Tumor Progression In Esophageal Squamous Cell Carcinoma Research Articles

Prognostic value of PLCE1 expression in upper gastrointestinal cancer: a systematic review and meta-analysis.

A number of studies have identified a shared susceptibility locus in phospholipase C epsilon 1 (PLCE1) for esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinomas (GCA). However, the results of PLCE1 expression in esophageal and gastric cancer remain inconsistent and controversial. Moreover, the effects on clinicopathological features remain undetermined. This study aimed to provide a precise quantification of the association between PLCE1 expression and the risk of ESCC and GCA through meta-analysis. Eligible studies were identified from PubMed, Wanfang Data, ISI Web of Science, and the Chinese National Knowledge Infrastructure databases. Using RevMan5.2 software, pooled odds ratios (ORs) with 95% confidence intervals (CIs) were employed to assess the association of PLCE1 expression with clinicopathological features relative to ESCC or GCA. Seven articles were identified, including 761 esophageal and gastric cancer cases and 457 controls. Overall, we determined that PLCE1 expression was associated with tumor progression in both esophageal cancers (pooled OR=5.93; 95%CI=3.86 to 9.11) and gastric cancers (pooled OR=9.73; 95%CI=6.46 to 14.7). Moreover, invasion depth (pooled OR=3.62; 95%CI=2.30 to 5.70) and lymph node metastasis (pooled OR=4.21; 95%CI=2.69 to 6.59) were linked with PLCE1 expression in gastric cancer. However, no significant associations were determined between PLCE1 overexpression and the histologic grade, invasion depth, and lymph node metastasis in esophageal cancer. Our meta- analysis results indicated that upregulated PLCE1 is significantly associated with an increased risk of tumor progression in ESCC and GCA. Therefore, PLCE1 expression can be appropriately regarded as a promising biomarker for ESCC and GCA patients.

Abstract 5209: MicroRNA-193a-5p suppresses tumor proliferation and enhances radio-sensitivity through ERBB2 in esophageal squamous cell carcinoma

Abstract Esophageal cancer is the ninth leading cause of cancer death in Taiwan. Esophageal squamous cell carcinoma (ESCC) is usually managed with combined modalities, but the prognosis for ESCC patients is still dismal. MicroRNAs (miRNAs) have been implicated in a variety of human cancers progression, and their expression signatures can provide insight into the diagnosis and prognosis of human cancers. However, the dysregulated miRNAs promoted tumor progression in ESCC remain unclear. To address this goal, 1097 miRNAs were analyzed in nine pairs of ESCC and corresponding normal parts with microarray. Tumor suppressive miRNA, miR-193a-5p, was characterized and inversely correlated with poor prognosis of ESCC patients. Manipulating miR-193a-5p in ESCC cell lines and mouse tumor model, the cell proliferation was decreased and the radio-sensitivity was increased. We further used reporter assay to identify ERBB2 as the target of miR-193a-5p. Restored the ERBB2 expression abolished the effects of miR-193a-5p on cell proliferation and radio-sensitivity. These results indicated that miR-193a-5p played a tumor suppressive role through suppressing ERBB2, expression in esophageal squamous cell carcinoma. Key words: miR-193a-5p, esophageal squamous cell carcinoma, radiotherapy Note: This abstract was not presented at the meeting. Citation Format: Pei-Jung Lu. MicroRNA-193a-5p suppresses tumor proliferation and enhances radio-sensitivity through ERBB2 in esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5209. doi:10.1158/1538-7445.AM2014-5209

Stromal fibroblasts are predictors of disease-related mortality in esophageal squamous cell carcinoma.

