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Diffuse-type gastric cancer (DGC) is a subtype of gastric cancer that is prone to peritoneal dissemination, with poor patient prognosis. Although intercellular adhesion loss between cancer cells is a major characteristic of DGCs, the mechanism underlying the alteration in cell-to-extracellular matrix (ECM) adhesion is unclear. We investigated how DGCs progress and cause peritoneal dissemination through interactions between DGC cells and the tumour microenvironment (TME). P53 knockout and KRAS G12V -expressing (GAN-KP) cells and Cdh1-deleted GAN-KP (GAN-KPC) cells were orthotopically transplanted into the gastric wall to mimic peritoneal dissemination. The GAN-KPC tumour morphology was similar to that of human DGCs containing abundant stroma. RNA sequencing revealed that pathways related to Rho GTPases and integrin-ECM interactions were specifically increased in GAN-KPC cells compared with GAN-KP cells. Notably, we found that Rac Family Small GTPase 1 (RAC1) induces Integrin Subunit Alpha 6 (ITGA6) trafficking, leading to its enrichment on the GC cell membrane. Fibroblasts activate the FAK/AKT pathway in GC cells by mediating extracellular matrix (ECM)-Itga6 interactions, exacerbating the malignant phenotype. In turn, GC cells induce abnormal expression of fibroblast collagen and its transformation into cancer-associated fibroblasts (CAFs), resulting in DGC-like subtypes. These findings indicate that Cdh1 gene loss leads to abnormal expression and changes in the subcellular localization of ITGA6 through RAC1 signalling. The latter, through interactions with CAFs, allows for peritoneal dissemination., Competing Interests: Declaration of competing interest The authors have no competing interests to disclose. Takatsugu Ishimoto is a member of the Editorial Board of the British Journal of Cancer., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Malignant ascites accompanied by peritoneal dissemination contain various factors and cell populations as well as cancer cells; however, how the tumor microenvironment is shaped in ascites remains unclear. Single-cell proteomic profiling and a comprehensive proteomic analysis are conducted to comprehensively characterize malignant ascites. Here, we find defects in immune effectors along with immunosuppressive cell accumulation in ascites of patients with gastric cancer (GC) and identify five distinct subpopulations of CD45(-)/EpCAM(-) cells. Mesothelial cells with mesenchymal features in CD45(-)/EpCAM(-) cells are the predominant source of chemokines involved in immunosuppressive myeloid cell (IMC) recruitment. Moreover, mesothelial-mesenchymal transition (MMT)-induced mesothelial cells strongly express extracellular matrix (ECM)-related genes, including tenascin-C (TNC), enhancing metastatic colonization. These findings highlight the definite roles of the mesenchymal cell population in the development of a protumorigenic microenvironment to promote peritoneal dissemination., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. Analyzing 1,256 gastric samples (1,152 IMs) across 692 subjects from a prospective 10-year study, we identify 26 IM driver genes in diverse pathways including chromatin regulation (ARID1A) and intestinal homeostasis (SOX9). Single-cell and spatial profiles highlight changes in tissue ecology and IM lineage heterogeneity, including an intestinal stem-cell dominant cellular compartment linked to early malignancy. Expanded transcriptome profiling reveals expression-based molecular subtypes of IM associated with incomplete histology, antral/intestinal cell types, ARID1A mutations, inflammation, and microbial communities normally associated with the healthy oral tract. We demonstrate that combined clinical-genomic models outperform clinical-only models in predicting IMs likely to transform to GC. By highlighting strategies for accurately identifying IM patients at high GC risk and a role for microbial dysbiosis in IM progression, our results raise opportunities for GC precision prevention and interception., Competing Interests: Declaration of interests P.T. has stock in Tempus Healthcare, previous funding from Kyowa Hakko Kirin and Thermo Fisher Scientific, and patents/other intellectual property through the Agency for Science and Technology Research, Singapore (all outside the submitted work). K.G.Y. is a co-inventor on patents “Serum MicroRNA Biomarker for the Diagnosis of Gastric Cancer” and “Methods Related to Real-Time Cancer Diagnostics at Endoscopy Utilizing Fiber-Optic Raman Spectroscopy”; a member of Scientific Advisory Board of MiRXES Pte Ltd. He has no stock or shares in the related companies. He has no conflicts of interest to disclose regarding this submitted work. R.S. has received honoraria from MSD, Eli Lilly, BMS, Roche, Taiho, Astra Zeneca, DKSH, and Ipsen; has advisory activity with Bristol Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, MSD, GSK, DKSH, and Astellas; received research funding from Paxman Coolers, MSD, and Natera; and has received travel grants from Roche, Astra Zeneca, Taiho, Eisai, and DKSH., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Hepatocellular carcinoma (HCC) mainly develops from chronic hepatitis. Metabolic dysfunction-associated steatohepatitis (MASH) has gradually become the main pathogenic factor for HCC given the rising incidence of obesity and metabolic diseases. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) degrades prostaglandin 2 (PGE2), which is known to exacerbate inflammatory responses. However, the role of PGE2 accumulation caused by 15 -PGDH downregulation in the development of MASH-HCC has not been determined., Methods: We utilised the steric animal model to establish a MASH-HCC model using wild-type and 15- Pgdh +/- mice to assess the significance of PGE2 accumulation in the development of MASH-HCC. Additionally, we analysed clinical samples obtained from patients with MASH-HCC., Results: PGE2 accumulation in the tumour microenvironment induced the production of reactive oxygen species in macrophages and the expression of cell growth-related genes and antiapoptotic genes. Conversely, the downregulation of fatty acid metabolism in the background liver promoted lipid accumulation in the tumour microenvironment, causing a decrease in mitochondrial membrane potential and CD8+ T-cell exhaustion, which led to enhanced development of MASH-HCC., Conclusions: 15- PGDH downregulation inactivates immune surveillance by promoting the proliferation of exhausted effector T cells, which enhances hepatocyte survival and proliferation and leads to the development of MASH-HCC., Impact and Implications: The suppression of PGE2-related inflammation and subsequent lipid accumulation leads to a reduction in the severity of MASH and inhibition of subsequent progression toward MASH-HCC., (© 2023 The Author(s).)

