The impact of sex on the prognosis of patients with esophageal cancer remains unclear. Evidence supports that sex- based disparities in esophageal cancer survival could be attributed to sex- specific risk exposures, such as age at diagnosis, race, socioeconomic status, smoking, drinking, and histological type. The aim of our study is to investigate the role of sex disparities in survival of patients who underwent surgery for esophageal cancer. A systematic review and meta-analysis of the existing literature in PubMed, EMBASE, and CENTRAL from December 1966 to February 2023, was held. Studies that reported sex-related differences in survival outcomes of patients who underwent esophagectomy for esophageal cancer were identified. A total of 314 studies were included in the quantitative analysis. Statistically significant results derived from 1-year and 2-year overall survival pooled analysis with Relative Risk (RR) 0.93 (95% Confidence Interval (CI): 0.90-0.97, I2 = 52.00) and 0.90 (95% CI: 0.85-0.95, I2 = 0.00), respectively (RR < 1 = favorable for men). In the postoperative complications analysis, statistically significant results concerned anastomotic leak and heart complications, RR: 1.08 (95% CI: 1.01-1.16) and 0.62 (95% CI: 0.52-0.75), respectively. Subgroup analysis was performed among studies with <200 and > 200 patients, histology types, study continent and publication year. Overall, sex tends to be an independent prognostic factor for esophageal carcinoma. However, unanimous results seem rather obscure when multivariable analysis and subgroup analysis occurred. More prospective studies and gender-specific protocols should be conducted to better understand the modifying role of sex in esophageal cancer prognosis.

Heat shock proteins (HSPs) are molecular chaperones that play an important role in cellular protection against stress events and have been reported to be overexpressed in many cancers. The prognostic significance of HSPs and their regulatory factors, such as heat shock factor 1 (HSF1) and CHIP, are poorly understood.

To investigate the relationship between HSP expression and prognosis in esophageal and esophagogastric cancer.

A systematic review was conducted in accordance with PRISMA recommendations (PROSPERO: CRD42022370653), on Embase, PubMed, Cochrane, and LILACS. Cohort, case-control, and cross-sectional studies of patients with esophagus or esophagogastric cancer were included. HSP-positive patients were compared with HSP-negative, and the endpoints analyzed were lymph node metastasis, tumor depth, distant metastasis, and overall survival (OS). HSPs were stratified according to the HSP family, and the summary risk difference (RD) was calculated using a random-effect model.

The final selection comprised 27 studies, including esophageal squamous cell carcinoma (21), esophagogastric adenocarcinoma (5), and mixed neoplasms (1). The pooled sample size was 3465 patients. HSP40 and 60 were associated with a higher 3-year OS [HSP40: RD = 0.22; 95% confidence interval (CI): 0.09-0.35; HSP60: RD = 0.33; 95%CI: 0.17-0.50], while HSF1 was associated with a poor 3-year OS (RD = -0.22; 95%CI: -0.32 to -0.12). The other HSP families were not associated with long-term survival. HSF1 was associated with a higher probability of lymph node metastasis (RD = -0.16; 95%CI: -0.29 to -0.04). HSP40 was associated with a lower probability of lymph node dissemination (RD = 0.18; 95%CI: 0.03-0.33). The expression of other HSP families was not significantly related to tumor depth and lymph node or distant metastasis.

The expression levels of certain families of HSP, such as HSP40 and 60 and HSF1, are associated with long-term survival and lymph node dissemination in patients with esophageal and esophagogastric cancer.

Esophageal cancer is a worldwide health problem with a very poor prognosis. Therefore, new diagnostic biomarkers or therapeutic strategies for identifying and managing esophageal squamous cell carcinoma (ESCC) are urgently needed. Glucose-regulated protein 94 (GRP94) is one of major endoplasmic reticulum-stress response proteins that plays a key role in cancer progression and therapeutic responses. However, the role of GRP94 in ESCC progression and metastasis remains unclear. The tissue array results indicated that higher GRP94 expression levels were associated with lower overall survival and higher lympho-node metastasis. Silencing GRP94 (GRP94-KD) reduced cell proliferation, migration and invasion in ESCC cells. In a xenotransplantation assay, silencing GRP94 reduced cell proliferation in the zebrafish embryo. Transmission electron microscopy revealed impaired mitochondria in GRP94-KD cells, which exhibited reduced basal respiration, spare respiratory capacity and ATP production and increased oxidative damage compared with scrambled control cells. Regarding the molecular mechanism underlying the effects of GRP94 knockdown, we found that silencing GRP94 may reduce the level of NF-kB, c-Jun, p38, IL-6, vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) as well as activation of AKT and ERK. In conclusion, our results indicate that silencing GRP94 in ESCC cells suppressed cancer growth and the metastatic potential via mitochondrial functions and NF-kB/COX-2/VEGF in ESCC cells.

A high percentage of oesophageal adenocarcinomas show an aggressive clinical behaviour with a significant resistance to chemotherapy. Heat-shock proteins (HSPs) and glucose-regulated proteins (GRPs) are molecular chaperones that play an important role in tumour biology. Recently, novel therapeutic approaches targeting HSP90/GRP94 have been introduced for treating cancer. We performed a comprehensive investigation of HSP and GRP expression including HSP27, phosphorylated (p)-HSP27((Ser15)), p-HSP27((Ser78)), p-HSP27((Ser82)), HSP60, HSP70, HSP90, GRP78 and GRP94 in 92 primary resected oesophageal adenocarcinomas by using reverse phase protein arrays (RPPA), immunohistochemistry (IHC) and real-time quantitative RT-PCR (qPCR). Results were correlated with pathologic features and survival. HSP/GRP protein and mRNA expression was detected in all tumours at various levels. Unsupervised hierarchical clustering showed two distinct groups of tumours with specific protein expression patterns: The hallmark of the first group was a high expression of p-HSP27((Ser15, Ser78, Ser82)) and low expression of GRP78, GRP94 and HSP60. The second group showed the inverse pattern with low p-HSP27 and high GRP78, GRP94 and HSP60 expression. The clinical outcome for patients from the first group was significantly improved compared to patients from the second group, both in univariate analysis (p = 0.015) and multivariate analysis (p = 0.029). Interestingly, these two groups could not be distinguished by immunohistochemistry or qPCR analysis. In summary, two distinct and prognostic relevant HSP/GRP protein expression patterns in adenocarcinomas of the oesophagus were detected by RPPA. Our approach may be helpful for identifying candidates for specific HSP/GRP-targeted therapies.