Evaluation of a new surgical procedure for simultaneous resection of synchronous thoracic middle-lower segment esophageal and distal gastric cancers.

Background: An increasing number of patients with synchronous esophageal cancer (EC) and gastric cancer (GC) have been diagnosed in recent years. Colon or jejunal interposition for esophageal reconstruction has been frequently performed. This study aimed to evaluate the technical feasibility of a new surgical procedure for patients with synchronous thoracic middle-lower segment EC and distal GC. Methods: Between July 2012 and December 2021, 18 patients underwent simultaneous esophagectomy and distal gastrectomy, in which the tubular stomach was formed by greater curvature of proximal stomach, with the right gastroepiploic vessels used as the blood supply. Patient demographics and perioperative data were analyzed. Results: All 18 patients were male, with a mean age of 64.9 years (range, 51-72 years). The mean ± standard deviation (SD) operative duration was 249.6±17.4 min (range, 195-275 min) and mean estimated blood loss was 200.0±86.6 mL (range, 100-400 mL). Ten (55.6%) patients recovered well without any complications, with a mean postoperative length of hospitalization of 9.2±2.6 days (range, 6-13 days). Overall, postoperative complications, defined as Clavien-Dindo grades I-V, occurred in eight (44.4%) patients, with anastomotic leakage in four (22.2%), and hydrothorax (11.1%), gastric retention (5.6%), pneumonia (5.6%), and jaundice (5.6%) occurring in two, one, one, and one patient(s), respectively. All patients who experienced complications recovered after treatment, except for one who died of anastomotic leakage. Conclusions: The surgical procedure might be a new treatment option for selected patients with synchronous thoracic middle-lower segment EC and distal GC.

Crocetin suppresses angiogenesis and metastasis through inhibiting sonic hedgehog signaling pathway in gastric cancer.

Gastric cancer (GC) is one of the major causes of cancer-related deaths and chemoresistance is a key obstacle to the treatment of GC, particularly in advanced GC. As an active component of saffron stigma, crocetin has important therapeutic effects on various diseases including tumors. However, the therapeutic potential of crocetin targeting GC is still unclear and the underlying mechanisms are remained to be further explored. In this study, crocetin significantly inhibited angiogenesis in GC, including tubes of HUVECs and vasculogenic mimicry (VM) formation of GC cells. Crocetin also suppressed cell proliferation, migration and invasion. To explore which signaling pathway involving in crocetin, HIF-1α, Notch1, Sonic hedgehog (SHH) and VEGF were examined with crocetin treatment and we found that SHH significantly decreased. Crocetin suppressed SHH signaling with SHH, PTCH2, Sufu and Gli1 protein level decreased in western blot assay. In addition, crocetin suppressed SHH secretion in GC and HUVEC cells. The promoted effects on cell migration induced by secreted SHH were also inhibited by crocetin in GC and HUVEC cell co-culture system. Furthermore, recombinant SHH promoted angiogenesis as well as cell migration and proliferation. However, these promoted effects were reversed by crocetin treatment. These results revealed that crocetin suppressed GC angiogenesis and metastasis through SHH signaling pathway, indicating that crocetin may function as an effective therapeutic drug against GC.

PCDHGA9 represses epithelial-mesenchymal transition and metastatic potential in gastric cancer cells by reducing ß-catenin transcriptional activity.

Gastric cancer (GC) has a high mortality rate, and metastasis is the main reason for treatment failure. It is important to study the mechanism of tumour invasion and metastasis based on the regulation of key genes. In a previous study comparing the expression differences between GES-1 and SGC-7901 cells, PCDHGA9 was selected for further research. In vitro and in vivo experiments showed that PCDHGA9 inhibited invasion and metastasis. A cluster analysis suggested that PCDHGA9 inhibited epithelial-mesenchymal transition (EMT) through the Wnt/ß-catenin and TGF-ß pathways. Laser confocal techniques and western blotting revealed that PCDHGA9 inhibited the nuclear translocation of ß-catenin, regulated T cell factor (TCF)/ /lymphoid enhancer factor (LEF) transcriptional activity, directly impacted the signal transmission of the TGF-ß/Smad2/3 pathway, strengthened the adhesion complex, weakened the effects of TGF-ß, and blocked the activation of the Wnt pathway. In addition, PCDHGA9 expression was regulated by methylation, which was closely related to poor clinical prognosis. The aim of this study was to elucidate the molecular mechanism by which PCDHGA9 inhibits EMT and metastasis in GC to provide a new theoretical basis for identifying GC metastasis and a new target for improving the outcome of metastatic GC.

CTHRC1 promotes gastric cancer metastasis via HIF-1α/CXCR4 signaling pathway.

