Alcohol Metabolism Enriches Squamous Cell Carcinoma Cancer Stem Cells That Survive Oxidative Stress via Autophagy

Background: Alcohol (ethanol) consumption is a major risk factor for head and neck and esophageal squamous cell carcinomas (SCCs). However, how ethanol (EtOH) affects SCC homeostasis is incompletely understood. Methods: We utilized three-dimensional (3D) organoids and xenograft tumor transplantation models to investigate how EtOH exposure influences intratumoral SCC cell populations including putative cancer stem cells defined by high CD44 expression (CD44H cells). Results: Using 3D organoids generated from SCC cell lines, patient-derived xenograft tumors, and patient biopsies, we found that EtOH is metabolized via alcohol dehydrogenases to induce oxidative stress associated with mitochondrial superoxide generation and mitochondrial depolarization, resulting in apoptosis of the majority of SCC cells within organoids. However, CD44H cells underwent autophagy to negate EtOH-induced mitochondrial dysfunction and apoptosis and were subsequently enriched in organoids and xenograft tumors when exposed to EtOH. Importantly, inhibition of autophagy increased EtOH-mediated apoptosis and reduced CD44H cell enrichment, xenograft tumor growth, and organoid formation rate. Conclusions: This study provides mechanistic insights into how EtOH may influence SCC cells and establishes autophagy as a potential therapeutic target for the treatment of EtOH-associated SCC

Successful subtotal gastrectomy and hepatectomy for HER2-positive gastric cancer with liver metastasis after trastuzumab-based chemotherapy: a case report

Abstract Background Conversion surgery (CS) after chemotherapy is weakly recommended as a promising tool for improving prognoses in patients with unresectable gastric cancer. Moreover, several investigators have demonstrated the clinical efficacy of subtotal gastrectomy (sTG) with a small remnant stomach for the nutritional status and surgical outcome compared with total gastrectomy. Here, we report a patient with liver metastasis from human epidermal growth factor receptor 2 (HER2)-positive gastric cancer who underwent sTG and hepatectomy after trastuzumab-based chemotherapy. Case presentation An 84-year-old male patient was diagnosed with HER2-positive gastric cancer with a single liver metastasis. He was treated with eight courses of trastuzumab in combination with S-1 and oxaliplatin as first-line chemotherapy. The primary tumor and liver metastasis shrank significantly. The metastatic liver lesion’s reduction rate was 65%. According to the Response Evaluation Criteria in Solid Tumors, the patient had a partial response. Therefore, he underwent an sTG with D2 lymphadenectomy and partial hepatectomy of segment 2. Histopathological examination revealed a grade 3 histological response without lymph node metastases from the primary tumor. No viable cancer cells were observed in the resected liver specimens. The patient received adjuvant chemotherapy with S-1. The postoperative quality of life (QOL) evaluated using the Postgastrectomy Syndrome Assessment Scale-45 was maintained, and the patient was still alive 8 months after the CS without recurrence. Conclusions An sTG with a small remnant stomach might be clinically useful for preventing a decline in QOL and improving prognoses in patients with stage IV gastric cancer after chemotherapy

MicroRNA-Based Cancer Mortality Risk Scoring System and hTERT Expression in Early-Stage Oral Squamous Cell Carcinoma

We have previously constructed a novel microRNA (miRNA)-based prognostic model and cancer-specific mortality risk score formula to predict survival outcome in oral squamous cell carcinoma (OSCC) patients who are already categorized into “early-stage” by the TNM staging system. A total of 836 early-stage OSCC patients were assigned the mortality risk scores. We evaluated the efficacy of various treatment regimens in terms of survival benefit compared to surgery only in patients stratified into high (risk score ≥0) versus low (risk score <0) mortality risk categories. For the high-risk group, surgery with neck dissection significantly improved the 5-year survival to 75% from 46% with surgery only (p<0.001); a Cox proportional hazard model on time-to-death demonstrated a hazard ratio of 0.37 for surgery with neck dissection (95% CI: 0.2–0.6; p=0.0005). For the low-risk group, surgery only was the treatment of choice associated with 5-year survival benefit. Regardless of treatment selected, those with risk score ≥2 may benefit from additional therapy to prevent cancer relapse. We also identified hTERT (human telomerase reverse transcriptase) as a gene target common to the prognostic miRNAs. There was 22-fold increase in the hTERT expression level in patients with risk score ≥2 compared to healthy controls (p<0.0005). Overexpression of hTERT was also observed in the patient-derived OSCC organoid compared to that of normal organoid. The DNA cancer vaccine that targets hTERT-expressing cells currently undergoing rigorous clinical evaluation for other tumors can be repurposed to prevent cancer recurrence in these high-risk early-stage oral cancer patients

Three-Dimensional Organoids Reveal Therapy Resistance of Esophageal and Oropharyngeal Squamous Cell Carcinoma CellsSummary

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. Keywords: 3D Organoids, Autophagy, CD44, 5-Fluorouraci