Abstract
Early detection of gastric cancers saves lives, but remains a diagnostic challenge. In this study, we aimed to identify cell-surface biomarkers of early gastric cancer. We hypothesized that a subset of plasma membrane proteins induced by the Helicobacter pylori oncoprotein CagA will be retained in early gastric cancers through non-oncogene addiction. An inducible system for expression of CagA was used to identify differentially upregulated membrane protein transcripts in vitro. The top hits were then analyzed in gene expression datasets comparing transcriptome of gastric cancer with normal tissue, to focus on markers retained in cancer. Among the transcripts enriched upon CagA induction in vitro, a significant elevation of CEACAM6 was noted in gene expression datasets of gastric cancer. We used quantitative digital immunohistochemistry to measure CEACAM6 protein levels in tissue microarrays of gastric cancer. We demonstrate an increase in CEACAM6 in early gastric cancers, when compared to matched normal tissue, with an AUC of 0.83 for diagnostic validity. Finally, we show that a fluorescently conjugated CEACAM6 antibody binds avidly to freshly resected gastric cancer xenograft samples and can be detected by endoscopy in real time. Together, these results suggest that CEACAM6 upregulation is a cell surface response to H. pylori CagA, and is retained in early gastric cancers. They highlight a novel link between CEACAM6 expression and CagA in gastric cancer, and suggest CEACAM6 to be a promising biomarker to aid with the fluorescent endoscopic diagnosis of early neoplastic lesions in the stomach.
Highlights
The clinical need for an endoscopic marker of early gastric cancerGastric cancer is a leading cause of mortality from neoplastic disease, and is prevalent in Asian populations [1]
We show that the cell surface protein CEACAM6 is upregulated by the H. pylori CagA oncoprotein, and highly expressed on early gastric cancers as well as premalignant lesions
Among the hits identified in the CagA screen, 4 of them (MMP1, CEACAM6, ITGA2, C3) showed at least 2-fold increases in gastric cancer when compared to normal controls (Table 1)
Summary
The clinical need for an endoscopic marker of early gastric cancerGastric cancer is a leading cause of mortality from neoplastic disease, and is prevalent in Asian populations [1]. Diagnosis of gastric cancer through endoscopic methods, and its treatment by submucosal resection has enabled 5-year survival rates of up to 95% in cohort studies [3, 4]. The overall 5-year survival www.impactjournals.com/oncotarget of all patients with gastric cancer, as determined from the NCI Surveillance Epidemiology and End Results database (http://seer.cancer.gov) is only 26%, as many of the patients have regional or distant spread at the time of diagnosis. This has resulted in the categorization of ‘Early Gastric Cancer’ (EGC) as a unique entity, defined by T1 disease, and good clinical outcomes. There is an urgent need for improved methods to facilitate early diagnosis of cancer and pre-malignant lesions of the stomach, and thereby ensure early and effective treatment
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