Peritoneal Metastasis Of Gastric Cancer Research Articles

Dynamic change in the peritoneal cancer index based on CT after chemotherapy in the overall survival prediction of gastric cancer patients with peritoneal metastasis

PurposeThe purpose of this research was to investigate the efficacy of the CT-based peritoneal cancer index (PCI) to predict the overall survival of patients with peritoneal metastasis in gastric cancer (GCPM) after two cycles of chemotherapy.MethodsThis retrospective study registered 112 individuals with peritoneal metastasis in gastric cancer in our hospital. Abdominal and pelvic enhanced CT before and after chemotherapy was independently analyzed by two radiologists. The PCI of peritoneal metastasis in gastric cancer was evaluated according to the Sugarbaker classification, considering the size and distribution of the lesions using CT. Then we evaluated the prognostic performance of PCI based on CT, clinical characteristics, and imaging findings for survival analysis using multivariate Cox proportional hazard regression.ResultsThe PCI change ratio based on CT after treatment (ΔPCI), therapy lines, and change in grade of ascites were independent factors that were associated with overall survival (OS). The area under the curve (AUC) value of ΔPCI for predicting OS with 0.773 was higher than that of RECIST 1.1 with 0.661 (P < 0.05). Patients with ΔPCI less than −15% had significantly longer OS.ConclusionCT analysis after chemotherapy could predict OS in patients with GCPM. The CT-PCI change ratio could contribute to the determination of an appropriate strategy for gastric cancer patients with peritoneal metastasis.

68Ga-FAPI-04 positron emission tomography/CT and laparoscopy for the diagnosis of occult peritoneal metastasis in newly diagnosed locally advanced gastric cancer: study protocol of a single-centre prospective cohort study

IntroductionAccurate baseline clinical staging is critical to inform treatment decision-making for patients with gastric cancers. Peritoneal metastasis (PM) is the most common form of metastasis in gastric cancer and mainly...

Dual-energy CT quantitative parameters to evaluate occult peritoneal metastasis in advanced gastric cancer preoperatively.

To explore whether dual-energy CT (DECT) quantitative parameters could provide analytic value for the diagnosis of patients with occult peritoneal metastasis (OPM) in advanced gastric cancer preoperatively. This retrospective study included 219 patients with advanced gastric cancer and DECT scans. The patient's clinical data and DECT related iodine concentration (IC) parameters and effective atomic number (Zeff) were collated and analyzed among noun-peritoneal metastasis (NPM), OPM and radiologically peritoneal metastasis (RPM) groups. The predictive performance of the DECT parameters was compared with that of the conventional CT features and clinical characteristics through evaluating area under curve of the precision-recall (AUC-PR), F1 score, balanced accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). Borrmann IV type diagnosed on CT and serum tumor indicator CA125 index were statistically different between the NPM and OPM groups. DECT parameters included IC, normalized IC (NIC), and Zeff of PM group were lower than the NPM group. The DECT predictive nomogram combined three independent DECT parameters produced a better diagnostic performance than the conventional CT feature Borrmann IV type and serum CA125 index in AUC-PR with 0.884 vs 0.368 vs 0.189, but similar to the combined indicator which was based on the DECT parameters, the conventional CT feature, and serum CA125 index in AUC-PR with 0.884 vs 0.918. The lower quantitative NIC, IC ratio, and Zeff on DECT was associated with peritoneal metastasis in advanced gastric cancer and was promising to identify patients with OPM noninvasively.

Abstract LB264: Intracavitary gene therapy using miRNA-29b-encoding adeno-associated virus for peritoneal dissemination

