Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer, and its development, growth, and invasiveness are regulated by the tumor microenvironment (TME). Insulin-like growth factor-binding protein-7 (IGFBP7), which is closely related to various tumors, transforming growth factor-β1 (TGFβ1), which is a key signal mediator in oncogenesis, α-smooth muscle actin (α-SMA), and collagen I are important components of the TME. IGFBP7 can upregulate the expression of TGFβ1 and activate the TGFβ1/SMAD signaling pathway, which leads to an increase in collagen I in hepatic stellate cells (HSCs). However, the contribution of IGFBP7 to TGFβ1 and the TME in the progression of ESCC remains unknown. In the present study, we investigated IGFBP7 expression and its effects on TGFβ1 and the TME in ESCC. A total of 45 patients were divided into three groups: early-tumor group (n=15), advanced-tumor group (n=15), and paracancer control group (n=15). The EC109 cell line was cultured and treated with AdIGFBP7 and LvshTGFβ1, and the expression levels of IGFBP7, TGFβ1, α-SMA, collagen I, and p-SMAD2/3 were determined by immunohistochemical staining and western blotting analysis. IGFBP7, TGFβ1, α-SMA, and collagen I were upregulated in the ESCC samples compared with the control samples (P<0.05), and the values peaked in the advanced-tumor group (P<0.05). Compared with the control group, the TGFβ1, α-SMA, p-SMAD2/3, and collagen I proteins were gradually increased from 24 to 72 h in the EC109 cells treated with AdIGFBP7 (P<0.05). Inhibition of TGFβ1 expression in the EC109 cells treated with AdIGFBP7 gradually reduced the expression of α-SMA, collagen I, and p-SMAD2/3 from 24 to 72 h (P<0.05). These findings suggest that increased IGFBP7 may accelerate the progression of ESCC by upregulating TGFβ1, α-SMA, and collagen I via activating the TGFβ1/SMAD signaling pathway, which could remodel the TME.

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IGFBP7 remodels the tumor microenvironment of esophageal squamous cell carcinoma by activating the TGFβ1/SMAD signaling pathway

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers in the world, with a high rate of morbidity. The invasion and metastasis of ESCC is the main reason for high mortality. More and more evidence suggests that metastasized cancer cells require cellular elements that contribute to ESCC tumor microenvironment (TME) formation. TME contains many immune cells and stromal components, which are critical to epithelial–mesenchymal transition, immune escape, angiogenesis/lymphangiogenesis, metastasis niche formation, and invasion/metastasis. In this review, we will focus on the mechanism of different microenvironment cellular elements in ESCC invasion and metastasis and discuss recent therapeutic attempts to restore the tumor-suppressing function of cells within the TME. It will represent the whole picture of TME in the metastasis and invasion process of ESCC.

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The Role of Tumor Microenvironment in Invasion and Metastasis of Esophageal Squamous Cell Carcinoma

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From NLR to TIN: What Can’t Neutrophils Tell Us About Prognosis in Resectable Esophageal Cancer?

Background Esophageal cancer (EC), a common malignant tumor of digestive tract, is also one of the most deadly cancers. Accumulating studies have shown that the initiating and progressing multiple human diseases were closely related to the expression of MAIP. However, the specific roles and mechanisms of MAIP1 in EC remain incompletely defined. Purpose This study aims to determine the clinical significance of MAIP1 in EC and explores its potential molecular mechanisms regulating tumor immune infiltration. Methods We obtained RNA-seq datasets and corresponding clinical data for EC patients from the Cancer Genome Atlas (TCGA) database via the UCSC Xena browser to extract MAIP1 expression and plot survival curves to determine their prognosis. Based on the differential expression of MAIP1, EC patients were divided into high and low group to investigate the mechanism of MAIP1 in EC. In addition, the single sample gene set enrichment analysis (ssGSEA) quantified the expression of various immune cell signature marker genes and assessed the degree of immune infiltration in EC. Results In the TCGA-EC cohort, the overexpression of MAIP1 was observed in tumor tissues compared to normal tissues (p = 0.0038). Overall survival analysis showed that EC patients with the overexpression of MAIP1 presented a lower overall survival and worse prognosis (p = 0.004). Enrichment analysis revealed that the differential genes (DEGs) between high and low group are involved in biological functions such as extracellular matrix and organization extracellular structure. The results of ssGSEA showed that DCs, iDCs, macrophages, mast cells, and NK cells were significantly different in MAIP1high and MAIP1low groups, and all showed high expression in the MAIP1low group. Conclusion We proposed that MAIP1 overexpression was associated with poor prognosis and tumor immune infiltration in EC. At present, there are few MAIP1-related tumor immune infiltration studies in EC, and further investigation is needed.

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MAIP1-Related Tumor Immune Infiltration: As a Potential Prognostic Biomarker for Esophageal Cancer

Background We aimed to construct nomograms based on clinicopathological features and routine preoperative hematological indices to predict cancer-specific survival (CSS) and disease-free survival (DFS) in patients with stage II/III gastric adenocarcinoma (GA) after radical resection. Methods We retrospectively analyzed 468 patients with stage II/III GA after curative gastrectomy between 2012 and 2018; 70% of the patients were randomly assigned to the training set (n = 327) and the rest were assigned to the validation set (n = 141). The nomogram was constructed from independent predictors derived from the Cox regression in the training set. Using the consistency index, the calibration and the time-dependent receiver operating characteristic curves were used to evaluate the accuracy of the nomogram. Decision curve analysis was used to assess the value of the model in clinical applications. Patients were further divided into low- and high-risk groups based on the nomogram risk score. Results Multivariate Cox model identified depth of invasion, lymph node invasion, tumor differentiation, adjuvant chemotherapy, CA724, and platelet-albumin ratio as covariates associated with CSS and DFS. CA199 is a risk factor unique to CSS. The nomogram constructed using the results of the multivariate analysis showed high accuracy with a consistency index of 0.771 (CSS) and 0.771 (DFS). Moreover, the area under the curve values for the 3-and 5-year CSS were 0.868 and 0.918, and the corresponding values for DFS were 0.872 and 0.919, respectively. The nomogram had a greater clinical benefit than the TNM staging system. High-risk patients based on the nomogram had a worse prognosis than low-risk patients. Conclusion The prognostic nomogram for patients with stage II/III GA after radical gastrectomy established in this study has a good predictive ability, which is helpful for doctors to accurately evaluate the prognosis of patients to make more reasonable treatment plans.

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Development and validation of a nomogram for patients with stage II/III gastric adenocarcinoma after radical surgery

Esophageal cancer (EC) is the eighth most common type of cancer and the sixth leading cause of cancer-related deaths worldwide. At present, the clinical treatment for EC is based mainly on radical surgery, chemotherapy, and radiotherapy. However, due to the limited efficacy of conventional treatments and the serious adverse reactions, the outcome is still unsatisfactory (the 5-year survival rate for patients is less than 25%). Thus, it is extremely important and urgent to identify new therapeutic targets. The concept of tumor microenvironment (TME) has attracted increased attention since it was proposed. Recent studies have shown that TME is an important therapeutic target for EC. Microenvironment-targeting therapies such as immunotherapy and antiangiogenic therapy have played an indispensable role in prolonging survival and improving the prognosis of patients with EC. In addition, many new drugs and therapies that have been developed to target microenvironment may become treatment options in the future. We summarize the microenvironment of EC and the latest advances in microenvironment-targeting therapies in this review.

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Mei Yang

Papers

Targeting the Microenvironment in Esophageal Cancer