Fibroblast activation protein (FAP) generally shows low or undetectable expression in most normal tissues but is highly expressed in fibroblasts in almost all carcinomas. FAP is one of the potential molecules to detect activated fibroblasts and has multiple roles in tumour progression. We generated transgenic mice that specifically expressed tdTomato along with FAP promoter activity. Coculturing a mouse gastric cancer cell line and FAP-tdTomato transgenic mouse-derived fibroblasts showed that tdTomato expression was elevated in the cocultured fibroblasts. Moreover, stomach wall transplanted tumours in mice also showed FAP-tdTomato expression in fibroblasts of the stomach and each metastatic legion. These results indicated that FAP-tdTomato expression in fibroblasts was elevated by stimulation through the interaction with cancer cells. Functionally, collagen production was increased in FAP/tdTomato-positive fibroblasts cocultured with mouse cancer cells. These FAP-tdTomato transgenic mice have the potential to be used to investigate real-time FAP dynamics and the importance of FAP expression in tumour development., (© 2022 Federation of European Biochemical Societies.)

Excess stroma and cancer-associated fibroblasts (CAF) enhance cancer progression and facilitate immune evasion. Insights into the mechanisms by which the stroma manipulates the immune microenvironment could help improve cancer treatment. Here, we aimed to elucidate potential approaches for stromal reprogramming and improved cancer immunotherapy. Platelet-derived growth factor C (PDGFC) and D expression were significantly associated with a poor prognosis in patients with gastric cancer, and PDGF receptor beta (PDGFRβ) was predominantly expressed in diffuse-type gastric cancer stroma. CAFs stimulated with PDGFs exhibited markedly increased expression of CXCL1, CXCL3, CXCL5, and CXCL8, which are involved in polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) recruitment. Fibrotic gastric cancer xenograft tumors exhibited increased PMN-MDSC accumulation and decreased lymphocyte infiltration, as well as resistance to anti-PD-1. Single-cell RNA sequencing and spatial transcriptomics revealed that PDGFRα/β blockade reversed the immunosuppressive microenvironment through stromal modification. Finally, combining PDGFRα/β blockade and anti-PD-1 treatment synergistically suppressed the growth of fibrotic tumors. These findings highlight the impact of stromal reprogramming on immune reactivation and the potential for combined immunotherapy for patients with fibrotic cancer., Significance: Stromal targeting with PDGFRα/β dual blockade reverses the immunosuppressive microenvironment and enhances the efficacy of immune checkpoint inhibitors in fibrotic cancer. See related commentary by Tauriello, p. 655., (©2022 American Association for Cancer Research.)

Background: Remodeling the tumor microenvironment (TME) to benefit cancer cells is crucial for tumor progression. Although diffuse-type gastric cancer (DGC) preferentially interacts with the TME, the precise mechanism of the complicated network remains unknown. This study aimed to investigate the mutual activation mechanism underlying DGC progression., Methods: Mass cytometry analysis of co-cultured macrophages, noncancerous fibroblasts (NFs), and DGC cells was performed. RNA sequencing was applied to examine gene expression in fibroblasts. DGC cells were treated with cytokines to examine their effect on characteristic changes. The TCGA and Kumamoto University cohorts were used to evaluate the clinical relevance of the in vitro findings., Results: Cohort analysis revealed that DGC patients had a poor prognosis. The fibroblasts and macrophages interacted with DGC cells to form a cell cluster in the invasive front of DGC tissue. The original 3D triple co-culture system determined the promotional effects of nonmalignant cells on DGC invasive growth. We notably identified a mixed-polarized macrophage cell type with M1/M2 cell surface markers in a triple co-culture system. IL-1β from mixed-polarized macrophages induced the conversion of NFs to cancer-associated fibroblast-like (CAF-like) cells, promoting the malignant phenotype of DGC cells by inducing the secretion of IL-6, IL-24, and leukemia inhibitory factor (LIF). Moreover, IL-6 and colony stimulating factor 2 (GM-CSF) cooperated to maintain the stable state of mixed-polarized macrophages. Finally, we found that mixed-polarized macrophages were frequently detected in DGC tissues., Conclusion: These findings demonstrated that mixed-polarized macrophages exist as a novel subtype through the reciprocal interaction between DGC cells and nonmalignant cells., (© 2022. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

