Cancer stem cell (CSC) epithelial cell adhesion molecule (Ep-CAM) is frequently expressed in colorectal cancer (CRC). However, the clinical significance of Ep-CAM expression in CRC is not clear. This study evaluated whether Ep-CAM provided valuable insight as a molecular biomarker for CRC diagnosis and prognosis and the potential of Ep-CAM as a novel therapeutic target in CRC. Publications were selected online using electronic databases. The pooled odds ratios (ORs) or hazard ratios (HRs) with their 95% confidence intervals (95% CIs), and the combined sensitivity, specificity, and area under the curve (AUC) were calculated and summarized. Eleven eligible articles published in English involving 4561 cases were analyzed in this study. Ep-CAM expression was significantly higher in CRC compared with normal controls, and its overexpression was negatively linked to tumor differentiation, tumor stage, vascular invasion, depth of tumor invasion, lymph node metastasis, distant metastasis, and tumor budding in CRC patients. The loss of Ep-CAM expression positively correlated with these characteristics. Multivariate analysis of loss of Ep-CAM expression correlated with a poor prognosis in disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). The pooled sensitivity, specificity and AUC values of Ep-CAM expression in patients with CRC vs. normal controls were 0.93, 0.90, and 0.94, respectively. The present findings suggest that Ep-CAM expression may be associated with CRC carcinogenesis, while the loss of Ep-CAM expression is correlated with the progression, metastasis, and poor prognosis of CRC. Ep-CAM expression may be a useful biomarker for the clinical diagnosis of CRC.

CD166 has been identified as an important cancer stem cell (CSC) marker in colorectal cancer (CRC). The purpose of our study was to investigate the relationship between CD166 expression and clinical features and to examine the role of CD166 expression on the survival of patients with CRC. A total of 15 studies with 3,332 cases were identified in this meta-analysis. The pooled OR indicated that CD166 expression was significantly higher in CRC than in colonic adenomas or normal colonic mucosa (OR = 3.48, P = 0.002 and OR = 55.13, P = 0.017, respectively). CD166 expression was found to be negatively correlated with vascular invasion (OR = 0.75, P = 0.017), but it was not associated with gender, tumor location, lymph node status, distant metastasis, clinical stage, T classification or tumor differentiation. Meanwhile, CD166 expression was not associated with the prognosis of overall survival (OS) (HR = 1.20, 95% CI = 0.45-3.22, P = 0.72) in multivariate regression analysis. One study reported that CD166 expression may be a predictor of survival in stage II CRC patients using multivariate logistic regression analysis (OS: OR = 9.97, P = 0.035; disease-specific survival: OR = 29.02, P = 0.011). Our findings suggest that CD166 expression may be correlated with CRC carcinogenesis and a decreased risk of vascular invasion, and it may become a predictive biomarker of survival for stage II CRC patients, but additional studies with large sample sizes are essential to validate the prognostic and predictive values of CD166 expression.

Expression of hypoxia-inducible factors (HIFs) has been observed, but their prognostic role in advanced cancers remains uncertain. We conducted a meta-analysis to establish the prognostic effect of HIFs and to better guide treatment planning for advanced cancers. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Trial sequential analysis (TSA) was also performed. The clinical outcomes included overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), cancer-specific survival (CSS), relapse/recurrence-free survival (RFS), and metastasis-free survival (MFS) in patients with advanced tumors according to multivariate analysis. A total of 31 studies including 3453 cases who received chemotherapy, radiotherapy, or chemoradiotherapy were identified. Pooled analyses revealed that HIF-1α expression was correlated with worse OS (HR = 1.61, p < 0.001), DFS (HR = 1.61, p < 0.001), PFS (HR = 1.49, p = 0.01), CSS (HR = 1.65, p = 0.056), RFS (HR = 2.10, p = 0.015), or MFS (HR = 2.36, p = 0.002) in advanced cancers. HIF-1α expression was linked to shorter OS in the digestive tract, epithelial ovarian, breast, non-small cell lung, and clear cell renal cell carcinomas. Subgroup analysis by study region showed that HIF-1α expression was correlated with poor OS in Europeans and Asians, while an analysis by histologic subtypes found that HIF-1α expression was not associated with OS in squamous cell carcinoma. No relationship was found between HIF-2α expression and OS, DFS, PFS, or CSS. Targeting HIF-1α may be a useful therapeutic approach to improve survival for advanced cancer patients. Based on TSA, more randomized controlled trials are strongly suggested.