The growth, invasiveness and metastasis of human cancers are determined not only by cancer cells, but also by their microenvironment. Activated stromal fibroblasts promote tumor progression by secreting growth factors. In the present study, we focused on interrelations between cancer and fibroblasts, the main component of tumor stroma. We retrospectively analyzed the relations of mortality to clinical, pathological, and α-smooth muscle actin (α-SMA) characteristics in 97 consecutive patients with esophageal squamous cell carcinoma (ESCC). In vitro, we used TE-11, KYSE150 and KYSE220 ESCC cell lines and isolated esophageal stromal fibroblasts, some of which were immortalized. Migration assays were conducted to assess the effects of fibroblasts on cancer-cell migration and 3-dimensional organotypic cultures. In vivo, TE-11 and KYSE220 cells plus immortalized fibroblasts were co-transplanted subcutaneously in Nod/Scid mice to assess the effects of fibroblasts on tumorigenicity. Clinicopathologically, the α-SMA expression of cancer stroma was correlated with venous invasion (p<0.01), nodal involvement (p=0.02), recurrence (p=0.01), and was a predictor of survival in patients with stage I and II ESCC (p=0.04). In vitro, the presence of fibroblasts strongly promoted the migration of TE-11, KYSE150 and KYSE220 cells. On organotypic culture, stromal invasion was observed only in the presence of immortalized fibroblasts. In vivo, tumors developed or grew in a fibroblast‑dependent manner after implantation. Our findings provide evidence that stromal fibroblasts and tumor cells interact to promote tumor progression in ESCC. In patients with earlier stage ESCC, α-SMA may be a predictor of mortality. Inhibition of paracrine systems associated with tumor fibroblasts may slow or reverse tumor progression, potentially leading to the development of new targeted therapies.

Specific MUC1 Splice Variants Are Correlated With Tumor Progression in Esophageal Cancer

Mucin 1 (MUC1) is a complex glycoprotein expressed on the apical surface of normal glandular epithelial cells. It plays a role in a number of biologic processes, and its overexpression is associated with various malignancies. A growing body of literature suggests that MUC1 is a potential diagnostic and therapeutic marker. Increasing numbers of variants are being identified for the MUC1 gene, but their role in carcinogenesis is unclear. Alternative splicing and a specific region on a variable number of tandem repeats are characteristic features of MUC1. However, the underlying mechanisms, overall prevalence, and the function of various MUC1 isoforms are not well characterized. In the present study, mRNA expression of nine variants of the MUC1 gene (A-D, X-Z, REP, SEC) was evaluated in normal and tumor tissues obtained from 50 patients with esophageal squamous cell carcinoma (ESCC). Associations between expression of various isoforms of MUC1 and important clinicopathologic factors were studied. Specific MUC1 splice variants (i.e., MUC1/C, D, and Z) are correlated with tumor progression in ESCC, whereas MUC1/B-previously suggested as a "normal" variant in some other cancers-has protective effects and is associated with more favorable tumor behavior and better prognosis. Specific isoforms of ESCC are associated with prognosis. Further characterization of different isoforms of MUC1 and their biologic effects is needed to explore their diagnostic and prognostic potential in clinical practice.

Overexpression of matriptase correlates with poor prognosis in esophageal squamous cell carcinoma

Matriptase is one of the type II transmembrane serine proteases and is known to be involved in cancer progression. Increased matriptase expression has been reported in a variety of human cancers, and its association with poor prognosis has been highlighted in some cancer types. However, its exact role in cancer progression and its effect on patient survival in esophageal squamous cell carcinoma (ESCC) are still unclear. We performed immunohistochemical staining of matriptase in 171 ESCC samples after antibody validation and evaluated the association of its expression with clinicopathological parameters and prognosis. High matriptase expression was observed in 38.6 % (66/171) of ESCC samples and more frequently in N3 stage and in poorly differentiated tumors. Both overall survival (OS) and disease-free survival (DFS) were significantly lower for patients with high expression of matriptase than for patients with low expression (5-year OS rate, 38.6 vs 55.3 %; p=0.034 and 5-year DFS rate, 30.5 vs 49.4 %; p=0.007). High matriptase expression was an independent prognostic factor for OS [hazard ratio (HR), 1.65 (95 % confidence interval (CI), 1.01-2.68); p=0.045] and for DFS [HR, 1.79 (95 % CI, 1.14-2.81); p=0.012]. In conclusion, higher expression of matriptase is an independent prognostic factor involved in the progression of ESCC, which suggests that matriptase is a factor in ESCC tumor progression and also a potential molecular therapeutic target.

