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Esophageal cancer is a common type of digestive tract tumor, that occurs when cancer cells develop in the esophagus, a tube-like structure that runs from throat to stomach. Esophageal cancer has become the sixth most common cause of cancer deaths worldwide. There are two main types of esophageal cancer, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC).
Signs and symptoms of esophageal cancer include difficulty swallowing (dysphagia); weight loss; chest pain, pressure, or burning; worsening indigestion or heartburn; coughing or hoarseness.
It's not exactly clear what causes esophageal cancer. However, several factors have been determined that will increase the risk of esophagus cancer. There are having gastroesophageal reflux disease (GERD), smoking, having precancerous changes in the cells of the esophagus (Barrett's esophagus), obesity, drinking alcohol, having bile reflux, having a habit of drinking very hot liquids, have undergone radiation treatment to the chest or upper abdomen, etc.
Signaling pathways are essential components in all cells; they are important to stimulate cell growth, proliferation, differentiation, invasion, and apoptosis. Certain pathways are specifically important in embryonic development, inflammation, and carcinogenesis.TP53 mutation is the most common genetic alteration in esophageal squamous cell carcinoma, along with overexpression of EGFR and CYCLIN D1. WNT and NOTCH signaling pathways may act as activators for EGFR. Additionally, in metastatic ESCC in lymph nodes, phosphorylated-AKT (p-AKT) expression increased, shows that the phosphatidylinositol-3-kinase (PI3K)/AKT pathway has a crucial role in esophageal cancer invasion and metastasis.
In esophageal adenocarcinoma, key pathways include MAP and PI3 Kinase pathways, Wnt signaling, Transforming growth factor-β pathway, nuclear factor-κB pathways, Transcription factors, Tyrosine kinase receptors, etc. RTKs on the cell surface are key activators of MAPK and PI3K pathways. Components of the Wnt signaling pathway are altered in esophageal adenocarcinoma. APC, Axin, and Wnt ligand inhibitors are silenced by loss of heterozygosity or DNA methylation and collectively these events increase β-catenin activity. Transforming growth factor-β (TGF-β) is a tumor suppressor gene and a potent inhibitor of cell growth. Nuclear factor-κB (NF-κB) is a proinflammatory transcription factor. It exists as a heterodimer p50/p65.
Fig. 1 Signaling pathways in esophageal adenocarcinoma
Tests and procedures used to diagnose esophageal cancer include barium swallow study (X-rays), endoscopy, biopsy, IHC, etc. Tests for metastasis detection may include bronchoscopy, endoscopic ultrasound, computerized tomography, positron emission tomography, serum biomarker detection, etc. The serum biomarkers of esophageal cancer mainly include CEA, CA19-9, CYFRA21-1, SCC, etc. Immunohistochemical biomarkers is the most widely applied pathological technique in determining the expression of tumor-associated proteins. There are biomarkers EGFR, p53, VEGF, Cyclin D1, Survivin, Podoplanin, Fascin, p-mTOR, and ER, etc. EGFR can activate several pathways such as ERK/MAPK, PI3K, and JAK/STAT to regulate cell proliferation and migration. An inverse association has been shown between EGFR expression and the survival rate of ESCC patients in which higher levels of EGFR are associated with chemo-radiotherapeutic resistance and lymph node metastasis. In addition, PKM2 indicates an unfavorable prognosis, and three other markers (P27, P16, and E-cadherin) indicate a favorable prognosis of ESCC.
For the treatment of early esophageal cancer, EMR and endoscopic ablation can be applied to remove the tumor. chemotherapy and radiation therapy are also options. For advanced EC, surgery is almost always recommended after chemoradiotherapy. Additionally, targeted therapy and immunotherapy are increasingly used in the treatment of esophageal cancer.
Targeted therapies have been confirmed to play an important role in the treatment of esophageal cancer. These include Cetuximab and Bevacizumab, which target epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), respectively, Trastuzumab (targeting HER2, and used to help treat some HER2-positive cancers of the gastroesophageal (GE) junction), Fam-Trastuzumab deruxtecan (ADC, targeting HER2), Ramucirumab (VEGF inhibitor, blocks VEGF and the process of making new blood vessels), Entrectinib and Larotrectinib (TRK inhibitors, targeting cells with NTRK abnormal gene fusion), Nivolumab and Pembrolizumab (PD-1 inhibitors), and PD-L1 inhibitor pembrolizumab has been approved as a highly efficient drug for patients with PD-L1-positive or advanced ESCC.
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