Published online Dec 14, 2013. doi: 10.3748/wjg.v19.i46.8714
Revised: September 25, 2013
Accepted: November 3, 2013
Published online: December 14, 2013
AIM: To investigate the differential expression of leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) in gastric cancer tissues and its significance related to tumor growth and spread.
METHODS: Formalin-fixed biopsy specimens of intestinal metaplasia (n = 90), dysplasia (n = 53), gastric adenocarcinoma (n = 180), metastases in lymph nodes and the liver (n = 15), and lesion-adjacent normal gastric mucosa (controls; n = 145) were obtained for analysis from the Peking University Cancer Hospital’s Department of Pathology and Gastrointestinal Surgery tissue archives (January 2003 to December 2011). The biopsied patients’ demographic and clinicopathologic data were retrieved from the hospital’s medical records database. Each specimen was subjected to histopathological typing to classify the tumor node metastasis (TNM) stage and to immunohistochemistry staining to detect the expression of the cancer stem cell marker LGR5. The intergroup differences in LGR5 expression were assessed by Spearman’s rank correlation analysis, and the relationship between LGR5 expression level and the patients’ clinicopathological characteristics was evaluated by the χ2 test or Fisher’s exact test.
RESULTS: Significantly more gastric cancer tissues showed LGR5+ staining than normal control tissues (all P < 0.01), with immunoreactivity detected in 72.2% (65/90) and 50.9% (27/53) of intestinal metaplasia and dysplasia specimens, respectively, 52.8% (95/180) of gastric adenocarcinoma specimens, and 73.3%% (11/15) of metastasis specimens, but 26.9% (39/145) of lesion-adjacent normal gastric mucosa specimens. Comparison of the intensity of LGR5+ staining showed an increasing trend that generally followed increasing dedifferentiation and tumor spread (normal tissue < dysplasia, < gastric adenocarcinoma < metastasis; all P < 0.001), with the exception of expression level detected in intestinal metaplasia which was higher than that in normal gastric tissues (P < 0.001). Moreover, gastric cancer-associated enhanced expression of LGR5 was found to be significantly associated with age, tumor differentiation, Lauren type and TNM stage (I + II vs III + IV) (all P < 0.05), but not with sex, tumor site, location, size, histology, lymphovascular invasion, depth of invasion, lymph node metastasis or distant metastasis. Patients with LGR5+ gastric cancer specimens and without signs of metastasis from the original biopsy experienced more frequent rates of recurrence or metastasis during follow-up than patients with LGR5- specimens (P < 0.05).
CONCLUSION: Enhanced LGR5 is related to progressive dedifferentiation and metastasis of gastric cancer, indicating the potential of this receptor as an early diagnostic and prognostic biomarker.
Core tip: This is the first study to evaluate the expression of leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), a putative cancer stem cell marker, in progressive stages of gastric carcinogenesis. The observation of increasing LGR5 expression in human gastric cancer lesions, following the loss of differentiation (from dysplastic to gastric cancer cases) and risk of spread (metastatic cases), suggests that this receptor may represent an important biomarker for early detection of patients at higher risk for gastric tumorigenesis. The observed distinctive expression pattern of LGR5 in intestinal metaplasia suggests that these cells may represent a precancerous condition but not carcinoma precursors.