Porphyromonas gingivalis infection exacerbates oesophageal cancer and promotes resistance to neoadjuvant chemotherapy

Background The effect of Porphyromonas gingivalis (Pg) infection on oesophageal squamous cell carcinoma (ESCC) prognosis, chemotherapeutic efficacy, and oesophageal cancer cell apoptosis resistance and proliferation remain poorly understood.Methods Clinicopathological data from 312 ESCC oesophagectomy patients, along with the computed tomography imaging results and longitudinal cancerous tissue samples from a patient subset (n = 85) who received neoadjuvant chemotherapy (NACT), were analysed. Comparison of overall survival and response rate to NACT between Pg-infected and Pg-uninfected patients was made by multivariate Cox analysis and Response Evaluation Criteria in Solid Tumours v.1.1 criteria. The influence of Pg on cell proliferation and drug-induced apoptosis was examined in ESCC patients and validated in vitro and in vivo.Results The 5-year overall survival was lower in Pg-positive patients, and infection was associated with multiple clinicopathological factors and pathologic tumour, node, metastasis stage. Of the 85 patients who received NACT, Pg infection was associated with a lower response rate and 5-year overall survival. Infection with Pg resulted in apoptosis resistance in ESCC and promoted ESCC cell viability, which was confirmed in longitudinal cancerous tissue samples. Pg-induced apoptosis resistance was dependent on fimbriae and STAT3.Conclusions Pg infection is associated with a worse ESCC prognosis, reduced chemotherapy efficacy, and can potentiate the aggressive behaviour of ESCC cells.Subject terms: Pathogenesis, Risk factors, Oesophageal cancer     

Role of multidrug resistance protein 2 (MRP2) in chemoresistance and clinical outcome in oesophageal squamous cell carcinoma

Background:

Although multidrug resistance protein 2 (MRP2) confers chemoresistance in some cancer types, its implication on oesophageal squamous cell carcinoma (ESCC) remains unclear.

Methods:

We evaluated MRP2 expression by immunohistochemistry and RT–PCR using 81 resected specimens from ESCC patients who did or did not receive neo-adjuvant chemotherapy (NACT), including 5-fluorouracil, doxorubicin, and cisplatin (CDDP). Correlation between MRP2 expression and response to chemotherapy was also examined in 42 pre-therapeutic biopsy samples and eight ESCC cell lines.

Results:

MRP2-positive immunostaining was more frequently observed in ESCCs with NACT than in those without NACT (27.3 vs 5.4%). The MRP2-positive patients showed poorer prognosis than MRP2-negative patients (5-year survival rate, 25.6 vs 55.7%). Concordantly, ESCC with NACT showed 2.1-fold higher mRNA expression of MRP2 than those without NACT (P=0.0350). In pre-therapeutic biopsy samples of patients with NACT, non-responders showed 2.9-fold higher mRNA expression of MRP2 than responders (P=0.0035). Among the panel of ESCC cell lines, TE14 showed the highest MRP2 mRNA expression along with the strongest resistance to CDDP. Inhibition of MRP2 expression by small-interfering RNA reduced chemoresistance to CDDP.

Conclusion:

Our data suggested that MRP2 is one of molecules, which regulate the sensitivity to chemotherapy including CDDP in advanced ESCC patients.     

Stemness and chemotherapeutic drug resistance induced by EIF5A2 overexpression in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies of the digestive tract in East Asian countries. Multimodal therapies, including adjuvant chemotherapy and neo-adjuvant chemotherapy, have become more often used for patients with advanced ESCC. However, the chemotherapy effect is often limited by patients'' drug resistance. This study demonstrated that EIF5A2 (eukaryotic translation initiation factor 5A2) overexpression induced stemness and chemoresistance in ESCC cells. We showed that EIF5A2 overexpression in ESCC cells resulted in increased chemoresistance to 5-fluorouracil (5-FU), docetaxel and taxol. In contrast, shRNAs suppressing eIF5A2 increased tumor sensitivity to these chemotherapeutic drugs. In addition, EIF5A2 overexpression was correlated with a poorer overall survival in patients with ESCC who underwent taxane-based chemotherapy after esophagectomy (P < 0.05). Based on these results, we suggest that EIF5A2 could be a predictive biomarker for selecting appropriate chemo-treatment for ESCC patients and EIF5A2 inhibitors might be considered as combination therapy to enhance chemosensitivity in patients with ESCC.     