The arachidonic acid cascade is a major inflammatory pathway that produces prostaglandin E 2 (PGE2). Although inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is reported to lead to PGE2 accumulation, the role of 15-PGDH expression in the tumor microenvironment remains unclear. We utilized Panc02 murine pancreatic cancer cells for orthotopic transplantation into wild-type and 15-pgdh +/- mice and found that 15-pgdh depletion in the tumor microenvironment leads to enhanced tumorigenesis accompanied by an increase in cancer-associated fibroblasts (CAFs) and the promotion of fibrosis. The fibrotic tumor microenvironment is widely considered to be hypovascular; however, we found that the angiogenesis level is maintained in 15-pgdh +/- mice, and these changes were also observed in a genetically engineered PDAC mouse model. Further confirmation revealed that fibroblast growth factor 1 (FGF1) is secreted by pancreatic cancer cells after PGE2 stimulation, consequently promoting CAF proliferation and vascular endothelial growth factor A (VEGFA) expression in the tumor microenvironment. Finally, in 15-pgdh +/- Acta2-TK mice, depletion of fibroblasts inhibited angiogenesis and cancer cell viability in orthotopically transplanted tumors. These findings highlighted the role of 15-pgdh downregulation in enhancing PGE2 accumulation in the pancreatic tumor microenvironment and in subsequently maintaining the angiogenesis level in fibrotic tumors along with CAF expansion., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Appendicitis caused by a foreign body is extremely rare. We report a case of chronic appendicitis caused by a perforating fish bone., Case Report: The patient was a 50-year-old Japanese man. He felt dull lower abdominal pain for 2 months and diagnosed as appendicitis caused by a perforating fish bone. He underwent emergency laparoscopic surgery. The fish bone had perforated through the appendix wall. The fish bone was initially removed followed by laparoscopic appendectomy. Pathological investigation revealed a transmural cut line of approximately 0.5 mm that was surrounded by fibrous tissue with inflammation., Conclusion: This is the first reported case of fish bone-induced chronic appendicitis that underwent laparoscopic appendectomy. For optimum outcome, a correct diagnosis based on a detailed consultation and imaging tests, and an operation performed after careful planning are needed., (Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The accidental ingestion of foreign bodies is a common clinical issue. While most foreign bodies pass through the gastrointestinal (GI) tract without complications, a few cases unfortunately result in GI perforation. Fish bones are one of the most frequent foreign bodies found in the GI tract, and they are high-risk objects for GI perforation due to their hard and sharp-pointed ends. Here, we present a rare case of a 64-year-old man with perforation of a colorectal tumor by a fish bone. The patient received emergency Hartmann's operation with lymph node dissection. Although the patient experienced recurrence in the liver rather than peritoneal dissemination, systemic chemotherapy was considerably effective, and conversion therapy with hepatectomy was successfully performed; the patient achieved 5-year relapse-free survival after the operation. To our knowledge, this is the first report of the perforation of a GI tumor by a fish bone. This rare case suggests the significant clinical implication that proper preoperative diagnosis and prompt surgical treatment lead to better postoperative outcomes for patients with tumor perforation by a foreign body., (© 2022. Japanese Society of Gastroenterology.)