Metastasis is the main cause of gastric cancer (GC) related death and the underlying mechanisms still remain unclear. Collagen triple helix repeat containing 1 (CTHRC1) protein is known to be involved in tissue remodeling processes and closely associated with carcinogenesis and metastasis in solid tumors, but the functional role of CTHRC1 and its underlying mechanism with tumor metastasis in GC have not been fully illuminated. In the present study, CTHRC1 was highly expressed in tumor tissues and associated with poor prognosis of GC according to TCGA and GEO database. Functional studies revealed that CTHRC1 overexpression in GC significantly increased cell migration and invasion capacity. However, the promoting effects were abolished subsequent to silencing of CXCR4. In addition, CTHRC1 increased CXCR4 expression through upregulating HIF-1α expression, which eventually contributed to the promotion of cell migration and invasion. Inhibiting HIF-1α expression decreased CXCR4 expression and suppressed cell migration and invasion in GC. These results substantiated our hypothesis that HIF-1α/CXCR4 signaling pathway mediated the promoting effect of CTHRC1 on cell migration and invasion in GC.

Potential mechanisms of sleeve gastrectomy for reducing weight and improving metabolism in patients with obesity.

Obesity is a severe medical problem endangering the health of individuals worldwide. Sleeve gastrectomy (SG), one of the most commonly performed bariatric procedures, has been widely applied to the treatment of such patients. Currently, the potential mechanisms underlying the significant weight loss and metabolic improvement after SG have been well studied. First, and most importantly, by removing a large volume of stomach, the SG directly or indirectly restricts food intake. Then, there are alterations in the absorption and metabolism of both macro- and micronutrients, which may benefit or worsen the patients' well-being. Another profound change is enhanced secretion of the satiety gut hormone and reduced secretion of the hunger hormone as a consequence of the operation. Additionally, adjustment of gastrointestinal motility, alteration in the gut microbial community, and an inflammatory response were found after surgery. Therefore, the purpose of the present review was focused on such hypotheses and to compile the accumulated facts on the physiologic mechanism of bariatric surgery so that these results can help improve the understanding of how SG produces substantial weight loss and a significant improvement in the metabolism of patients with metabolic syndrome.

HGF-mediated crosstalk between cancer-associated fibroblasts and MET-unamplified gastric cancer cells activates coordinated tumorigenesis and metastasis.

Cancer-associated fibroblasts (CAFs) are important components of tumor stroma and play a key role in tumor progression. CAFs involve in crosstalk with tumor cells through various kinds of cytokines. In the present study, we screened hepatocyte growth factor (HGF) as a cytokine predominantly originating from CAFs. CAFs-derived HGF was found to promote MET-unamplified gastric cancer (GC) proliferation, migration, and invasion through the activation of HGF/c-Met/STAT3/twist1 pathway. It also activated interleukin (IL)-6/IL-6R/JAK2/STAT3/twist1 pathway by up-regulating IL-6R expression. As IL-6 was also found to upregulate c-Met expression, we identified the cooperation of HGF and IL-6 in enhancing the characteristics of CAFs. In vivo experiments revealed that CAFs-derived HGF promoted tumorigenesis and metastasis of MET-unamplified GC. Gene set enrichment analysis (GSEA) was performed to confirm our findings. Our study found that the increased expression of HGF in CAFs induced by MET-unamplified GC contributed to the malignant phenotype of both MET-unamplified GC and CAFs in tumor microenvironment.

HGF derived from cancer­associated fibroblasts promotes vascularization in gastric cancer via PI3K/AKT and ERK1/2 signaling.

Cancer­associated fibroblasts (CAFs) are predominate cells in tumor stroma and play a key role in tumor progression. Hepatocyte growth factor (HGF) is a cytokine mainly derived from fibroblasts. In the present study, we reported that HGF significantly promoted angiogenesis of human umbilical vein endothelial cells (HUVECs) and vasculogenic mimicry (VM) formation of gastric cancer cells, respectively, by increasing cell proliferation and migration. In addition, mosaic vessels formed by HUVECs and gastric cancer cells were also increased with treatment of recombinant human HGF and conditioned medium from CAFs. The opposite results were achieved in HGF­neutralized groups. In accordance with these observations, we determined that phosphorylation of AKT and ERK1/2 were upregulated in HUVECs and gastric cancer cells with HGF treatment and co­culture with CAFs. Both AKT inhibitor LY294002 and ERK1/2 inhibitor U0126 reduced the ability of angiogenesis and VM formation, as well as mosaic vessel formation induced by HGF. Gene Set Enrichment Analysis and correlation analysis were performed to confirm our findings. In conclusion, CAF­derived HGF promotes angiogenesis, VM and mosaic vessel formation via PI3K/AKT and ERK1/2 signaling in gastric cancer and HGF may serve as a potential therapeutic target for cancer anti­vascular treatment.