Gene Expression Profile Prospectively Predicts Peritoneal Relapse After Curative Surgery of Gastric Cancer

Takeno, Atsushi; Takemasa, Ichiro; Seno, Shigeto; Yamasaki, Makoto; Motoori, Masaaki; Miyata, Hiroshi; Nakajima, Kiyokazu; Takiguchi, Shuji; Fujiwara, Yoshiyuki; Nishida, Toshiro; Okayama, Toshitsugu; Matsubara, Kazuo; Takenaka, Yasuhiro; Matsuda, Hideo; Monden, Morito; Mori, Masaki; Doki, Yuichiro

doi:10.1245/s10434-009-0854-1

Cited by 48 publications

(39 citation statements)

References 41 publications

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“…In many less developed countries, however, GC is mostly detected only in its advanced stages, precluding curative surgical resection and necessitating systematic treatment. The low efficacy of current therapies results in advanced or metastatic GC having a low survival rate of 5–20%, and a particularly poor prognosis for peritoneal GC recurrence [5, 6]. Together, these facts thus reinforce the urgent need for improved biomarker-driven, “targeted” therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

Systematic approach identifies RHOA as a potential biomarker therapeutic target for Asian gastric cancer

et al. 2016

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Gastric cancer (GC) is a highly heterogeneous disease, in dire need of specific, biomarker-driven cancer therapies. While the accumulation of cancer "Big Data" has propelled the search for novel molecular targets for GC, its specific subpathway and cellular functions vary from patient to patient. In particular, mutations in the small GTPase gene RHOA have been identified in recent genome-wide sequencing of GC tumors. Moreover, protein overexpression of RHOA was reported in Chinese populations, while RHOA mutations were found in Caucasian GC tumors. To develop evidence-based precision medicine for heterogeneous cancers, we established a systematic approach to integrate transcriptomic and genomic data. Predicted signaling subpathways were then laboratory-validated both in vitro and in vivo, resulting in the identification of new candidate therapeutic targets. Here, we show: i) differences in RHOA expression patterns, and its pathway activity, between Asian and Caucasian GC tumors; ii) in vitro and in vivo perturbed RHOA expression inhibits GC cell growth in high RHOA-expressing cell lines; iii) inverse correlation between RHOA and RHOB expression; and iv) an innovative small molecule design strategy for RHOA inhibitors. In summary, RHOA, and its oncogenic signaling pathway, represent a strong biomarker-driven therapeutic target for Asian GC. This comprehensive strategy represents a promising approach for the development of "hit" compounds.

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Section: Introductionmentioning

confidence: 99%

Systematic approach identifies RHOA as a potential biomarker therapeutic target for Asian gastric cancer

et al. 2016

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“…The search for reliable tumor markers and consistent prognostic indicators has proven difficult. Several authors have attempted to predict GC disease and prognosis based on single or multiple genes [3-8], but there are discrepancies between the studies, and currently no gene signature or biomarkers are in routine clinical use. Understanding the mechanisms underlying gastric cancer is one of the major challenges in cancer genomics.…”