ATG7 deficiency promote apoptotic death induced by Cisplatin in human esophageal squamous cell carcinoma cells

Cisplatin-(DDP)-based adjuvant chemotherapy is widely used for the treatment of esophageal cancer. However, DDP-based combinatorial treatments can eventually result in tumor resistance response. Therefore, new therapeutic strategies and/or new adjuvant drugs still need to be explored. In this study, we aimed to understand the role of autophagy in ESCC cells resistance to Cisplatin and discuss its potential therapeutic implication. We found that exposure to Cisplatin induced a significant increase in LC3 formation. While the proliferation of ESCC cells was inhibited upon Cisplatin exposure, inhibition of autophagy by ATG7 interference further increased the sensitivity to chemotherapy. Meanwhile, the Cisplatin-induced apoptotic cell death was significantly enhanced. These results suggest that autophagy may function importantly in ESCC cells resistance to Cisplatin. Intriguingly, the resistance could be recovered by autophagy inhibition. This also points to potential therapy for ESCC by perturbing autophagy.     

RPN2 expression predicts response to docetaxel in oesophageal squamous cell carcinoma

Background:

Neoadjuvant chemotherapy – often using docetaxel in various combinatorial regimens – is a standard treatment choice for advanced oesophageal squamous cell carcinoma (ESCC) in Japan. However, no useful markers exist that predict docetaxel''s effects on ESCC. Ribophorin II (RPN2) silencing, which reduces glycosylation of P-glycoproteins and decreases membrane localisation, promotes docetaxel-dependent apoptosis. We investigated whether RPN2 expression in ESCC biopsy specimens could be a predictive biomarker in docetaxel-based neoadjuvant chemotherapy.

Methods:

We evaluated RPN2 expression immunohistochemically in biopsy specimens from 79 patients with node-positive ESCC, who received docetaxel-based adjuvant chemotherapy, and compared clinical and pathological responses between the RPN2-positive and RPN2-negative groups. We also studied susceptibility of RPN2-suppressed ESCC cells to docetaxel.

Results:

The RPN2-negative group had better clinical and pathological responses to docetaxel than the RPN2-positive group. We also found RPN2 suppression to alter docetaxel susceptibility in vitro.

Conclusion:

Expression of RPN2 in biopsy specimens could be a useful predictive marker for response to docetaxel-based neoadjuvant chemotherapy in ESCC.     

Topoisomerase expression and amplification in solid tumours: Analysis of 24,262 patients

BackgroundTopoisomerase I (TOPO1) and topoisomerase IIα (TOP2A) are specific targets of multiple chemotherapy drugs. Increased expression of TOPO1 protein and amplification of the TOP2A gene have been associated with treatment response in colorectal and breast cancers, respectively. TOPO1 and TOP2A may be potential therapeutic targets in other malignancies as well.Summary of methodsWe analysed TOPO1 protein expression and TOP2A gene amplification in patients (n = 24,262 specimens) with diverse cancers. Since HER2 and TOP2A co-amplification have been investigated for predictive value regarding anthracycline benefit, we analysed specimens for HER2 amplification as well.ResultsOverexpressed TOPO1 protein was present in 51% of the tumours. Four percent of the tumours had TOP2A amplification, with gallbladder tumours and gastroesophageal/oesophageal tumours having rates over 10%. Overall, 4903 specimens were assessed for both TOP2A and HER2 amplification; 129 (2.6%) had co-amplification. High rates (>40%) of HER2 amplification were seen in patients with TOP2A amplification in breast, ovarian, gastroesophageal/oesophageal and pancreatic cancer.ConclusionOur data indicate that increased TOPO1 expression and TOP2A amplification, as well as HER2 co-alterations, are present in multiple malignancies. The implications of these observations regarding sensitivity to chemotherapy not traditionally administered to these tumour types merits investigation.     

