Understanding Esophageal Cancer: The Challenges and Opportunities for the Next Decade

Yang, Jian-Guang; Liu, Xiguang; Cao, Shiping; Dong, Xiaoying; S, Rao; Cai, Kaican

doi:10.3389/fonc.2020.01727

Cited by 127 publications

(124 citation statements)

References 98 publications

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“… 6 , 7 Moreover, the dramatic development of immune checkpoint inhibitors, such as CTLA-4 and PD-1, suggests amazing therapeutic effects in clinical efficacy. 8 , 9 However, the therapy conditions are not eligible for most ESCC patients, which suggests that more studies on the molecular mechanisms’ elucidation and identifying useful biomarkers for immune checkpoint inhibitors are still urgently needed for cancer immunotherapy. 10 , 11 …”

Section: Introductionmentioning

confidence: 99%

Systematic profiling of ferroptosis gene signatures predicts prognostic factors in esophageal squamous cell carcinoma

et al. 2021

Molecular Therapy - Oncolytics

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We developed a predictive model associated with ferroptosis to provide a more comprehensive view of esophageal squamous cell carcinoma (ESCC) immunotherapy. Gene expression data and corresponding clinical outcomes were obtained from the GEO and The Cancer Genome Atlas (TCGA) databases, and a ferroptosis-related gene set was obtained from the FerrDb database. We identified 45 ferroptosis-related genes that were differentially expressed, including enrichment in genes involved in the immune system process. We established a ferroptosis-related gene-based prognostic model based on the results of univariate Cox regression and multivariate Cox regression analyses, with an area under the curve (AUC) of 0.76 (3 years). We found that the patients with low-risk scores showed a higher proportion of CD8 + T cells, CD4 + memory activated T cells, etc. Finally, a predictive ferroptosis-related prognostic nomogram, which included the predictive values of age, gender, grade, TNM stage, and risk score, was established to predict overall survival. In sum, we developed a ferroptosis-related gene-based prognostic model that provides novel insights into the prediction of ESCC prognosis and identifies the relevance of the immune microenvironment for patient outcomes.

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Section: Introductionmentioning

confidence: 99%

Systematic profiling of ferroptosis gene signatures predicts prognostic factors in esophageal squamous cell carcinoma

et al. 2021

Molecular Therapy - Oncolytics

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“…Currently, most targeting therapies in cancer are directly targeted at activated oncogenes or “gain of function” genetic aberrations, including gene mutation, amplification, and fusion. However, there are very limited studies that have focused on esophageal cancer targeting therapy, most of which target epidermal growth factor receptor, and a very limited number of druggable hotspot mutations have been reported 12,40‐45 . Unfortunately, not all identified mutations or aberrant expressions can be directly targeted.…”

Section: Discussionmentioning

confidence: 99%

Methylation of NRN1 is a novel synthetic lethal marker of PI3K‐Akt‐mTOR and ATR inhibitors in esophageal cancer

Gao

Herman

et al. 2021

Cancer Science

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Wnt, PI3K‐Akt‐mTOR, and NF‐κB pathways were reported to be involved in DNA damage repair (DDR). DDR‐deficient cancers become critically dependent on backup DNA repair pathways. Neuritin 1 (NRN1) is reported to be involved in PI3K‐Akt‐mTOR, and its role in DDR remains unclear. Methylation‐specific PCR, siRNA, flow cytometry, esophageal cancer cell lines, and xenograft mouse models were used to examine the role of NRN1 in esophageal cancer. The expression of NRN1 is frequently repressed by promoter region methylation in human esophageal cancer cells. NRN1 was methylated in 50.4% (510/1012) of primary esophageal cancer samples. NRN1 methylation is associated significantly with age (P < .001), tumor size (P < .01), TNM stage (P < .001), differentiation (P < .001) and alcohol consumption (P < .05). We found that NRN1 methylation is an independent prognostic factor for poor 5‐y overall survival (P < .001). NRN1 inhibits colony formation, cell proliferation, migration, and invasion, and induces apoptosis and G1/S arrest in esophageal cancer cells. NRN1 suppresses KYSE150 and KYSE30 cells xenografts growth in nude mice. PI3K signaling is reported to activate ATR signaling by targeting CHK1, the downstream component of ATR. By analyzing the synthetic efficiency of NVP‐BEZ235 (PI3K inhibitor) and VE‐822 (an ATR inhibitor), we found that the combination of NVP‐BEZ235 and VE‐822 increased cytotoxicity in NRN1 methylated esophageal cancer cells, as well as KYSE150 cell xenografts. In conclusion, NRN1 suppresses esophageal cancer growth both in vitro and in vivo by inhibiting PI3K‐Akt‐mTOR signaling. Methylation of NRN1 is a novel synthetic lethal marker for PI3K‐Akt‐mTOR and ATR inhibitors in human esophageal cancer.

