Understanding the cellular origin and progression of esophageal cancer using esophageal organoids.

Three-dimensional (3D) organoids are a novel tool to model epithelial cell biology and human diseases of the esophagus. 3D organoid culture systems have been utilized to investigate the pathobiology of esophageal cancer, including both squamous cell carcinoma and adenocarcinoma. Additional organoid-based approaches for study of esophageal development and benign esophageal diseases have provided key insights into esophageal keratinocyte differentiation and mucosal regeneration. These investigations have implications for the identification of esophageal cancer stem cells, as well as the potential to halt malignant progression through induction of differentiation pathways. Patient-derived organoids (PDOs) from human tissue samples allow for unique and faithful in vitro modeling of esophageal cancers, and provide an exciting platform for investigation into personalized medicine and targeted treatment approaches, as well as new models for understanding therapy resistance and recurrent disease. Future directions include high-throughput genomic screening using PDOs, and study of tumor-microenvironmental interactions through co-culture with immune and stromal cells and novel extracellular matrix complexes.

Sachdeva UM ，Shimonosono M ，Flashner S ，Cruz-Acuña R ，Gabre JT ，Nakagawa H ... -  《-》

Etiology, cancer stem cells and potential diagnostic biomarkers for esophageal cancer.

Esophageal cancer (EC) has been a leading cause of cancer death worldwide in part due to late detection and lack of precision treatment. EC includes two major malignancies, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Recent studies reveal that ESCC and EAC have distinct cell of origin and contain cancer stem cells (also known as tumor initiating cells) expressing different cell surface markers. These biomarkers have potentially important values for both early detection and finding effective therapy. In this review we summarize the updated findings for cell of origin and provide an overview of cancer cell biomarkers that have been tested for ESCC and EAC. In addition, we also discuss recent progress in the study of molecular mechanisms leading to these malignancies.

Liu K ，Zhao T ，Wang J ，Chen Y ，Zhang R ，Lan X ，Que J ... -  《-》

Cellular and molecular mechanisms responsible for progression of Barrett's metaplasia to esophageal carcinoma.

Beilstein M ，Silberg D 《-》

Aberrant epithelial-mesenchymal Hedgehog signaling characterizes Barrett's metaplasia.

The molecular mechanism underlying epithelial metaplasia in Barrett's esophagus remains unknown. Recognizing that Hedgehog signaling is required for early esophageal development, we sought to determine if the Hedgehog pathway is reactivated in Barrett's esophagus, and if genes downstream of the pathway could promote columnar differentiation of esophageal epithelium. Immunohistochemistry, immunofluorescence, and quantitative real-time polymerase chain reaction were used to analyze clinical specimens, human esophageal cell lines, and mouse esophagi. Human esophageal squamous epithelial (HET-1A) and adenocarcinoma (OE33) cells were subjected to acid treatment and used in transfection experiments. Swiss Webster mice were used in a surgical model of bile reflux injury. An in vivo transplant culture system was created using esophageal epithelium from Sonic hedgehog transgenic mice. Marked up-regulation of Hedgehog ligand expression, which can be induced by acid or bile exposure, occurs frequently in Barrett's epithelium and is associated with stromal expression of the Hedgehog target genes PTCH1 and BMP4. BMP4 signaling induces expression of SOX9, an intestinal crypt transcription factor, which is highly expressed in Barrett's epithelium. We further show that expression of Deleted in Malignant Brain Tumors 1, the human homologue of the columnar cell factor Hensin, occurs in Barrett's epithelium and is induced by SOX9. Finally, transgenic expression of Sonic hedgehog in mouse esophageal epithelium induces expression of stromal Bmp4, epithelial Sox9, and columnar cytokeratins. Epithelial Hedgehog ligand expression may contribute to the initiation of Barrett's esophagus through induction of stromal BMP4, which triggers reprogramming of esophageal epithelium in favor of a columnar phenotype.

Wang DH ，Clemons NJ ，Miyashita T ，Dupuy AJ ，Zhang W ，Szczepny A ，Corcoran-Schwartz IM ，Wilburn DL ，Montgomery EA ，Wang JS ，Jenkins NA ，Copeland NA ，Harmon JW ，Phillips WA ，Watkins DN ... -  《-》

Biology of Barrett's esophagus and esophageal adenocarcinoma.

The past few years have brought new advances in our understanding of the molecular mechanisms underlying the development of Barrett's esophagus and esophageal adenocarcinoma. Although knowledge of the genetic basis for these conditions has not yet translated into clinically useful biomarkers, the current pace of biomedical discovery holds endless possibilities for molecular medicine to improve the diagnosis and management of patients with these conditions. This article provides a useful conceptual basis for understanding the molecular events involved in the making of Barrett metaplasia and in its neoplastic progression, and provides a rationale for evaluating studies on the application of molecular medicine to the diagnosis and management of patients with Barrett's esophagus and esophageal adenocarcinoma.

Wang DH ，Souza RF 《-》