Clinical significance of interleukin-6 (IL-6) in the spread of gastric cancer: role of IL-6 as a prognostic factor

Ashizawa, Tetsuo; Okada, Ryosuke; Suzuki, Yoshiaki; Takagi, Makoto; Yamazaki, Tetsuo; Sumi, Toshiyuki; Aoki, Toshiaki; Ohnuma, Shinobu; Aoki, Tatsuya

doi:10.1007/s10120-005-0315-x

Cited by 137 publications

(121 citation statements)

References 21 publications

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“…[33][34][35][36] In human gastric cancer, significant relationships are reported between IL-6 and stage, depth of tumor invasion, lymphatic invasion, venous invasion, lymph node metastasis and hepatic metastasis. 26 These data suggest that IL-6 is involved in the growth and progression of human gastric carcinoma. However, the underlying mechanisms are unclear.…”

Section: Discussionmentioning

confidence: 87%

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IL-6 induces AGS gastric cancer cell invasionvia activation of the c-Src/RhoA/ROCK signaling pathway

et al. 2007

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Interleukin-6 (IL-6) is a multifunctional cytokine that is associated with the disease status and outcomes of gastric cancer. Nonetheless, the underlying mechanism of how IL-6 promotes the spread of gastric cancer is still unclear. In this study, we used a modified Boyden chamber assay to test the invasion ability of different gastric cancer cell lines. Liposome-mediated transfection was used to introduce an IL-6 expression vector into AGS cells, and the transfectants were further examined for the expression of active RhoA and phosphorylated Src using a pull-down assay and coimmunoprecipitation/Western blot analysis. Furthermore, RhoA expression in gastric adenocarcinoma specimens was investigated immunohistochemically. We documented that IL-6 could promote AGS cell motility and invasiveness, and inhibition of RhoA expression by dominant negative RhoA, C3 transferase, or dominant negative Src expressing plasmids could effectively decrease the invasiveness of IL-6 transfectants. We also documented an interaction between active RhoA and phosphorylated-Src following IL-6 treatment. Gastric cancers displaying high expression of RhoA are highly correlated with aggressive lymph node metastasis, more advanced tumor stage, histologically diffuse type and poorer survival. In conclusion, IL-6 induces AGS gastric cancer cell invasion via activation of the c-Src/RhoA/ROCK signaling pathway and RhoA expression could be used as a prognostic factor in patients with gastric adenocarcinoma. ' 2007 Wiley-Liss, Inc.Key words: interleukin-6; Rho-A; Src; Rho-kinase; gastric cancer Gastric cancer is one of the most common malignancies throughout the world, 1 and the incidence rates show substantial variation internationally, with highest rates in Japan, China and eastern Asia.2-4 About 90% of stomach tumors are adenocarcinomas, which can be subdivided into 2 histologic types: (i) well-differentiated or intestinal type adenocarcinoma and (ii) undifferentiated or diffuse-type adenocarcinoma. Infection with Helicobacter pylori, atrophic gastritis and intestinal metaplasia or dysplasia are identified as important steps in the pathogenesis of gastric cancer, 5 but the precise molecular mechanisms of this progression remain largely unknown. Because invasion and lymphatic metastasis is a frequent event in human gastric cancer, partial or complete gastrectomy with lymphadenectomy is the only potentially curative therapy for gastric cancer. Although surgery carries a high cure rate for early stage cancers, the 5-year survival rate for all patients is only about 20%. Death from gastric cancer is mainly due to recurrent disease (40-60% relapse rate in prospective studies), 6,7 where the most common form is loco-regional recurrence.