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“…ESCC is the type of esophageal cancer predominant in East Asia, especially in China, where it accounts for more than 90% of cases [ 1 , 2 ]. It has been reported that there are more than 280,000 new cases of ESCC every year in China [ 3 – 6 ].…”

Section: Introductionmentioning

confidence: 99%

Apatinib induces endoplasmic reticulum stress-mediated apoptosis and autophagy and potentiates cell sensitivity to paclitaxel via the IRE-1α–AKT–mTOR pathway in esophageal squamous cell carcinoma

Wang

Tang

et al. 2021

Cell Biosci

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Background Apatinib, a novel vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor, has been approved for the treatment of metastatic gastric cancer and other tumors. Apatinib exerts antiproliferative and proapoptotic effects in different kinds of cancer cells. However, the molecular mechanisms by which apatinib effective against esophageal squamous cell carcinoma (ESCC) have only been partially researched and whether it has a sensitizing effect on paclitaxel remains unclear. Materials and methods The effects of apatinib or paclitaxel on endoplasmic reticulum (ER) stress, autophagy, apoptosis and proliferation of ESCC cell lines were evaluated. Western blot and immunohistochemistry analyses were performed to detect the expression of related genes. The weight and volume of xenograft tumors in mice were measured. Results In the current study, we elucidated the antiproliferative and ER-stress-mediated autophagy-inducing effects of apatinib on ECA-109 and KYSE-150 esophageal squamous cancer cells and identified the underlying mechanisms of its action. We demonstrated that apatinib not only inhibited the proliferation and induced the apoptosis of ESCC cells, but also activated ER stress and triggered protective autophagy. Moreover, inhibiting autophagy by chloroquine (CQ) enhanced the apatinib-induced apoptosis of ESCC cells through the IRE-1α–AKT–mTOR pathway. In addition, we showed, for the first time, the paclitaxel combined with apatinib and CQ exhibited the best antitumor effect on ESCC both in vivo and in vitro via the IRE-1α–AKT–mTOR pathway. Conclusions Our data showed that apatinib induced ER stress, autophagy and apoptosis in ESCC. Inhibiting autophagy by CQ enhanced apatinib-induced apoptosis. The combination of apatinib and CQ sensitized ESCC cells to paclitaxel to induce apoptosis through the IRE-1α–AKT–mTOR signaling pathway, thus providing the basis for its use in innovative anticancer therapeutic strategies. Graphic abstract

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Understanding Esophageal Cancer: The Challenges and Opportunities for the Next Decade

Cited by 127 publications

References 98 publications

Systematic profiling of ferroptosis gene signatures predicts prognostic factors in esophageal squamous cell carcinoma

Systematic profiling of ferroptosis gene signatures predicts prognostic factors in esophageal squamous cell carcinoma

Methylation of NRN1 is a novel synthetic lethal marker of PI3K‐Akt‐mTOR and ATR inhibitors in esophageal cancer

Apatinib induces endoplasmic reticulum stress-mediated apoptosis and autophagy and potentiates cell sensitivity to paclitaxel via the IRE-1α–AKT–mTOR pathway in esophageal squamous cell carcinoma

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