Elevated Maspin Expression Is Associated with Better Overall Survival in Esophageal Squamous Cell Carcinoma (ESCC)

Tumor suppressor maspin is a differentially regulated gene in the progression of many types of cancer. While the biological function of maspin in blocking tumor invasion and metastasis is consistent with the loss of maspin expression at the late stage of tumor progression, the differential expression and the biological significance of maspin in early stage of tumor progression appear to be complex and remain to be elucidated. In the current study, we examined the expression of maspin in 84 esophageal squamous cell carcinoma (ESCC) cases (stages I–III) and 55 non-tumor adjacent esophageal tissue specimens by immunohistochemical (IHC) staining. The correlation of maspin with clinicopathological parameters was analyzed. Compared to normal esophageal squamous tissue where 80% (47/55) of the cases expressed maspin at a low to moderate level, all ESCC specimens (100% (84/84)) were positive for maspin expression at a moderate to high level. ESCC with low or moderate maspin expression had significantly shorter postoperative survival rates compared to those that had high maspin expression (p<0.001). Since the correlation of maspin with ESCC histology and the correlation of maspin with ESCC prognosis seem to be at odds, we further investigated the biological function of maspin in ESCC using the established ESCC cell lines. The expression of maspin in five human esophageal squamous cancer cell lines (T12, E450, KYSE150, EC109, and KYSE510) was examined by the Western blot. ESCC cell line KYSE510 that did not express maspin and was stably transfected by maspin cDNA or an empty vector. The resulting transfected cells were characterized in vitro. Maspin expression significantly inhibited cell proliferation, motility and matrigel invasion. Taken together, our data suggest that the transient up-regulation of maspin in the early development of ESCC may be a defense mechanism against further transition towards more malignant phenotypes, ultimately slowing down ESCC tumor progression.

Loss of p53 in esophageal squamous cell carcinoma and the correlation with survival: Analyses of gene mutations, protein expression, and loss of heterozygosity in Japanese patients

A high frequency of p53 protein expression or gene mutation has been reported in the early stages of esophageal squamous cell carcinoma (ESCC), and thus loss of p53 function is thought to be very important in esophageal carcinogenesis. However, there is controversy surrounding the correlation between p53 dysfunction and ESCC tumor progression. The complexity arises from the different modalities, such as mutation analysis, immunohistochemistry, and the detection of loss of heterozygosity (LOH) at the p53 genomic locus. In this study, we comprehensively analyzed p53 gene mutation, p53 protein expression, and LOH at 17p13 in 94 surgically resected Japanese cases of ESCC. The frequency of p53 gene mutation was 60.6%. The rate of positive p53 protein expression was 56.4%. The frequency of LOH at 17p13 was 67.5%. There was a statistically significant correlation between the presence of a gene mutation and LOH, whereas, there was no significant correlation between gene mutation and protein expression. Despite the importance of loss of p53 function in esophageal carcinogenesis, none of the examined parameters, either singly or combined, correlated with overall survival. Taken together, p53 function is a primary target for esophageal carcinogenesis but there is no apparent correlation with the malignant phenotype in ESCC.