Aspirin enhances the therapeutic efficacy of cisplatin in oesophageal squamous cell carcinoma by inhibition of putative cancer stem cells

Background Cancer stem cells (CSCs) are related to the patient’s prognosis, recurrence and therapy resistance in oesophageal squamous cell carcinoma (ESCC). Although increasing evidence suggests that aspirin (acetylsalicylic acid, ASA) could lower the incidence and improve the prognosis of ESCC, the mechanism(s) remains to be fully understood.Methods We investigated the role of ASA in chemotherapy/chemoprevention in human ESCC cell lines and an N-nitrosomethylbenzylamine-induced rat ESCC carcinogenesis model. The effects of combined treatment with ASA/cisplatin on ESCC cell lines were examined in vitro and in vivo. Sphere-forming cells enriched with putative CSCs (pCSCs) were used to investigate the effect of ASA in CSCs. Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) was performed to determine the alterations in chromatin accessibility caused by ASA in ESCC cells.Results ASA inhibits the CSC properties and enhances cisplatin treatment in human ESCC cells. ATAC-seq indicates that ASA treatment results in remarkable epigenetic alterations on chromatin in ESCC cells, especially their pCSCs, through the modification of histone acetylation levels. The epigenetic changes activate Bim expression and promote cell death in CSCs of ESCC. Furthermore, ASA prevents the carcinogenesis of NMBzA-induced ESCC in the rat model.Conclusions ASA could be a potential chemotherapeutic adjuvant and chemopreventive drug for ESCC treatment.Subject terms: Cancer prevention, Cancer stem cells, Chemotherapy, Oesophageal cancer     

Comparison of efficacy and safety between pembrolizumab combined with chemotherapy and simple chemotherapy in neoadjuvant therapy for esophageal squamous cell carcinoma

BackgroundImmunotherapy can activate the recognition of tumor antigen, build immune memory, and more and more clinical trials have taken the scheme of immunochemotherapy or immunoradiotherapy as a treatment strategy for esophageal squamous cell carcinoma (ESCC). Our objective was to compare the efficacy and safety between pembrolizumab combined with the chemotherapy group and simple chemotherapy in neoadjuvant therapy of ESCC.MethodsFifty-four ESCC patients with stage II–IVa were enrolled at the Fifth Affiliated Hospital of Sun Yat-sen University between January 2018 and December 2020, including 23 in the pembrolizumab combined with chemotherapy group (combined group), and 31 in the simple chemotherapy group. All patients received radical surgical treatment after two cycles of neoadjuvant therapy.ResultsThe pathological complete response (pCR) and objective response rate (ORR) in the combined group were significantly higher than that of the simple chemotherapy group (30.4% vs. 9.7%, P=0.048; 86.9% vs. 95.7%, P=0.017) as well as the score of tumor regression ≥2 (80.7% vs. 50.0%, P=0.013). And the complete rate of esophagectomy and R0 /R1 resection rate in the two groups were not statistically significant. Otherwise, the incidence of adverse events in the combined group was similar compared with the simple chemotherapy group.ConclusionsPembrolizumab combined with chemotherapy showed promising activity with a manageable safety profile. And it could offer a potential new neoadjuvant treatment approach for patients with ESCC.     

The activation of Akt during preoperative chemotherapy for esophageal cancer correlates with poor prognosis

The activation of the PI3K/Akt/mTOR pathway plays an important role in tumorigenesis and resistance to anticancer drugs. The aim of this study was to elucidate the role of the Akt/mTOR pathway in chemoresistance and the prognosis of patients with esophageal squamous cell carcinoma (ESCC) who received preoperative chemotherapy. We evaluated p-Akt and p-mTOR expression by immunohistochemistry in the surgical specimens of 143 ESCC (51 patients with and 92 without preoperative chemotherapy). In 37 patients of the former group, paired tissue samples obtained before and after chemotherapy were examined immunohistochemically. The incidence of p-Akt expression was higher in ESCC with than without chemotherapy (51.0 vs. 25.0%, p=0.0018). Although p-Akt expression was not associated with an advanced tumor stage, a comparison between before and after chemotherapy demonstrated an increased p-Akt expression during chemotherapy (p=0.0348). The p-Akt expression did not correlate with survival in ESCC without chemotherapy, but was associated with poor prognosis in those with chemotherapy (p=0.0058). In particular, an increased p-Akt expression during chemotherapy was associated with poor survival (p=0.0022). Notably, the p-mTOR expression did not correlate with p-Akt expression (p=0.1482). The depth of the tumor invasion, clinical response and p-Akt expression correlated with the prognosis of 51 ESCC with chemotherapy. A multivariate analysis showed that p-Akt expression was the only independent predictor of poor prognosis in ESCC patients with chemotherapy. p-Akt expression increases after chemotherapy in ESCC and a high expression correlates with poor prognosis. Our results suggest that the activation of Akt is a potentially useful therapeutic target in ESCC patients treated with chemotherapy.     

