive Surgery
• /
• v.30 no.6
• /
• pp.529-539
• /
• 2008

Background and Purpose : Oral squamous cell carcinoma (OSCC) is one of the most aggressive tumors of the head and neck area. OSCC is known to preferentially metastasize via lymphatic system, and resulting cervical lymph node metastasis is the most reliable of treatment failure. But the biological mechanism of the regional nodal metastasis is not clear. So, we determined metastasis-related factors in orthotopic nude mouse models of OSCC. Experimental Design : Two cell lines-KB and YD-10B cells, established from human oral mucosal squamous cell carcinoma, were xenografted into the tissue space of athymic murine mouth floor. The mice were followed for tumor development and growth, the murine tumors were examined histopathologically for local invasion or regional or distant metastasis. Finally, we performed immunohistochemical assays with antiepithelial growth factor (EGF), EGF receptor (EGFR), phosphorylated EGFR (pEGFR), and anti-vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)-2, phosphorylated VEGFR-2/3 (pVEGFR-2/3) antibodies. We also determined the microvessel density. Results : Transplantation of human OSCC tumor cells into the mouth floor successfully resulted in the formation of orthotopic tumors. KB cell line showed significantly higher tumor proliferation and higher nodal metastatic potential than YD-10B cell line. Furthermore, immunohistochemical staining demonstrated higher expression of EGFR/pEGFR, VEGF, and pVEGFR-2/3 as well as higher microvessel density in KB murine tumors than in YD-10B murine tumors. Conclusion : An orthotopic model of OSCC in athymic mice was established which copies the cervical lymph nodal metastasis of human OSCC. Our mouth floor model should facillitate the understanding of the molecular pathogenesis of cervical nodal metastasis of OSCC.

• Archives of Pharmacal Research
• /
• v.20 no.6
• /
• pp.539-544
• /
• 1997

Anti-metastatic activities of IH901, an intestinal bacterial metabolic derivative formed from Ginseng protopanaxadiol saponins, was determined in vitro and in vivo. Under in vitro conditions, IH901 inhibited the migration of bovine aortic endothelial cells 25 times stronger than suramin and suppressed the invasion of HT1080 human fibrosarcoma cells into reconstituted basement membrane components of Matrigel 1000 times stronger than RGDS peptide. IH901 also showed inhibitory effect on type-IV collagenase secretion from HT 1080 cells and platelet aggregation. When the anti-metastatic activity of IH901 was evaluated in comparison with that of 5-FU using a spontaneous lung metastatic model of Lewis lung carcinoma, the administration of IH901 (10 mg/kg p. o.) to tumor-bearing mice led to a significant decrease in lung metastasis (43% of untreated control), which was slightly more effective than that obtained with 5-FU (56% of control). Thus, IH901 seems to exhibit its anti-metastatic activity partly through the inhibition of tumor invasion which results from the blockade of type IV collagenase secretion and also through anti-platelet and anti-angiogenic activities.