Section: Introductionmentioning

confidence: 99%

Up-regulation of CLDN1 in gastric cancer is correlated with reduced survival

et al. 2013

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BackgroundThe genetic changes in gastric adenocarcinoma are extremely complex and reliable tumor markers have not yet been identified. There are also remarkable geographical differences in the distribution of this disease. Our aim was to identify the most differentially regulated genes in 20 gastric adenocarcinomas from a Norwegian selection, compared to matched normal mucosa, and we have related our findings to prognosis, survival and chronic Helicobacter pylori infection.MethodsBiopsies from gastric adenocarcinomas and adjacent normal gastric mucosa were obtained from 20 patients immediately following surgical resection of the tumor. Whole genome, cDNA microarray analysis was performed on the RNA isolated from the sample pairs to compare the gene expression profiles between the tumor against matched mucosa. The samples were microscopically examined to classify gastritis. The presence of H. pylori was examined using microscopy and immunohistochemistry.Results130 genes showed differential regulation above a predefined cut-off level. Interleukin-8 (IL-8) and Claudin-1 (CLDN1) were the most consistently up-regulated genes in the tumors. Very high CLDN1 expression in the tumor was identified as an independent and significant predictor gene of reduced post-operative survival. There were distinctly different expression profiles between the tumor group and the control mucosa group, and the histological subsets of mixed type, diffuse type and intestinal type cancer demonstrated further sub-clustering. Up-regulated genes were mapped to cell-adhesion, collagen-related processes and angiogenesis, whereas normal intestinal functions such as digestion and excretion were associated with down-regulated genes. We relate the current findings to our previous study on the gene response of gastric epithelial cells to H. pylori infection.ConclusionsCLDN1 was highly up-regulated in gastric cancer, and CLDN1 expression was independently associated with a poor post-operative prognosis, and may have important prognostic value. IL-8 and CLDN1 may represent central links between the gene response seen in acute H. pylori infection of gastric epithelial cells, and ultimately gastric cancer.

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“…Next, to further support the association between PTX3 expression and metastatic potential in gastric cancer, PTX3 gene expression profiles from a cohort of 108 gastric cancer tissues associated or not associated with peritoneal relapse (GSE15081) were analyzed. Peritoneal relapse is one of the most common features of tumor progression associated with advanced gastric cancer [34]. Gene expression data from these patients with gastric cancer demonstrated that relapsed gastric cancer tissues expressed higher levels of PTX3 than relapse-free tissues (Figure 2B, P <0.005), indicating an increase in PTX3 expression in relapsed gastric cancer, despite a lower level of PTX3 expression in primary gastric cancer than in nonmalignant tissues.…”

Section: Resultsmentioning

confidence: 97%

“…Bone-metastasized tumor cells compete with HSCs to occupy the osteoblastic niche during the process of bone-associated metastasis [6, 7, 34, 38]. We next hypothesized that elevated PTX3 expression in bone metastatic HTB135 cells stimulates the interaction of bone metastatic gastric cancer cells with OBs.…”

Section: Resultsmentioning

confidence: 99%

Upregulation of brain-derived neurotrophic factor in advanced gastric cancer contributes to bone metastatic osteolysis by inducing long pentraxin 3

et al. 2016

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The brain-derived neurotrophic factor (BDNF) activates its receptor, tropomyosin receptor kinase B (TrkB; also called NTRK2) that has been shown to promote the malignant progression of several cancers. In this study, we investigated the clinical and biological significance of the BDNF/TrkB axis in the progression of human gastric cancer. The increased co-expression of the BDNF/TrkB axis was significantly correlated with bone metastatic properties in advanced gastric cancers. BDNF acting via TrkB receptors increased the levels of long pentraxin 3 (PTX3) that was related to bone metastatic status of gastric cancer by enhancing gastric cancer–osteoblastic niche interactions. In bone metastatic gastric cancer, PTX3 knockdown using small interfering RNA significantly inhibited BDNF-induced interactions of cancer cells with osteoblasts. Moreover, BDNF-derived PTX3 induction supported subsequent osteoclastogenesis, and this effect was significantly reversed by PTX3 silencing. These findings suggest that a functional interaction between BDNF/TrkB and PTX3 enhances the osteolysis of bone metastatic gastric cancer, thereby providing potential prognostic factors for the development of bone metastasis of gastric cancer.

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Gene Expression Profile Prospectively Predicts Peritoneal Relapse After Curative Surgery of Gastric Cancer

Abstract: Gene expression profile inherent to primary gastric cancer tissues can be useful in prospective prediction of peritoneal relapse after curative surgery, potentially allowing individualized postoperative management to improve the prognosis of patients with advanced gastric cancer.

Cited by 48 publications

References 41 publications

Systematic approach identifies RHOA as a potential biomarker therapeutic target for Asian gastric cancer

Systematic approach identifies RHOA as a potential biomarker therapeutic target for Asian gastric cancer

Up-regulation of CLDN1 in gastric cancer is correlated with reduced survival

Upregulation of brain-derived neurotrophic factor in advanced gastric cancer contributes to bone metastatic osteolysis by inducing long pentraxin 3

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