Apollon modulates chemosensitivity in human esophageal squamous cell carcinoma

Patients with esophageal squamous cell carcinoma (ESCC) are often diagnosed with advanced diseases that respond poorly to chemotherapy. Here we reported that Apollon, a membrane-associated inhibitor of apoptosis protein, was overexpressed in ESCC cell lines and clinical ESCC tissues, and Apollon overexpression clinically correlated with poor response to chemotherapy (P = 0.001), and short overall survival (P = 0.021). Apollon knockdown increased cisplatin/docetaxel-induced apoptosis, mitochondrial dysfunction and cytochrome c release in two ESCC cell lines. Apollon knockdown potentiated cisplatin/docetaxel-induced long-term cell growth inhibition, and enhanced chemosensitivity of ESCC cells to cisplatin/docetaxel in xenograft tumor models. Apollon knockdown also enhanced cisplatin/docetaxel-induced activation of caspase-8 (extrinsic pathway) and caspase-9 (intrinsic pathway) in ESCC cells and xenograft tumor models. Mechanism studies revealed that the effect of Apollon on chemosensitivity is mainly mediated by Smac. Apollon expression strongly and negatively correlated with Smac expression in clinical ESCC tissues (P = 0.001). Apollon targeted Smac for degradation in ESCC cells. The effect of Apollon on chemosensitivity was reversed by Smac knockdown in ESCC cells. Taken together, our data show association of Apollon expression with chemotherapeutic response in ESCC, and provide a strong rationale for combining Apollon antagonism with chemotherapy to treat ESCC.     

Toripalimab Plus Paclitaxel and Carboplatin as Neoadjuvant Therapy in Locally Advanced Resectable Esophageal Squamous Cell Carcinoma

IntroductionImmune checkpoint inhibitors (ICIs) are effective in the treatment of advanced esophageal squamous cell carcinoma (ESCC); however, their efficacy in locally advanced resectable ESCC and the potential predictive biomarkers have limited data.MethodsIn this study, locally advanced resectable ESCC patients were enrolled and received neoadjuvant toripalimab (240 mg, day 1) plus paclitaxel (135 mg/m², day 1) and carboplatin (area under the curve 5 mg/mL per min, day 1) in each 3-week cycle for 2 cycles, followed by esophagectomy planned 4-6 weeks after preoperative therapy. The primary endpoints were safety, feasibility, and the major pathological response (MPR) rate; the secondary endpoints were the pathological complete response (pCR) rate, disease-free survival (DFS), and overall survival (OS). Association between molecular signatures/tumor immune microenvironment and treatment response was also explored.ResultsTwenty resectable ESCC patients were enrolled. Treatment-related adverse events (AEs) occurred in all patients (100%), and 4 patients (22.2%) experienced grade 3 or higher treatment-related AEs. Sixteen patients underwent surgery without treatment-related surgical delay, and the R0 resection rate was 87.5% (14/16). Among the 16 patients, the MPR rate was 43.8% (7/16) and the pCR rate was 18.8% (3/16). The abundance of CD8⁺ T cells in surgical specimens increased (P = .0093), accompanied by a decreased proportion of M2-type tumor-associated macrophages (P = .036) in responders upon neoadjuvant therapy. Responders were associated with higher baseline gene expression levels of CXCL5 (P = .03) and lower baseline levels of CCL19 (P = .017) and UMODL1 (P = .03).ConclusionsThe combination of toripalimab plus paclitaxel and carboplatin is safe, feasible, and effective in locally advanced resectable ESCC, indicating its potential as a neoadjuvant treatment for ESCC.Clinical Trial registration{"type":"clinical-trial","attrs":{"text":"NCT04177797","term_id":"NCT04177797"}}NCT04177797     

The safety and efficacy of neoadjuvant PD-1 inhibitor with chemotherapy for locally advanced esophageal squamous cell carcinoma

