Abstract
BackgroundG-protein-coupled receptors (GPCRs) are prime candidates for novel cancer prevention and treatment strategies. We searched for differentially expressed GPCRs in node positive gastric carcinomas.Methodology/Principal FindingsDifferential expression of GPCRs in three node positive vs. three node negative intestinal type gastric carcinomas was analyzed by gene array technology. The candidate genes CXCL12 and its receptor CXCR4 were validated by real-time reverse-transcription polymerase chain reaction in an independent set of 37 gastric carcinomas. Translation was studied by immunohistochemistry in 347 gastric carcinomas using tissue microarrays as well as in 61 matching lymph node metastases. Protein expression was correlated with clinicopathological patient characteristics and survival. 52 GPCRs and GPCR-related genes were up- or down-regulated in node positive gastric cancer, including CXCL12. Differential expression of CXCL12 was confirmed by RT-PCR and correlated with local tumour growth. CXCL12 immunopositivity was negatively associated with distant metastases and tumour grade. Only 17% of gastric carcinomas showed CXCR4 immunopositive tumour cells, which was associated with higher local tumour extent. 29% of gastric carcinomas showed CXCR4 positive tumour microvessels. Vascular CXCR4 expression was significantly associated with higher local tumour extent as well as higher UICC-stages. When expressing both, CXCL12 in tumour cells and CXCR4 in tumour microvessels, these tumours also were highly significantly associated with higher T- and UICC-stages. Three lymph node metastases revealed vascular CXCR4 expression while tumour cells completely lacked CXCR4 in all cases. The expression of CXCL12 and CXCR4 had no impact on patient survival.Conclusions/SignificanceOur results substantiate the significance of GPCRs on the biology of gastric carcinomas and provide evidence that the CXCL12-CXCR4 pathway might be a novel promising antiangiogenic target for the treatment of gastric carcinomas.
Highlights
Gastric cancer is one of the most common cancers worldwide, ranking fourth in overall frequency and accounting for over 650,000 deaths annually [1]
Differential gene expression in node negative and node positive gastric cancer tissue First, we studied the differential expression of mRNA in a series of 6 intestinal type gastric cancer patients (3 with and 3 without lymph node metastases) using the GeneChipH Human Genome U133 Plus 2.0 Array from Affymetrix which detects 47,000 transcripts and variants as well as 38,500 well characterized human genes. mRNA was extracted and transcribed only from tissue samples obtained from the primary tumours
Since the CXCL12-CXCR4 axis plays a prominent role in tumourigenesis, promoting angiogenesis and migration of tumour cells to metastatic sites [17,18,19], we selected CXCL12 and its receptor CXCR4 for further analyses
Summary
Gastric cancer is one of the most common cancers worldwide, ranking fourth in overall frequency and accounting for over 650,000 deaths annually [1]. The mortality of gastric cancer is only excelled by lung cancer. Gastric cancer often causes no specific symptoms. 80–90% of Western patients with gastric cancer present with advanced tumours when local or distant metastases had already occured [1]. The lymph node status, especially the ratio of metastasis-positive/metastasis-negative lymph nodes, is the strongest prognostic factor of gastric cancer [2]. The 5-year survival rate for patients with 1–6 lymph node metastases is 44% and ending with only 11% in patients with more than 15 positive lymph nodes. There exists no specific predictive marker like HER2 in breast carcinoma, EGFR in non small cell lung carcinoma or K-RAS in colorectal carcinoma, which enables a more individualized therapeutic strategy. G-protein-coupled receptors (GPCRs) are prime candidates for novel cancer prevention and treatment strategies. We searched for differentially expressed GPCRs in node positive gastric carcinomas
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