Background: Signet ring cell carcinoma (SRCC) is a particular histologic variant of gastric cancer (GC). However, the critical factor related to the aggressive characteristics of SRCC has not been determined., Methods: We collected surgically resected tissues from 360 GC patients in the Kumamoto University cohort and generated survival curves via the Kaplan-Meier method. In vitro, we identified the specific transcript variant of MUC20 in SRCC cells by direct sequencing and investigated the role of MUC20 in GC progression using GC cells with MUC20 silencing and forced expression. In vivo, we examined chemoresistance using MUC20 variant 2 (MUC20v2)-overexpressing non-SRCC cells to construct a xenograft mouse model., Results: We analyzed a comprehensive GC cell line database to identify the specifically expressed genes in gastric SRCC. We focused on MUC20 and investigated its role in GC progression. Survival analysis revealed that GC patients with high MUC20 expression exhibited a poor prognosis and that MUC20 expression was significantly correlated with SRCC histological type. Moreover, we found that gastric SRCC cells specifically expressed MUC20v2, which was dominantly expressed in the cytoplasm. Silencing MUC20v2 caused cell death with characteristic morphological changes in gastric SRCC cells. To further determine the types of cell death, we examined apoptosis, pyroptosis and ferroptosis by detecting cleaved PARP, gasdermin E-N-terminal (GSDME-N), and lipid reactive oxygen species (ROS) levels, respectively. We found that apoptosis and pyroptosis occurred in MUC20-silenced gastric SRCC cells. In addition, MUC20v2-overexpressing GC cells exhibited chemoresistance to cisplatin (CDDP) and paclitaxel (PTX). RNA sequencing revealed that the pathways involved in intracellular calcium regulation were significantly upregulated in MUC20v2-overexpressing GC cells. Notably, forced expression of MUC20v2 in the cytoplasm of GC cells led to the maintenance of mitochondrial calcium homeostasis and mitochondrial membrane potential (MMP), which promoted cell survival and chemoresistance by suppressing apoptosis and pyroptosis. Finally, we investigated the significance of MUC20v2 in a xenograft model treated with CDDP and showed that MUC20v2 overexpression caused chemoresistance by inhibiting cell death., Conclusion: These findings highlight the novel functions of MUC20v2, which may confer cell survival and drug resistance in GC cells., Significance: MUC20v2 protects GC cells from apoptosis and pyroptosis by maintaining mitochondrial calcium levels and mitochondrial membrane potential and subsequently induces drug resistance., (© 2022. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Background: A desmoid tumor is a rare neoplasm that is derived from soft tissues. Although it shows benign characteristics pathologically, local recurrence can occur., Case Report: We herein report the case of a patient with an intraabdominal desmoid tumor that developed 3 years after laparoscopic appendectomy for acute appendicitis. A 59-year-old male visited our emergency room with complaints of abdominal pain and fullness. Abdominal computed tomography revealed distention of the small intestine with a point of obstruction by an intraabdominal tumor-like region. Pathological findings showed that the tumor was compatible with desmoid fibromatosis., Conclusion: In cases with an intraabdominal tumor after laparoscopic surgery, it is important to consider the possibility of a desmoid tumor, since it is difficult to diagnose it accurately before surgery., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Cancer cells craftily adapt their energy metabolism to their microenvironment. Nutrient deprivation due to hypovascularity and fibrosis is a major characteristic of pancreatic ductal adenocarcinoma (PDAC); thus, PDAC cells must produce energy intrinsically. However, the enhancement of energy production via activating Kras mutations is insufficient to explain the metabolic rewiring of PDAC cells. Here, we investigated the molecular mechanism underlying the metabolic shift in PDAC cells under serine starvation. Amino acid analysis revealed that the concentrations of all essential amino acids and most nonessential amino acids were decreased in the blood of PDAC patients. In addition, the plasma serine concentration was significantly higher in PDAC patients with PHGDH-high tumors than in those with PHGDH-low tumors. Although the growth and tumorigenesis of PK-59 cells with PHGDH promoter hypermethylation were significantly decreased by serine starvation, these activities were maintained in PDAC cell lines with PHGDH promoter hypomethylation by serine biosynthesis through PHGDH induction. In fact, DNA methylation analysis by pyrosequencing revealed that the methylation status of the PHGDH promoter was inversely correlated with the PHGDH expression level in human PDAC tissues. In addition to PHGDH induction by serine starvation, PDAC cells showed enhanced serine biosynthesis under serine starvation through 3-PG accumulation via PGAM1 knockdown, resulting in enhanced PDAC cell growth and tumor growth. However, PHGDH knockdown efficiently suppressed PDAC cell growth and tumor growth under serine starvation. These findings provide evidence that targeting the serine biosynthesis pathway by inhibiting PHGDH is a potent therapeutic approach to eliminate PDAC cells in nutrient-deprived microenvironments., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background/aim: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor. Research using an innovative research approach is needed to identify effective biomarkers or therapeutic targets for PDAC. We aimed to identify proteins related to the peritoneal dissemination of PDAC., Materials and Methods: We performed proteomic analysis using ascites samples from patients with advanced PDAC and peritoneal dissemination and patients with liver cirrhosis (LC). Proteins specific to PDAC were identified in comparison to the findings for ascites from patients with LC as a control group., Results: In total, 336 proteins were identified in ascites from patients with PDAC. We identified 18 specific proteins in ascites from patients with advanced PDAC. Among these proteins, CD13, lymphatic vessel endothelial hyaluronan receptor 1, ficolin-3, and V-set and immunoglobulin domain containing 4 were the most frequently detected. In addition, these 18 proteins could be classified into four categories: extracellular matrix, immunity, metabolism, and others., Conclusion: The identified proteins could be informative for developing treatment strategies for patients with PDAC and peritoneal dissemination., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