BackgroundNeoadjuvant therapy followed by esophagectomy has been recognized as an effective treatment for locally advanced esophageal cancer, though still has a dismal prognosis. Antibodies against programmed death 1 (PD-1) protein improve survival in patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) compared with chemotherapy in second-line therapy. However, neoadjuvant PD-1 inhibitor combined with chemotherapy has not been tested in locally advanced ESCC. We conducted this study to evaluate the efficacy and safety of pd-1 inhibitor in neoadjuvant chemotherapy.MethodsIn this study, we administered 28 adults with untreated, surgically resectable locally advanced ESCC. PD-1 inhibitor with chemotherapy [albumin paclitaxel 100 mg/m² on days 1 and 8 + carboplatin with an area under the curve (AUC) of 5 on day 1] were administered every 3 weeks intravenously, and surgery was performed approximately 3–5 weeks after the second dose. The primary purpose of the study was to evaluate the feasibility and safety of this regimen.ResultsIn all, 28 locally advanced ESCC patients were enrolled, 27 patients received surgery, 9 (33.3%) patients’ postoperative pathological specimens suggested pCR, and 11 (40.7%) patients’ primary tumor suggested complete response. Neoadjuvant PD-1 inhibitor with chemotherapy had an acceptable side-effect profile, 26 patients’ tumors were completely resected (96.3% were R0). According to the RESIST v.1.1, the response in all 27 patients was evaluated by a computed tomography (CT) scan before surgery, showing 12 patients with complete response (CR), 12 with partial response (PR), and 3 with stable disease (SD). For surgical procedures, 15 (55.6%) patients underwent minimal invasive surgery, 4 (14.8%) underwent right transthoracic open esophagectomy, and 8 (29.6%) underwent hybrid approaches.ConclusionsThe novel treatment of PD-1 inhibitor with chemotherapy in the neoadjuvant setting for locally advanced ESCC produced satisfactory outcomes: an unprecedentedly high pCR rate for neoadjuvant chemotherapy, a high R0 resection rate, and a low-toxicity profile were achieved. The long-term efficiency of this novel treatment and the validity of the present findings should be confirmed with longer follow-up and prospective comparative trials.     

Tryptophanyl-tRNA Synthetase Sensitizes Hormone Receptor-Positive Breast Cancer to Docetaxel-Based Chemotherapy

PurposeA relatively low response to chemotherapy has been reported for hormone receptor (HR)-positive breast cancer. In this study, we investigated the role of tryptophanyl-transfer RNA synthetase (WARS) in the chemotherapeutic response of HR-positive breast cancer.MethodsPre-chemotherapeutic needle biopsy samples of 45 HR-positive breast cancer patients undergoing the same chemotherapeutic regimen were subjected to immunohistochemistry. To investigate the biological functions of WARS in HR-positive breast cancer, we conducted cell viability assay, flow cytometry analysis, caspase activity assay, Quantitative real-time polymerase chain reaction, and western blotting using WARS gene-modulated HR-positive breast cancer cells (T47D, ZR-75-1, and MCF7).ResultsWARS overexpression in HR-positive breast cancer patients showed a significant correlation with favorable chemotherapy response. Downregulation of WARS increased cell viability following docetaxel treatment in tumor cell lines. On the other hand, WARS overexpression sensitized the therapeutic response to docetaxel. Additionally, downregulation of WARS caused a decrease in the number of apoptotic cell populations by docetaxel. Poly (ADP-ribose) polymerase cleavage and caspase 3/7 activity were increased in docetaxel-treated tumor cells with WARS overexpression.ConclusionOur results suggest that WARS might be a potential predictor for chemotherapy response in patients with HR-positive breast cancer as well as a novel molecular target to improve chemosensitivity.     

The impact of primary tumour origins in patients with advanced oesophageal,oesophago–gastric junction and gastric adenocarcinoma—individual patient data from 1775 patients in four randomised controlled trials

