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◥Extracellular vesicles (EV) from cancer-associated fibroblasts (CAF) are composed of diverse payloads. Although CAFs impact the aggressive characteristics of gastric cancer cells, the contribution of CAF-EV to gastric cancer progression has not been elucidated. Here, we investigated the molecular mechanism of the changes in gastric cancer characteristics induced by CAF-EV. CAF abundance in gastric cancer tissues was associated with poor prognosis of patients with gastric cancer receiving chemotherapy. Moreover, CAF-EV induced tubular network formation and drug resistance of gastric cancer cells in the extracellular matrix (ECM). Comprehensive proteomic analysis of CAF-EV identified that Annexin A6 plays a pivotal role in network formation and drug resistance of gastric cancer cells in the ECM via activation of b1 integrin-focal adhesion kinase (FAK)-YAP. A peritoneal metastasis mouse model revealed that CAF-EV induced drug resistance in peritoneal tumors, and inhibition of FAK or YAP efficiently attenuated gastric cancer drug resistance in vitro and in vivo. These findings demonstrate that drug resistance is conferred by Annexin A6 in CAF-EV and provide a potential avenue for overcoming gastric cancer drug resistance through the inhibition of FAK-YAP signaling in combination with conventional chemotherapeutics.Significance: This study elucidates a novel molecular mechanism through which Annexin A6 in CAF-EV activates FAK-YAP by stabilizing b1 integrin at the cell surface of gastric cancer cells and subsequently induces drug resistance.

Highlights d EZH2 downregulation leads to SASP maintenance through depletion of H3K27me3 marks d Senescent CAFs in ascites of GC patients with peritoneal dissemination exhibit SASP d Senescent CAFs enhance the peritoneal tumor formation through JAK/STAT3 signaling d A JAK inhibitor blocks peritoneal tumor formation driven by systemic inflammation

Salvage esophagectomy remains correlated with a high incidence of postoperative complications. Avoiding non-curative surgery and reducing the incidence of severe postoperative complications are important if patients are to receive prognostic benefit of this highly invasive surgery.

Over the past few decades, advances in this field have demonstrated that the complexity of cancer is not only dependent on the intrinsic characteristics of tumor cells but also mainly determined by crosstalk between altered cancer cells and various components of the tumor microenvironment (TME). This complexity has become a considerable obstacle in discovering the specific mechanism(s) underlying treatment failure. Many various cell types are present within the TME, including fibroblasts and endothelial, adipose, mesenchymal, and proinflammatory immune cells. 1 Among these cell types, fibroblasts have emerged as a pivotal effector of cancer metabolism and transformation due to their abundance in the tumor stromal tissue and their diverse biological functions. Fibroblasts usually remain in a quiescent state and are flexibly activated and deactivated in response to changes due to tissue damage and wound healing; this results in the generation of myofibroblasts characterized by the expression of α-smooth muscle actin (α-SMA), a fibroblast marker. 2-4 These activated fibroblasts interact closely with tumor cells through multiple mechanisms and produce different results 5 , therefore they are defined as cancer-associated fibroblasts (CAFs) rather than normal fibroblasts (NFs). Among the tumor-promoting functions of CAFs, their reinforcement of chemoresistance is a crucial component due to the importance of establishing an effective anticancer

Chronic inflammation has a crucial role in cancer development and the progression of various tumors, including pancreatic ductal adenocarcinoma (PDAC). The arachidonate cascade is a major inflammatory pathway that produces several metabolites, such as prostaglandin E2. The enzyme 15‐hydroxyprostaglandin dehydrogenase (15‐PGDH) degrades prostaglandin and is frequently decreased in several types of cancer; however, the molecular mechanisms of 15‐PGDH suppression are unclear. The current study was carried out to elucidate the molecular mechanisms and clinical significance of 15‐PGDH suppression in PDAC. Here, we showed that interleukin‐1β (IL‐1β), a pro‐inflammatory cytokine, downregulates 15‐PGDH expression in PDAC cells, and that IL‐1β expression was inversely correlated with 15‐PGDH levels in frozen PDAC tissues. We also found that activated macrophages produced IL‐1β and reduced 15‐PGDH expression in PDAC cells. Furthermore, the number of CD163‐positive tumor‐associated macrophages was shown to be inversely correlated with 15‐PGDH levels in PDAC cells by immunohistochemical staining of 107 PDAC samples. Finally, we found that low 15‐PGDH expression was significantly associated with advanced tumors, presence of lymph node metastasis and nerve invasion, and poor prognosis in PDAC patients. Our results indicate that IL‐1β derived from TAMs suppresses 15‐PGDH expression in PDAC cells, resulting in poor prognosis of PDAC patients.

The incidence rate of esophagogastric junction (EGJ) adenocarcinoma has been rapidly increasing worldwide. Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) are major serum tumor markers in gastrointestinal cancers. However, the role of these markers in EGJ adenocarcinoma has not been thoroughly investigated. A total of 211 patients with EGJ adenocarcinoma who underwent surgery or endoscopic submucosal dissection at two academic institutions, Kumamoto University Hospital or Kyushu University Hospital between January 1996 and March 2014, were eligible for this study. Serum CEA and CA19-9 were examined within 1 month before resection. The cut-off values for CEA and CA19-9 were set at 5.0 ng/mL and 37 U/mL, respectively. The clinicopathological features and prognostic roles of the markers were examined using univariate and multivariate analyses. The positive ratios for preoperative CEA (>5.0 ng/mL) and CA19-9 (>37 U/mL) were 20.3% and 12.9%, respectively. The positive ratio of CEA and CA19-9 was significantly higher in patients with tumors invading muscular or deeper layers (P = 0.002 and <0.001, respectively). Cox proportional hazards model revealed that CA19-9 positivity, but not CEA positivity, was an independent prognostic factor in patients with EGJ adenocarcinoma for cancer-specific survival (multivariate hazard ratio [HR] = 3.89, 95% confidence interval [CI] 1.41–10.33; P = 0.010) and overall survival (multivariate HR = 2.43, 95% CI 1.03–5.35; P = 0.043). Preoperative serum CA19-9 is a useful prognostic marker in patients with EGJ adenocarcinoma.

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