In the tumor microenvironment, senescent non-malignant cells, including cancer-associated fibroblasts (CAFs), exhibit a secretory profile under stress conditions; this senescence-associated secretory phenotype (SASP) leads to cancer progression and chemoresistance. However, the role of senescent CAFs in metastatic lesions and the molecular mechanism of inflammation-related SASP induction are not well understood. We show that pro-inflammatory cytokine-driven EZH2 downregulation maintains the SASP by demethylating H3K27me3 marks in CAFs and enhances peritoneal tumor formation of gastric cancer (GC) through JAK/STAT3 signaling in a mouse model. A JAK/STAT3 inhibitor blocks the increase in GC cell viability induced by senescent CAFs and peritoneal tumor formation. Single-cell mass cytometry revealed that fibroblasts exist in the ascites of GC patients with peritoneal dissemination, and the fibroblast population shows p16 expression and SASP factors at high levels. These findings provide insights into the inflammation-related SASP maintenance by histone modification and the role of senescent CAFs in GC peritoneal dissemination., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Advanced esophageal cancer often results in esophageal stenosis or tracheoesophageal fistula. Esophageal bypass surgery and esophageal stent insertion are palliative treatments for esophageal cancer. With improvements in metallic stents and the stent insertion technique, esophageal stent insertion appears to be performed more frequently than bypass surgery, worldwide. The aim of this study was to evaluate the outcomes of bypass surgery and stent insertion in our hospital and reevaluate which patients would benefit from bypass surgery., Methods: A total of 70 esophageal cancer patients who could not tolerate oral feeding due to esophageal stenosis or tracheoesophageal fistula underwent palliative treatment [esophageal bypass surgery (N = 34) and esophageal stent insertion (N = 36)] at Kumamoto University. We retrospectively investigated the clinicopathological factors, postoperative outcomes, and complications., Results: Both treatments could significantly improve the amount of food intake and the dietary form (P < 0.01). The length of hospital stay was shorter (P < 0.01) and complications associated with treatment were reduced in the stent group (P = 0.03). The overall survival did not differ significantly between the groups (log rank P = 0.22). Importantly, in the bypass surgery group, the patients who received postoperative treatment had a better prognosis than those who did not receive postoperative treatment (log rank P < 0.01)., Conclusion: Both bypass surgery and stent insertion allowed oral intake in patients who could not tolerate oral feeding because of esophageal stenosis or tracheoesophageal fistula. Considering that patients who undergo stent insertion have a shorter hospital stay and fewer complications, stent insertion may be a better first choice for treatment than bypass surgery. However, bypass surgery may be an option for patients who can tolerate postoperative treatment.

The effectiveness of current chemotherapies for cancer is gradually progressing; however achieving a complete cure through chemotherapy is still difficult and has been the main goal in treatment of advanced cancer. Drug resistance is an issue in cancer therapy, therefore increasing numbers of investigations into drug resistance have focused on the characteristics of the cancer cells themselves. The interaction between the tumor microenvironment (TME) and cancer cells is also intimately involved in the development of drug resistance. Cancer-associated fibroblasts (CAFs) are a predominant component of the TME and affect tumor progression by secreting soluble factors. This review summarizes the most up-to-date knowledge of CAFs and drug resistance in cancer, with a focus on factors secreted from CAFs including proteins, cytokines, extracellular vesicles, and metabolites. A perspective on the potential role of anti-CAF therapies in overcoming CAF-induced drug resistance is also discussed., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

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 β1 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 β1 integrin at the cell surface of gastric cancer cells and subsequently induces drug resistance. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/16/3222/F1.large.jpg., (©2020 American Association for Cancer Research.)

Background: Anatomical esophageal position may affect the short-term outcomes after minimally invasive esophagectomy (MIE). A previous single-institutional retrospective study suggested that the presence of a left-sided esophagus (LSE) made MIE more difficult and increased the incidence of postoperative complications., Methods: The current study was a multicenter retrospective study of 303 patients with esophageal cancer who underwent MIE at six esophageal cancer high-volume centers in Kyushu, Japan, between April 2011 and August 2016. The patients were divided into the LSE (66 patients) and non-LSE groups (237 patients) based on the esophageal position on computed tomography images obtained with the patients in the supine position., Results: Univariate analysis showed that patients with LSE were significantly older than those with non-LSE (69 ± 8 vs. 65 ± 9 years; P = 0.002), had a significantly greater incidence of cardiovascular comorbidity (65.2% vs. 47.7%; P = 0.013), and a significantly longer operating time (612 ± 112 vs. 579 ± 102 min; P = 0.025). Logistic regression analysis verified that LSE was an independent risk factor for the incidence of pneumonia (odds ratio 3.3, 95% confidence interval 1.254-8.695; P = 0.016)., Conclusions: The presence of a LSE can increase the procedural difficulty of MIE and the incidence of morbidity after MIE. Thus, careful attention must be paid to anatomical esophageal position before performing MIE.

Gastric cancer (GC) is a leading cause of cancer-related death worldwide. Cancer stem cells (CSCs) are known to be involved in chemotherapy resistance and the development of metastases. Although CSCs harbor self-renewal and tumorigenic abilities, the immune microenvironment surrounding CSCs provides various factors and supports the maintenance of CSC properties. The current review summarizes the accumulating findings regarding the relationship between the immune microenvironment and gastric CSCs (GCSCs), which will support the possibility of developing novel therapeutic strategies for targeting GCSCs., Competing Interests: The authors declare that they have no conflict of interest.