Objective: Cancer stem cell marker CD44 and its variant isoforms (CD44v) may be correlated with tumor growth, metastasis and chemo-radiotherapy resistance. However, the prognostic power of CD44 and CD44v in advanced cancer remains controversial. Therefore, the purpose of our study was to generalize the prognostic significance of these cancer stem cell markers in advanced cancer patients. Methods: Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated from multivariable analysis to assess the associations among CD44, CD44v6, and CD44v9 positivity and overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), cancer-specific survival (CSS), and recurrence-free survival (RFS). Trial sequential analysis (TSA) was also conducted. Results: We included 15 articles that reported on 1,201 patients with advanced cancer (CD44: nine studies with 796 cases, CD44v6: three studies with 143 cases, and CD44v9: three studies with 262 cases). CD44 expression was slightly linked to worse OS (HR = 2.03, P = 0.027), but there was no correlation between CD44 expression and DFS, RFS, or PFS. Stratified analysis showed that CD44 expression was not correlated with OS at ≥ 5 years or OS in patients receiving adjuvant therapy. CD44v6 expression was not associated with OS. CD44v9 expression was closely associated with poor 5-year CSS in patients treated with chemo/radiotherapy (HR = 3.62, P < 0.001). However, TSA suggested that additional trials were needed to confirm these conclusions. Conclusions: CD44 or CD44v9 might be novel therapeutic targets for improving the treatment of advanced cancer patients. Additional prospective clinical trials are strongly needed across different cancer types.

Novel prognostic markers and therapeutic targets for advanced cancer are urgently needed. This report with trial sequential analysis (TSA) was first conducted to provide robust estimates of the correlation between aldehyde dehydrogenase 1 (ALDH1) and Nestin and clinical outcomes of advanced cancer patients. Hazard ratios (HRs) with 95% confidence intervals (CIs) were summarized for overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), cancer-specific survival (CSS), relapse/recurrence-free survival (RFS), and metastasis-free survival (MFS) from multivariable analysis. TSA was performed to control for random errors. A total of 20 studies with 2050 patients (ALDH1: 15 studies with 1557 patients and Nestin: 5 studies with 493 patients) were identified. ALDH1 (HR = 2.28, p < 0.001) and Nestin (HR = 2.39, p < 0.001) were associated with a worse OS, as confirmed by TSA. Nestin positivity was linked to a poor PFS (HR = 2.08, p < 0.001), but ALDH1 was not linked to DFS, RFS, MFS, or PFS, and TSA showed that more studies were needed. Subgroup analysis by tumor type indicated that ALDH1 positivity may be associated with shorter OS in breast, head and neck cancers, but there was no association with colorectal cancer. Subgroup analysis by study source showed that ALDH1 positivity was correlated with a worse OS for Japanese (HR = 1.94, p = 0.002) and European patients (HR = 4.15, p < 0.001), but there was no association for Chinese patients. Subgroup analysis by survival rate showed that ALDH1 positivity correlated with poor OS at ⩾ 5 years (HR = 2.33, p < 0.001) or 10 years (HR = 1.76, p = 0.038). ALDH1 may be more valuable as an effective therapeutic target than Nestin for improving the long-term survival rate of advanced cancer. Additional prospective clinical trials are needed across different cancer types.

Background. The prognostic value of CD133 and SOX2 expression in advanced cancer remains unclear. This study was first conducted to investigate the association between CD133 or SOX2 positivity and clinical outcomes for advanced cancer patients.Methods. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated to evaluate the correlation between CD133 or SOX2 positivity and overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), cancer-specific survival (CSS), or recurrence-free survival (RFS) from multivariable analysis. Trial sequential analysis (TSA) was also performed.Results. 13 studies with 1358 cases (CD133) and five studies with 433 cases (SOX2) were identified. CD133 positivity was correlated with worse CSS and OS, but there was no correlation between CD133 positivity and DFS. SOX2 positivity was associated with poor DFS and RFS but was not linked to PFS. Stratified analysis by study source showed that only CD133 positivity can decrease OS for Chinese patients. Stratified analysis by treatment regimens indicated that CD133 positivity was linked to poor OS in patients treated with adjuvant therapy. TSA showed that additional studies were necessary.Conclusions. CD133 and SOX2 might be associated with worse prognosis in advanced cancer. More prospective studies are strongly needed.Impact. CD133 and SOX2 may be promising targeted molecular therapy for advanced cancer patients.