BackgroundIt is unclear if differential chemotherapy effects exist on overall survival (OS), response rate (RR) and toxicity depending on primary tumour origin [oesophageal versus oesophago–gastric junction (OGJ) versus gastric adenocarcinoma].Patients and methodsA total of 2110 patients were enrolled in four randomised controlled trials (RCTs) assessing fluoropyrimidine ± platinum-based chemotherapy. This analysis used individual patient data and restricted to patients with adenocarcinoma who received one or more dose of chemotherapy. Gastric origin was the control in comparisons of tumour origin.ResultsOf the 2110 patients randomised, 1775 (84%) patients had adenocarcinoma with oesophageal (n = 485), OGJ (n = 457) and gastric (n = 833) origins. The median OS was 9.5 months in oesophageal, 9.3 months in OGJ and 8.7 months in gastric cancer (P = 0.68). RR was 44.1% in oesophageal, 41.1% in OGJ and 35.6% in gastric cancers (P = 0.11 and 0.27, respectively, compared with gastric cancer on multivariate analysis). Toxicity composite end point occurred in 46%, 47% and 45% in oesophageal, OGJ and gastric cancers, respectively (P = 0.85 and 0.62 compared with gastric).ConclusionsIn our large multicentre RCT dataset, no significant differences were demonstrated on multivariate analyses in OS, RR and toxic effects among patients with advanced oesophageal, OGJ and gastric adenocarcinoma. Future RCTs should not exclude oesophageal adenocarcinoma.     

Overexpression of PFTK1 predicts resistance to chemotherapy in patients with oesophageal squamous cell carcinoma

Background:

Recently, PFTK1 was identified as a member of the cyclin-dependent kinase family; however, its expression and clinical significance in oesophageal squamous cell carcinoma (ESCC) have not been evaluated.

Methods:

PFTK1 expression was initially examined by expression microarray in 77 ESCC patients. Using independent samples of 223 patients, PFTK1 expression was evaluated immunohistochemically to assess the relationship between expression and various clinicopathological parameters. The association between PFTK1 and the response to chemotherapy was also investigated in pretreatment samples of 85 patients who received chemotherapy as first treatment.

Results:

Significant upregulation of PFTK1 expression was noted in ESCC compared with normal epithelium. PFTK1 expression was positive in 51.6% (115 out of 223) of the tumours, but did not correlate with any clinicopathological parameter. The 5-year overall survival rate was poorer in patients positive for PFTK1 (43.6%) than those with negative expression (66.2%, P<0.001). Uni- and multivariate analyses identified PFTK1 as an independent marker of prognosis (RR=2.428, 95% CI=1.615–3.711, P<0.001). Out of 85 biopsy samples, 40 (47.1%) tumours showed PFTK1-positive expression, and the response rate to chemotherapy was significantly lower than PFTK1-negative tumours (27.9% vs 72.1%, P<0.001).

Conclusion:

PFTK1 is not only useful as a prognostic marker, but also as a predictor of the response to chemotherapy.     

Combined fibrinogen and neutrophil‐lymphocyte ratio as a prognostic marker of advanced esophageal squamous cell carcinoma

Patients with advanced esophageal squamous cell carcinoma (ESCC) is received chemoradiotherapy or chemotherapy for clinical management. However, it is difficult to predict tumor response and prognosis using blood markers before starting treatments. The purpose of this study was to investigate the pre‐treatment plasma fibrinogen and neutrophil–lymphocyte ratio (NLR) in patients with advanced ESCC treated with chemoradiotherapy or chemotherapy, and to assess the clinical utility of a combined score using these blood markers, named as the F‐NLR (fibrinogen and NLR) score, as a predictor of tumor response and prognosis. A total of 98 advanced ESCC patients, treated with chemoradiotherapy or chemotherapy, were classified into three groups: F‐NLR score of 2, having both hyperfibrinogenemia (>400 mg/dL) and high NLR (>3.0), score of 1, one of these hematological abnormalities, and score of 0, having neither hyperfibrinogenemia nor high NLR. Fibrinogen and NLR were significantly higher in the progressive disease (PD) group than the non‐PD group (P = 0.0419, and P = 0.0001, respectively). A significantly higher F‐NLR score was found in the PD group than the non‐PD group (P = 0.0140). Overall survival was significantly lower in patients with an F‐NLR score of 2 than in those with an F‐NLR score of 0 or 1 (P < 0.0001). Multivariate analysis showed that the F‐NLR score was one of the independent prognostic factors (P = 0.0081). Our study demonstrates that the F‐NLR score is promising as a predictive marker for therapeutic effects and prognosis in patients with advanced ESCC.     

Detection of oesophageal cancer biomarkers by plasma proteomic profiling of human cell line xenografts in response to chemotherapy

Background:

The incidence of oesophageal adenocarcinoma is increasing worldwide but survival remains poor. Neoadjuvant chemotherapy may improve survival, but targeting treatment to patients who respond to chemotherapy could be improved by the availability of markers of response. This study sought proteomic markers of therapeutic response using an adenocarcinoma xenograft model.