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Section: Discussionmentioning

confidence: 87%

“…24 It is associated with the disease status and outcomes of gastric cancer. 25,26 To gain insight into the molecular mechanism(s) of IL-6 promoting the spread of gastric cancer, we designed experiments to investigate the effects of IL-6 on migration and invasion abilities of human AGS cells.…”

mentioning

confidence: 99%

IL-6 induces AGS gastric cancer cell invasionvia activation of the c-Src/RhoA/ROCK signaling pathway

et al. 2007

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“…The cutoff values of IL-6 and IL-10 were determined according to the values in healthy volunteers (mean + 2 × SD; IL-6, 0.8 pg/ml; IL-10, 14 pg/ml) as described previously [21,22]. High CEA levels were found in 17 of the 90 GC patients (18.9%), high CA19-9 levels were found in 13 (14.4%), high CRP levels were found in 14 (15.5%), high IL-6 levels were found in 53 (58.9%), and high IL-10 levels were found in 11 (12.2%).…”

Section: Correlation Between Serum Cytokine Levels and Clinicopatholomentioning

confidence: 99%

Serum interleukin-6 and -10 levels in patients with gastric cancer

et al. 2009

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Section: Discussionmentioning

confidence: 99%

“…It is related to hemopoiesis, immunity, and inflammation, and is a multifunctional regulator in the nervous and endocrine systems [15]. Moreover, IL-6 has been reported as a prognostic factor in gastric carcinoma, and was significantly correlated with the incidence of lymph node metastasis and of liver metastasis [15]. IL-8 is an 8kDa molecular weight polypeptide and is one of the α-chemokines which belong to the C-X-C family, which are produced mainly by monocytes, macrophages, and endothelial cells, and is related to the migration of white corpuscles and inflammation [16].…”

Section: Discussionmentioning

confidence: 99%

Comparison between the Gastric Cancer Cell Line MKN-45 and the High-Potential Peritoneal Dissemination Gastric Cancer Cell Line MKN-45P

et al. 2011

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Summary: Peritoneal metastasis is the most common form of recurrence in gastric cancer, and is associated with a poor prognosis. It is clear that many agents are involved at the various stages of this process, however, many aspects of the progression remain unclear. In the present study we compared the gastric cancer cell line MKN-45 with the high-potential peritoneal dissemination gastric cancer cell line MKN-45P, established from MKN-45. The supernatant of culture medium of MKN-45 cells or MKN-45P cells was collected, and the concentrations of interleukin-1β (IL-1β), IL-6, IL-8, hepatocyte growth factor (HGF), Transforming growth factor beta-β1 (TGF-β1), vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2), MMP-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) proteins were measured using an enzyme-linked immuno sorbent assay (ELISA) method. Invasion, wound healing and adhesion assays were performed in vitro to examine interstitial invasion, migration and adhesion in the gastric cancer cell lines. Moreover, Western blotting was performed to determine the expression of cyclooxygenase-1 (COX-1) and COX-2 proteins in the culture media of the cell lines. The concentrations of IL-6, IL-8, VEGF and MMP-2 protein in the culture supernatant of MKN-45P were significantly higher than those of MKN-45. Percent adhesion of MKN-45P was significantly higher than that of MKN-45 in the fibronectin-coated group. There was no significant difference in invasion or migration between MKN-45 and MKN-45P. COX-1 and COX-2 proteins were observed in both cell lines. These results suggested that secretion of IL-6, IL-8, VEGF and MMP-2 from cancer cells, and adhesion of cancer cells to fibronectin, were related to the establishment of peritoneal dissemination.

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Clinical significance of interleukin-6 (IL-6) in the spread of gastric cancer: role of IL-6 as a prognostic factor

Abstract: We suspect that IL-6 is involved in cancer invasion and lymph node and/or hepatic metastasis. Our results indicate that IL-6 could be used as a prognostic factor for survival.

Cited by 137 publications

References 21 publications

IL-6 induces AGS gastric cancer cell invasionvia activation of the c-Src/RhoA/ROCK signaling pathway

IL-6 induces AGS gastric cancer cell invasionvia activation of the c-Src/RhoA/ROCK signaling pathway

Serum interleukin-6 and -10 levels in patients with gastric cancer

Comparison between the Gastric Cancer Cell Line MKN-45 and the High-Potential Peritoneal Dissemination Gastric Cancer Cell Line MKN-45P

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