Increasing lines of evidence show that the malignant behavior of cancer is not exclusively attributable to cancer cells but also radically influenced by cancerous stroma activity and controlled through various mechanisms by the microenvironment. In addition to structural components, such as the extracellular matrix, stromal cells, such as macrophages, endothelial cells, and specifically cancer-associated fibroblasts (CAFs), have attracted substantial attention over recent decades. CAFs provide routes for aggressive carcinomas and contribute to invasion and metastasis through the biochemical alteration and regulation of cancer-related pathways. However, another facet of CAFs that has been neglected by numerous studies is that CAFs might serve as a negative regulator of cancer progression under certain circumstances. The various origins of CAFs, the diverse tissues in which they reside and their interactions with different cancer cells appear to be responsible for this inconsistency. This review summarizes the latest knowledge regarding CAF heterogeneity and offers a novel perspective and a beneficial approach for obtaining an improved understanding of CAFs.

The accumulation of prostaglandin E2 (PGE 2 ) during chronic inflammation has been implicated in the progression of several cancers. Cyclooxygenase is the key synthesizing enzyme of PGE 2 , although the degradation enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) has received considerable attention recently. We investigated the molecular mechanisms of pancreatic ductal adenocarcinoma (PDAC) progression via 15-PGDH downregulation. Here, we found that 15-PGDH expression was inversely correlated with ALDH1, an important cancer stem cell-associated marker indicative of poor prognosis in humans. Moreover, we demonstrated that pharmacological inhibition of 15-PGDH enhanced CYP26A1 expression, leading to depletion of all-trans retinoic acid (ATRA) and expansion of the ALDH1-positive subset in both human PDAC cells and tumor cells of Kras LSL-G12D/+ ; Ptf1a Cre/+ (KC) mice. Furthermore, genetic deletion of 15-Pgdh in KC mice showed PGE 2 accumulation and ATRA depletion in the pancreas, resulting in PDAC with high levels of Aldh1 and Ki-67. Finally, ATRA replacement suppressed 15-PGDH inhibition-induced tumor progression in KC mice, and ATRA treatment attenuated Aldh1 activity in tumor cells isolated from the pancreas of 15-Pgdh -/- KC mice. These findings provide evidence that 15-PGDH inhibition enhances KRAS-driven tumor progression via ATRA depletion in the pancreas. Therefore, ATRA replacement could be a potential strategy for PDAC treatment.

Purpose: This study investigated the predictors associated with early recurrence (i.e. within 12 months) after curative gastrectomy for gastric cancer (GC)., Methods: We evaluated the clinicopathological factors in 429 patients who underwent curative gastrectomy for GC without preoperative chemotherapy and analyzed these factors' associations with early recurrence., Results: Of 429 patients, 57 experienced recurrences, which were associated with gender, diameter, depth of invasion, lymph node (LN) metastasis, the LN ratio (LNr; LNs with metastasis/dissected LNs), lymphatic invasion, vascular invasion, carbohydrate antigen 19-9 (CA19-9) levels, C-reactive protein levels and the neutrophil/lymphocyte ratio. Twenty-one patients (36.8%) recurred within 12 months. Early recurrence was associated with a high LNr (P = 0.0020) and high CA19-9 levels (P = 0.0415). The other factors were not significantly associated with early recurrence. The 12-month recurrence rate was 33.9% in patients with a high LNr and 1.9% in those with a low LNr and 20.3% in patients with high CA19-9 levels and 3.5% in those with low CA19-9 levels. The 12-month recurrence rate was 62.5% in patients with a high LNr and high CA19-9 levels, 18.4% in those with a high LNr or high-CA19-9 levels, and 1.4% in those with a low LNr and low CA19-9 levels., Conclusion: LNr ≥ 0.15 and CA19-9 ≥ 37 U/ml were effective surrogate markers for predicting early recurrence.

Background: The aim of this study was to confirm prognostic factors for salvage esophagectomy for remnant or recurrent esophageal squamous cell carcinoma after definitive chemoradiotherapy., Study Design: We retrospectively analyzed clinicopathological backgrounds of 50 patients who underwent salvage esophagectomy between April 2005 and January 2016. Salvage esophagectomy comprised 40 three-incision esophagectomies, two transhiatal esophagectomies and eight pharyngolaryngoesophagectomies. Independent prognostic factors for overall survival were assessed using Cox regression analysis of the factors., Results: Salvage esophagectomy remains a highly invasive surgery and correlated with a higher incidence of all morbidities of Clavien-Dindo classification (CDc) ≥II, severe morbidities of CDc ≥ IIIb, any pulmonary morbidities and chylorrhea, compared with those in patients without preoperative definitive chemoradiotherapy. Cox regression analysis suggested that R0 resection (hazard ratio [HR] 6.39; 95% confidence interval [CI] 2.03-9.68, P = 0.002), absence of severe complications (HR 4.97; 95% CI 1.70-14.81, P = 0.004) and early pStage (0-II) (HR 3.42; 95% CI 1.24-10.12, P = 0.018) were independent prognostic factors for salvage esophagectomy., Conclusions: 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.

