Prognostic markers in esophageal cancer: from basic research to clinical use

Abstract

Esophageal cancer (EC) remains a leading cause of cancer-related death in Asian countries. Due to the biology of EC, including aggressive local invasion, early metastasis and drug resistance, EC has a low survival rate. Therefore, molecular markers for prognosis judgment are urgently required so as to identify subgroups of patients that will benefit from more aggressive therapeutic interventions. So far, many genes and miRNAs, such as VEGF, cyclin D1, and miR-21, have been shown to be valuable when predicting the prognosis of EC. Some circulating molecules, including miR-200c, miR-1246, miR-31, have been identified as the independent risk factors for poor survival. However, the function and mechanism of these molecules in EC remains unclear. More clinical studies should be performed to promote the clinical use of prognosis-related markers in the management of EC.

Keywords:

• esophageal cancer
• prognosis
• survival

Esophageal cancer (EC), consisting of squamous cell carcinoma and adenocarcinoma, is the eighth most common cancer in the world, and its prevalence is rapidly increasing worldwide [1]. Esophageal squamous cell carcinoma (ESCC) accounts for most of EC in Asian countries, whereas esophageal adenocarcinoma (EAC) affects white populations predominantly. Despite improvements in detection, surgical resection, and adjuvant therapy, EC is usually determined by clinical diagnosis in the middle-late period, delaying timely treatment and leading to poor survival.

There is overwhelming evidence that aberrantly expressed molecules of EC tissues are useful for predicting the prognosis of EC patients. Chen et al. [2] have performed a systematic review and meta-analysis of the published literature to summarize evidence for the discriminatory ability of prognostic biomarkers for EC. As a result, VEGF (1329 ESCC patients, hazard ratio[HR]: 1.85), cyclin D1 (1295 ESCC patients, HR: 1.82), Ki-67 (308 ESCC patients, HR: 1.11), and SCC-Ag (260 ESCC patients, HR: 2.05) appeared to hold potential as predictors of outcome in ESCC. The prognostic markers for EAC included COX-2 (235 EAC patients, HR: 3.06) and HER-2 (291 EAC patients, HR: 2.15). In addition, p21 (n:858, HR: 1.27), p53 (n:2851, HR:1.33), C-reactive protein (n:382, HR: 2.6), and hemoglobin (n: 544, HR: 0.91) were prognostic markers for uncategorized EC.

Tumor-associated macrophages are associated with the EC response to chemotherapy [3]. Sugimura et al. [3] have found that filtration of CD68(+) macrophages and CD163(+) macrophages was significantly associated with tumor depth, lymphatic invasion and venous invasion of EC. High infiltration of CD68(+) macrophages and CD163(+) macrophages was significantly associated with poor response to chemotherapy for EC patients undergoing neoadjuvant chemotherapy. In addition, the expression of HMGB3, LSD1, ANGPTL2, Fas/Fas ligand, and Topo2A was significantly associated with survival of EC [4–8]. EI24 was a p53-induced proapoptotic factor with a potential physiologic role as a tumor suppressor [9]. Recently, our laboratory found that EI24 was a valuable marker for predicting metastasis and prognosis of EC. Down-regulation of EI24 contributed significantly to resistance of EC cells to chemotherapeutic agents.

Because of their relatively small molecular weight and the endogenous power of targeting broad-range regulators, miRNAs are superior to protein in clinical management of EC [10]. For example, miR-21 may be both an important factor in determining prognosis and a biomarker in predicting response to treatment [11]. miR-21 is over-expressed in most tumor types, and acts as an oncogene. As for patients with EC, who have received preoperative chemotherapy followed by surgery, over-expression of miR-21 correlates significantly with poor survival. Inactivating endogenous miR-21 is considered a new strategy that may increase the sensitivity of EC cells to anti-cancer drugs [12]. The EC patients with high miR-21 concentrations in plasma have significantly poorer prognosis than other patients [13]. The ESCC patients with high plasma miR-21 concentration show a tendency toward vascular invasion [14]. Fu et al. [15] have performed a meta-analysis to evaluate the prognostic role of miRNAs in EC. A total of 25 studies and 2258 subjects were involved in the study. Higher expression of miR-21 (HR: 1.84) and miR-375 (HR: 0.55) could significantly predict poorer survival of ESCC.

We have found that deduced expression of miR-296 was able to distinguish long-term survivors with node-positive ESCC from those dying within 20 months [16]. High expression of miR-483 and miR-214 might predict less sensitivity to chemotherapy, and might predict poor overall survival in ESCC [17]. Although studies investigating prognosis-related miRNAs comprise an extremely promising field for clinical application, the function and mechanism of prognosis-related miRNAs in EC remains unclear. There is currently no international standardized definition of the expression levels for miRNAs. Many studies use the mean value of relative quantity to define the expression levels.

Plasma/serum miRNAs have recently become known as novel biomarkers related to the progression of EC. Tanaka et al. [18] have detected the serum levels of miR-145, miR-200c, and let-7c in 64 cases of ESCC patients who underwent neoadjuvant chemotherapy and 27 healthy volunteers by quantitative RT-PCR. High expression of miR-200c correlated significantly with shortened progression-free survival and poor response to chemotherapy. Takeshita et al. [19] have detected the serum miR-1246 level in 101 ESCC patients and 46 healthy controls. The results showed that the serum miR-1246 was the independent risk factor for poor survival. In addition, ESCC patients with high levels of serum miR-31 had a poorer prognosis in relapse-free survival and tumor-specific survival [20]. However, there are some problems in estimating circulating miRNA levels. So far, the mechanisms underlying the role of circulating miRNAs in tumor progression remain unclear.

Many molecules, such as VEGF, cyclin D1, and miR-21, have been identified as prognostic markers in EC. Some circulating molecules, including miR-200c, miR-1246, and miR-31, have an appealing role in guiding EC therapy. However, there is still a significant gap between basic research and clinical application. More investigations should be performed along the following avenues that are likely to lead to exciting results. First, it is necessary to screen and identify more prognosis-related molecules so that we can gain further insight into the molecular pathogenesis of ESCC and EAC. In addition, more research should evaluate whether the SNPs and mutations of some molecules are useful for predicting the prognosis of EC. Second, to identify the functions and mechanisms of prognosis-related molecules in EC, especially circulating markers. Third, more clinical trials are needed for validation of the potential markers in large cohorts of patients before they can be used as biomarkers for clinical usage. The Asian clinical trials should focus on the ESCC patients because of its high incidence, while western countries on EAC patients. Additional translational work should evaluate whether combination of these markers as a kit has the potential of predicting survival efficiently.

More and more clinical trials are being carried out to examine whether the use of prognostic markers are feasible and safe. As scientific and technological methods become increasingly sophisticated, the next few years will see significant progress in their clinical applications.

Financial & competing interests disclosure

The authors were supported by a grant from the National Natural Scientific Foundation of China (81100714, 81171923). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.