Decreased expression of FBXW7 is correlated with poor prognosis in patients with esophageal squamous cell carcinoma

FBXW7 is a tumor suppressor gene that induces the degradation of positive cell-cycle regulators such as c-Myc, cyclin E, c-Jun and Notch. The loss of FBXW7 promotes cell-cycle progression and cell proliferation. In the present study, we investigated the relationship between FBXW7 expression and the clinicopathological characteristics of patients with esophageal squamous cell carcinoma (ESCC). The expression of FBXW7 was quantified by real-time reverse transcription polymerase chain reaction in 43 primary ESCCs and their paired normal esophageal mucosa in patients who had not received preoperative therapy. FBXW7 expression levels were significantly correlated with the progression of the cancer and with local invasiveness. In muscle-invasive tumor cases (T2-4), lymphatic invasive tumor cases and stage II-IV cases, FBXW7 expression levels were significantly decreased (P=0.0315, P=0.0336 and P=0.0289, respectively). Decreased expression of FBXW7 was correlated with poor prognosis (P=0.0255). In conclusion, this study examined the relationship between FBXW7 expression and tumor progression in ESCC. We suggest that FBXW7 is a molecular prognostic marker and can be used to elucidate the mechanism of carcinogenesis.

Loss of p16INK4a expression is associated with vascular endothelial growth factor expression in squamous cell carcinoma of the esophagus.

Vascular endothelial growth factor (VEGF) expression has been suggested to correlate with intratumoral microvessel density, tumor advancement and prognosis in esophageal squamous cell carcinoma (ESCC). Previous studies have showed that disruption of cell cycle regulator p16 is related to oncogenesis and tumor progression in ESCC. We hypothesized that VEGF expression in ESCC is reflected by abnormalities in the p16(INK4a) gene. To clarify the regulatory role of p16(INK4a) in VEGF expression in vitro, we transferred the p16(INK4a) gene into a p16(INK4a)-deleted ESCC cell line and observed changes in VEGF expression. Furthermore, we immunohistochemically assessed the expression of the cell cycle regulators (p16, p53 and RB) and VEGF in 90 surgically resected specimens of ESCC. Introduction of p16(INK4a) cDNA by the p16 expression vector significantly suppressed cell proliferation in the p16(INK4a)-deleted cell line TE8 (p < 0.0001). VEGF secretion by TE8 cells transfected with the p16(INK4a) vector was significantly suppressed as compared to non-transfected TE8 cells (p < 0.0001) and TE8 cells transfected with a control vector (p = 0.0015). The immunohistochemical studies of ESCC primary tumor specimens showed that loss of p16 expression was significantly correlated with VEGF-positive expression (p = 0.0004). The cumulative postoperative survival rate in the group with p16-positive and VEGF-negative expression was significantly higher than in the other groups. Neither p53 nor RB expression had any impact on outcome. Aberrant p53 expression tended to be associated with VEGF expression, but the trend did not reach statistical significance. Our study demonstrated that VEGF expression was correlated with p16 expression in ESCC. Our results suggest that p16 may have a regulatory role in VEGF expression in ESCC.

Protein and gene expression of tumor-associated antigen RCAS1 in esophageal squamous cell carcinoma

RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) is expressed on the tumor cell membrane and induces apoptosis on infiltrated immune lymphocytes. RCAS1 has been reported to correlate with the escape of tumor cells from host immune surveillance, and with poor prognosis. However, the clinical importance of RCAS1 protein and gene expression in esophageal squamous cell carcinoma (ESCC) has not been well investigated. In the present study, RCAS1 gene and protein expression levels were evaluated and compared with clinical findings in 67 patients with ESCC. Expression levels of RCAS1 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) messenger RNAs (mRNAs) from tumors and non-cancerous epithelia were analyzed quantitatively by real-time reverse transcriptase polymerase chain reaction (RT-PCR). RCAS1 protein expression was analyzed by immunohistochemistry. The mean RCAS1/GAPDH ratio of tumors (0.7) was not different from that of non-cancerous epithelia (0.7, p=0.715). RCAS1 immunoreactivity was detected in 19 tumors (28.4%). The mean RCAS1/GAPDH ratio of tumors with RCAS1 protein positive (0.6) did not differ from tumors without RCAS1 expression (0.8, p=0.131). RCAS1 gene and protein expressions did not correlate with tumor size, depth of invasion, lymph node metastasis, or patient prognosis. Thus, RCAS1 gene or protein expression may not correlate with tumor progression in ESCC.