Search

Background & Aims Oropharyngeal and esophageal squamous cell carcinomas, especially the latter, are a lethal disease, featuring intratumoral cancer cell heterogeneity and therapy resistance. To facilitate cancer therapy in personalized medicine, three-dimensional (3D) organoids may be useful for functional characterization of cancer cells ex vivo. We investigated the feasibility and the utility of patient-derived 3D organoids of esophageal and oropharyngeal squamous cell carcinomas. Methods We generated 3D organoids from paired biopsies representing tumors and adjacent normal mucosa from therapy-naïve patients and cell lines. We evaluated growth and structures of 3D organoids treated with 5-fluorouracil ex vivo. Results Tumor-derived 3D organoids were grown successfully from 15 out of 21 patients (71.4%) and passaged with recapitulation of the histopathology of the original tumors. Successful formation of tumor-derived 3D organoids was associated significantly with poor response to presurgical neoadjuvant chemotherapy or chemoradiation therapy in informative patients (P = 0.0357, progressive and stable diseases, n = 10 vs. partial response, n = 6). The 3D organoid formation capability and 5-fluorouracil resistance were accounted for by cancer cells with high CD44 expression and autophagy, respectively. Such cancer cells were found to be enriched in patient-derived 3D organoids surviving 5-fluorouracil treatment. Conclusions The single cell-based 3D organoid system may serve as a highly efficient platform to explore cancer therapeutics and therapy resistance mechanisms in conjunction with morphological and functional assays with implications for translation in personalized medicine., Graphical abstract

Interest in the common marmoset (Callithrix jacchus) as a primate model animal has grown recently, in part due to the successful demonstration of transgenic marmosets. However, there is some debate as to the suitability of marmosets, compared to more widely used animal models, such as the macaque monkey and mouse. Especially, the usage of marmoset for animal models of human cognition and mental disorders, is still yet to be fully explored. To examine the prospects of the marmoset model for neuroscience research, the Marmoset Gene Atlas (https://gene-atlas.bminds.brain.riken.jp/) provides a whole brain gene expression atlas in the common marmoset. We employ in situ hybridization (ISH) to systematically analyze gene expression in neonate marmoset brains, which allows us to compare expression with other model animals such as mouse. We anticipate that these data will provide sufficient information to develop tools that enable us to reveal marmoset brain structure, function, cellular and molecular organization for primate brain research.

Background: The oral microbiota is reportedly associated with the gut microbiota and influences colorectal cancer (CRC) progression; however, the details remain unclear. Methods: This study included 52 patients diagnosed with CRC and 51 healthy controls. Saliva and stool samples were collected, and microbiota were evaluated using 16S rRNA analysis and next-generation sequencing. Comparative analysis was performed on both groups. Findings: Linear discriminant analysis Effect Size (LEfSe) revealed indigenous oral bacteria, such as Peptostreptococcus, Streptococcus, and Solobacterium spp., were present at a significantly higher relative abundance in CRC patients compared with controls, consistent for both saliva and stool. LEfSe was also performed after the CRC patients were divided into early stage (Stage I, II; n = 26; 50%) and advanced stage (Stage III, IV; n = 26;, 50%) disease. S. moorei was present at a significantly higher relative abundance in the advanced-stage group compared with the early-stage group, again consistent for both saliva and stool. Interpretation: Among the bacterial species whose relative abundance was significantly higher in CRC patients, P. stomatis, S. anginosus, S. koreensis and S. moorei were apparently supplied from the oral cavity, suggesting indigenous oral bacteria may have promoted initiation of CRC carcinogenesis. Furthermore, S. moorei may influence CRC progression. Funding Statement: This research was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (19K10361)(15H05045). Declaration of Interests: All authors declare no interests. Ethics Approval Statement: The study was conducted in accordance with the “Declaration of Helsinki.” The study protocols were approved by the ethics committee of Kagoshima University. Informed consent was obtained from all the study participants.

SummarySox2 regulates the self-renewal of multiple types of stem cells. Recent studies suggest it also plays oncogenic roles in the formation of squamous carcinoma in several organs, including the esophagus where Sox2 is predominantly expressed in the basal progenitor cells of the stratified epithelium. Here, we use mouse genetic models to reveal a mechanism by which Sox2 cooperates with microenvironmental signals to malignantly transform epithelial progenitor cells. Conditional overexpression of Sox2 in basal cells expands the progenitor population in both the esophagus and forestomach. Significantly, carcinoma only develops in the forestomach, where pathological progression correlates with inflammation and nuclear localization of Stat3 in progenitor cells. Importantly, co-overexpression of Sox2 and activated Stat3 (Stat3C) also transforms esophageal basal cells but not the differentiated suprabasal cells. These findings indicate that basal stem/progenitor cells are the cells of origin of squamous carcinoma and that cooperation between Sox2 and microenvironment-activated Stat3 is required for Sox2-driven tumorigenesis.

Background Recently, neoadjuvant chemoradiation therapy (CRT) has been introduced for treatment of esophageal squamous cell carcinoma (ESCC). This study was performed to investigate the usefulness of endoscopic ultrasonography (EUS) in comparison with EUS findings before and after CRT, and histologic findings. Methods There were 33 patients with potentially resectable ESCC who underwent neoadjuvant CRT. Preoperative EUS and histologic findings were compared. EUS criteria were established on the basis of low and high echoic regions. Resected specimens were examined by hematoxylin-eosin, azan, and cytokeratin immunohistochemical staining. Results Azan and cytokeratin staining clearly delineated fibrous changes and residual tumor. Low echoic regions corresponded to residual tumor and high echoic spots corresponded to fibrosis. All 12 patients classified as grade 1 on EUS diagnosis had histologic grade 1 tumors. Nineteen of 21 cases that presented with high echo were grade 2 or 3. The prognosis according to EUS diagnosis was similar to the histologic effect. Conclusions Preoperative EUS findings reflected the histologic effect after neoadjuvant CRT. EUS is a useful tool to assess the effect for CRT and to predict the prognosis in ESCC patients.

Background: A surplus of reactive oxygen species (ROS) in tissues leads to oxidative stress, resulting in various injurious consequences although ROS plays an important role in normal cellular physiology. As a member of NADPH oxidase family, Duox2 is a major sources of H2O2 for gastrointestinal epithelium. Duox2 expressed in mucosal surfaces is believed as an integral part of host defense system. Duox2 expression was elevated in inflammatory conditions of gastrointestinal and respiratory tracts and human colonic cancer caco-2 cell line. However, the expressions of Duox2 in gastrointestinal cancers are still uncertain. Here we detected the expressions of Duox2 mRNA and protein in the tissues of gastric and colorectal tumors to explore the role of it in the process of gastrointestinal cancers. Methods: The curative tumor tissues from gastric cancer patients (n=30) and colorectal cancer (CRC) patients (n=54) were collected from July 2012 to July 2013 at the first affiliated hospital of Henan university of science and technology. Duox2 protein expressionwas semiquantitatively assessed by immunohistochemical detection in all of both gastric cancer and CRC tissues and their matched normal samples, which were apart away from 5 cm of tumor. Duox2 mRNA expression was evaluated by Real Time PCR (gastric cancer n=16 and CRC n=20). Results: Low level of Duox2 protein expression was found in the epithelium mucosa of gastric and colonic normal tissues, where it was mainly located at the apical membrane in gastric epithelial cells and in the brush border of epithelial cells in colon and rectum. However, the expression of Duox2 protein in both gastric cancer and colorectal cancer were significantly higher than that in each corresponding normal epithelium mucosa (P