Background: Patients with gastric cancer (GC) are affected by changes in iron status. Before surgery, GC patients are likely to have iron-deficiency anemia; and after gastrectomy, patients suffer from low nutritional status and low iron. This study investigated preoperative iron status associated with prognosis after curative gastrectomy for gastric cancer., Methods: We evaluated preoperative serum hemoglobin (Hgb), Fe and total iron-binding capacity (TIBC) in 298 patients who underwent curative gastrectomy for GC without preoperative chemotherapy, and analyzed these factors' associations with prognosis after surgery., Results: Of the 298 patients, 129 (43.2%) had low Hgb levels, and 33 (11.1%) had low TIBC (< 260 µg/dl) that was not associated with Hgb or Fe level. Patients with low TIBC were significantly associated with older age (≥ 65 years old; P = 0.0085), low albumin (< 3.9 g/dl; P = 0.0388) and high CRP (≥ 0.15 mg/dl; P = 0.0018) in multivariate analysis. Low Fe (< 60 µg/dl) was not associated with disease-free survival (DFS) or overall survival (OS); however, low Fe was associated with longer cancer-specific survival in Stage III GC patients (P = 0.0333). Both low Hgb and low TIBC were significantly associated with shorter DFS (Hgb: P = 0.0433; TIBC: P < 0.0001) and shorter OS (Hgb: P = 0.0352; TIBC: P < 0.0001). Low TIBC were significantly associated with shorter DFS (HR 2.167, 95% CI 1.231-3.639, P = 0.0086) and shorter OS (HR 2.065, 95% CI 1.144-3.570, P = 0.0173) in multivariate Cox hazard regression analysis., Conclusions: Preoperative serum TIBC level of GC patients who undergo curative gastrectomy is a novel prognostic marker in univariate and multivariate analyses.

Background: Pulmonary morbidities after esophagectomy are still common and are a major cause of surgery-related mortality. The relationship between minimally invasive esophagectomy (MIE) and pulmonary morbidities is not clear. The current study aimed to examine the incidence of pulmonary morbidities after MIE and to clarify the associated risk factors., Methods: Between May 2011 and December 2016, 184 patients underwent MIE for esophageal cancer. Clinical data were prospectively collected and analyzed. Patient- and surgery-related factors, relating to pulmonary complications, were compared between the complicated and uncomplicated cases., Results: The incidence of any pulmonary morbidity following MIE was 17.9%. Univariate analysis showed that past heavy smoking [Brinkman index (BI) ≥ 1000], presence of neoadjuvant therapy, advanced clinical stage (stage III, IV), and intraoperative bleeding ≥ 600 g were candidates for being postoperative pulmonary morbidity risk factors. Multivariate analysis suggested that BI ≥ 1000 and advanced clinical stage were independent risk factors for causing pulmonary morbidities., Conclusions: Past heavy smoking and advanced stage are independent risk factors for pulmonary morbidities after MIE. When performing MIE for such cases, various preoperative precautions and careful postoperative monitoring are necessary.

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., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The cancer stem cell (CSC) paradigm suggests that tumors are organized hierarchically. Chugai previously established an LGR5 + human colorectal cancer (CRC) stem-cell-enriched cell line (colorectal CSCs) that expresses well-accepted colorectal CSC markers and that can dynamically switch between proliferative and drug-resistant noncycling states. We performed this study to elucidate the molecular mechanisms responsible for evading cell death in colorectal CSCs mediated by anticancer agents. During the cell cycle arrest caused by anticancer agents, we found that c-Myc expression was substantially decreased in colorectal CSCs. The c-Myc expression alterations were mediated by upregulation of F-box/WD repeat-containing protein 7 (FBXW7), as evidenced through FBXW7-small interfering RNA knockdown experiments that resulted in enhanced cell sensitivity to anticancer agents. Upregulation of FBXW7 following drug treatment was not evident in commercially available cancer cell lines. Colorectal CSCs were induced to differentiation by Matrigel and fetal bovine serum. Differentiated CSCs treated with anticancer agents did not show upregulation of FBXW7 and were more sensitive to irinotecan (CPT-11), highlighting the potential CSC-specific nature of our data. The FBXW7 over-expression was further validated in resected liver metastatic sites in CRC patients after chemotherapy. In conclusion, our study revealed that a CSC-specific FBXW7-regulatory mechanism is strongly associated with resistance to chemotherapeutic agents. Inhibition of FBXW7-upregulation in CSCs following chemotherapy may enhance the response to anticancer agents and represents an attractive strategy for the elimination of colorectal CSCs. Stem Cells 2017;35:2027-2036., (© 2017 AlphaMed Press.)