Methods:

Epirubicin, cisplatin or 5-fluorouracil was administered to severe combined immune-deficient mice bearing OE19 oesophageal adenocarcinoma xenografts. Murine plasma samples from treated and untreated xenografts were analysed by surface-enhanced laser desorption/ionisation time-of-flight mass spectroscopy, and panels of peaks were found using class prediction models that distinguished treatment groups. Proteins in these peaks were identified by mass spectroscopy in tryptic digests of purified fractions. Five paired samples from oesophageal cancer patients before and after chemotherapy were analysed using the same methodology.

Results:

Plasma protein peaks were identified that differed significantly (P<0.05, ANOVA) between the treated xenograft and control groups. Marker panels predicted treated vs untreated xenografts with sensitivities of 100%, specificities of 86–100% and test efficiencies of 89–100%. Three of the proteins identified in these panels, apolipoprotein A-I, serum amyloid A and transthyretin were confirmed in the clinical samples.

Conclusion:

Plasma protein markers can be detected in response to chemotherapy in oesophageal adenocarcinoma xenografts and in clinical samples, and have the potential to monitor response and guide chemotherapy in oesophageal adenocarcinoma.     

Prognostic factors for 495 nonoperative esophageal squamous cancer patients receiving IMRT plus chemotherapy: A retrospective analysis

PurposeChemoradiotherapy is regarded as a standard scheme for inoperable and unresectable esophageal cancers. Our aims were to explore the prognostic factors relevant to esophageal squamous cell carcinoma (ESCC) following intensity-modulated radiation therapy (IMRT) plus chemotherapy.Material and methodsTotally 495 ESCC patients undergoing IMRT combined with chemotherapy in our hospital between 2011 and 2020 were retrospectively analyzed. Potential clinical prognosis-related factors were assessed by uni- and multivariate analyses.ResultsThe median overall survival (OS) and progression-free survival (PFS) of the ESCC patients were 2.25 and 1.24 years, respectively. Uni- and multivariate analyses demonstrated the relevant independent prognostic factors of OS and PFS were gender, T stage, N stage, clinical stage, and tumor location (P < 0.05), but not chemotherapy or radiotherapy dose. We further compared the 5-year OS rates among different T stages, N stages, clinical stages, genders, and tumor locations. The survival rate at the higher clinical stage was significantly lower (P < 0.001). The 5-year OS in the upper thorax of the tumor was 46.0% and exceeded other tumor locations (P < 0.05). The 5-year OS was 56.1% among females and 33.3% among males (P = 0.001).ConclusionsFor ESCC patients receiving IMRT combined with chemotherapy, their long-term curative effects are influenced by T stages, N stages, clinical stages, genders, and tumor locations. ESCC patients who are females, or have upper thoracic tumor, or are at early clinical stage own better prognosis.     

Overexpression of microRNA-223 regulates the ubiquitin ligase FBXW7 in oesophageal squamous cell carcinoma

Background:

F-box and WD repeat domain-containing 7 (FBXW7) is a cell cycle regulatory gene whose protein product ubiquitinates positive cell cycle regulators such as c-Myc, cyclin E, and c-Jun, thereby acting as a tumour-suppressor gene. This study focused on microRNA-223 (miR-223), which is a candidate regulator of FBXW7 mRNA. The aim of this study was to clarify the clinical significance of miR-223 and FBXW7 in oesophageal squamous cell carcinoma (ESCC) patients, and to elucidate the mechanism by which FBXW7 is regulated by miR-223.

Methods:

The expression levels of miR-223 and the expression of FBXW7 protein was examined using 109 resected specimens to determine the clinicopathological significance. We also investigated the role of miR-223 in the regulation of FBXW7 expression in ESCC cell lines in an in vitro analysis.

Results:

We found that miR-223 expression was significantly higher in cancerous tissues than in the corresponding normal tissues. There was a significant inverse relationship between the expression levels of miR-223 and FBXW7 protein. Moreover, patients with high miR-223 expression demonstrated a significantly poorer prognosis than those with low expression. On the basis of a series of gain-of-function and loss-of-function studies in vitro, we identified FBXW7 as a functional downstream target of miR-223.

Conclusion:

Our present study indicates that high expression of miR-223 had a significant adverse impact on the survival of ESCC patients through repression of the function of FBXW7.