Background: Primary colonic and dedifferentiated liposarcomas are both remarkably rare. This work describes a case of primary colonic well-differentiated/dedifferentiated liposarcoma and reviews the clinical characteristics and current therapies for liposarcoma tumors., Case Presentation: A 52-year-old woman was referred to our hospital with a submucosal tumor of the ascending colon. Clinical analysis by ultrasound colonoscopy and computed tomography revealed a partially ossified tumor with irregular edges continuous with the muscular layer. High F-18 deoxyglucose uptake was detected by positron emission tomography. Radical resection with lymph node dissection was performed, yielding a tumor specimen approximately 6.5 × 4.0 × 3.2 cm. Neoplastic spindle cell proliferation was found from submucosa to subserosa. Well-differentiated adipose tissue surrounded the tumor, but contained atypical nuclei with condensed chromosomes. Immunohistochemical staining was positive for p16, CDK4, and MDM2 expression. Based on these findings, a diagnosis of well-differentiated/dedifferentiated liposarcoma was given. Dedifferentiated liposarcomas are more aggressive than their well-differentiated, low-grade counterparts. While local recurrence can occur with both tumor types, dedifferentiated liposarcomas are more prone to developing distant metastases. The patient received no postoperative therapy, and no recurrences have been observed 12 months after surgery., Conclusions: Here we report an extremely rare case of well-differentiated/dedifferentiated liposarcoma of the ascending colon. The dedifferentiated component was high-grade liposarcoma and well-differentiated liposarcoma was detected around the main tumor.

Background: The neutrophil-to-lymphocyte ratio (NLR) has been reported to predict the prognosis of various malignant tumors, including esophageal cancer. However, no previous reports have supported the use of the preoperative NLR as an independent prognostic marker focused on superficial (T1) esophageal cancer. The aim of this study was to elucidate the prognostic impact of the preoperative NLR in T1 esophageal cancer., Methods: This retrospective study recruited 245 consecutive patients with T1 esophageal cancer who underwent subtotal esophagectomy between 2005 and 2016. The relationship between the preoperative NLR and clinicopathological characteristics was analyzed., Results: The preoperative NLR was significantly higher in male patients (p = 0.029), patients with T1b esophageal cancer (p = 0.0274), and patients with venous vessel invasion (p = 0.0082). In the Kaplan-Meier analysis, the elevated preoperative NLR was significantly associated with a poorer disease-free survival (p < 0.0001) and overall survival (p = 0.0004). In the multivariate Cox model, the elevated preoperative NLR was an independent prognostic marker for both disease-free survival (p = 0.0013) and overall survival (p = 0.0027)., Conclusion: An elevated preoperative NLR predicts poor prognosis in T1 esophageal cancer, suggesting the utility of the NLR as an easily measurable and generally available independent prognostic marker.

The double stapling technique (DST) is an intestinal reconstruction technique that has been widely adopted in anterior resection (AR) for rectal cancer. However, anastomotic leakage (AL) after the operation remains a major concern for colorectal surgeons. The sharp-angled corner of the remnant rectum that is often created by the ordinary DST can be a risk factor for AL. We have developed a new method of performing intentional oblique transection DST (IOT-DST). Using this technique, the anal side of the rectum is intentionally obliquely transected with linear staplers, and the area of the sharp-angled edge is totally punched out with a circular stapler. Between September 2015 and March 2016, we used the IOT-DST technique in the treatment of 15 consecutive rectal cancer patients and experienced no anastomosis-related complications, including leakage and stenosis. IOT-DST is easy to use and less stressful to perform than other techniques. IOT-DST has the potential to become the standard technique for AR in rectal cancer surgery.

Intestinal metastasis of angiosarcoma is extremely rare. We herein report a case of intestinal perforation due to intestinal metastasis of angiosarcoma. The patient was a 72-year-old Japanese man with multiple recurrent angiosarcomas of the scalp. He developed acute abdominal pain with guarding, and we performed an emergency exploratory laparotomy. An intestinal perforation was found 80 cm from the ligament of Treitz, and partial jejunectomy was successfully performed. Macroscopic inspection revealed no obvious injury, ulcer, or tumor at or around the perforation site. Pathological examination revealed angiosarcoma cells penetrating through all layers of the jejunum at the site of intestinal perforation. This is the first reported case of intestinal perforation caused by indistinguishable intestinal metastasis of angiosarcoma. This case emphasizes intestinal metastasis of angiosarcoma as a possible cause of small bowel perforation in patients with advanced angiosarcoma, even when no visible tumor is present during surgery.

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., (© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

A 63-year-old man diagnosed with locally advanced pancreatic ductal adenocarcinoma (PDAC; stage IIa) was treated with chemotherapy (gemcitabine, 5-fluorouracil and cisplatin) followed by radiotherapy. He had complete response by imaging and relapse-free survival for 11 years. However, he subsequently presented with local tumor recurrence and underwent pancreaticoduodenectomy followed by chemotherapy; a partial response was achieved. As in liver metastasis of colonic cancer, complete response by imaging in PDAC may not mean pathological complete response. We would propose the importance of adjuvant surgery for a patient with PDAC with complete response by imaging after chemoradiotherapy., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)