Abstract INTRODUCTION: Peritoneal metastasis (PM) is the most critical prognostic factor in gastrointestinal cancers. Notably, the levels of microRNA (miR)-29b in peritoneal fluids have shown significant reduction in patients with PM of gastric cancer. Moreover, supplementation with miR-29b-incorporated exosomes has demonstrated the potential to suppress the formation of PM in a murine model. Nevertheless, given the technical demands associated with this method, we investigated the viability of intracavitary gene therapy as a potentially more advanced and practical approach for clinical implementation. METHODS: Using the calcium phosphate-based protocol, adeno-associated virus encoding miR-29b (AAV-miR-29b) was constructed, and its effects on mesothelial mesenchymal transition (MMT) were examined using peritoneal mesothelial cells (PMC) derived from human and murine omental tissues. PM was established in C57BL/6 mouse by intraperitoneal (IP) injection of a highly metastatic clone of gastric cancer cell, YTN16P or a pancreatic cancer cell, PAN02. In these syngeneic models, we examined the impact of IP injection of AAV-miR-29b at a single dose of 5 × 1010 vector genome (vg) on PM. RESULTS: AAV-miR-29b was effectively incorporated into PMCs, resulting in an increased level of miR-29b in extracellular vesicles produced by PMCs. Stimulation of PMCs with TGF-β1 (10ng/ml) decreased the expression of E-cadherin and increased vimentin and fibronectin expression along with enhanced migration activity. Importantly, all the changes were totally abrogated by AAV-miR-29b. Treatment of PMC with TGF-β1 notably increased the attachment of tumor cells, which was also entirely inhibited by AAV-miR-29b. Following IP administration of AAV-miR-29b in vivo, the expression level of miR-29b in peritoneal tissue and intraperitoneal exosomes increased significantly after two weeks. In both murine gastric and pancreatic cancer models, a single IP injection of AAV-miR-29b on day 0 led to a marked reduction in the number of PM nodules in the mesentery (gastric: 38.2 ± 18.7 vs. 8.0 ± 5.2, n=5, P &amp;lt; 0.05; pancreatic: 41.2 ± 7.5 vs. 14.4 ± 16.7, n=7, P &amp;lt; 0.001) and inhibited peritoneal fibrosis associated with PM. AAV-miR-29b elicits the same significant effects when administered on day3. Furthermore, when AAV-miR-29b was administered on day 7 in combination with low-dose Paclitaxel (PTX) (200 µg/mouse), a significant reduction in the number of PM nodules was observed, whereas the effect was not evident with PTX alone (35.8 ± 22.2, n=16 vs. 14.2 ± 16.0, n=12, P &amp;lt; 0.05). CONCLUSIONS: IP injection of AAV-miR-29b achieved robust transgene expression in PMCs and their exosomes, effectively suppressing MMT and peritoneal fibrosis leading to the inhibition of PM Intraabdominal gene therapy utilizing AAV containing tumor-suppressor miRNA could serve as a promising strategy for both the prevention and treatment of PM. Citation Format: Yuki Kaneko, Hideyuki Ohzawa, Yuki Kimura, Rei Takahashi, Misaki Matsumiya, Kohei Tamura, Yurie Futoh, Hideyo Miyato, Ryota Watano, Hiroaki Mizukami, Naohiro Sata, Joji Kitayama. Intracavitary gene therapy using miRNA-29b-encoding adeno-associated virus for peritoneal dissemination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB264.

Functional remodeling of intraperitoneal macrophages by oncolytic adenovirus restores anti-tumor immunity for peritoneal metastasis of gastric cancer

Intraperitoneal tumor-associated macrophages (TAMs) are involved in evading anti-tumor immunity and promoting the peritoneal metastasis (PM) of gastric cancer (GC). Oncolytic viruses are known to induce the activation of host anti-tumor immunity in addition to tumor lysis. This study investigated whether a wild-type p53-loading telomerase-specific oncolytic adenovirus (OBP-702) could elicit the remodeling of intraperitoneal macrophages and enhance the efficacy of immune therapy. Increased numbers of CD163 TAMs and few CD8+ lymphocytes were immunohistochemically observed in clinical samples with PM, which suggested that TAMs were associated with the suppression of anti-tumor immunity. OBP-702 induced immunogenic cell death and upregulated PD-L1 expression in human and murine GC cell lines. Intraperitoneal administration of OBP-702 increased recruitment of CD8+ lymphocytes into the PM via the functional remodeling of intraperitoneal macrophages from TAM towards a pro-inflammatory phenotype, resulting in significantly suppressed tumor growth for the in vivo model. Furthermore, the combination of intraperitoneal OBP-702 with anti-PD-1 Antibody enhanced anti-tumor immunity and prolonged the survival of mice bearing PM. Intraperitoneal immunotherapy using OBP-702 restores anti-tumor immunity via the remodeling of intraperitoneal macrophages in addition to direct tumor lysis and cooperates with immune checkpoint inhibitors to suppress PM in GC.

Abstract 1497: Humanized mouse model unveils niche conditioning in gastric cancer peritoneal metastasis

Abstract Background: Peritoneal metastases (PM) in gastric cancer (GC) portend a poor prognosis. Yet, biological mechanisms underpinning peritoneal colonization and transcoelomic metastases remain unclear. Utilizing a novel humanized mouse model of GCPM, we seek to understand the evolution of the peritoneum to allow for peritoneal dissemination. The humanized mouse model, defined as mice engrafted with functional human cells or tissues, was selected as the host immune system appears to play a significant role in the mechanisms of transcoelomic metastases. Methodology: Humanized (humice) and NOD-scid Il2rγnull (NSG) mice models were injected with GSU (diffuse type) GC cell lines in the flank (subcutaneous), stomach (orthotopic) and directly into the peritoneum (intra-peritoneal). After 1 month, the mouse models were sacrificed and samples from the primary tumor (PT), PM and adjacent peritoneum were retrieved. The tumors were then harvested, along with normal/adjacent peritoneum and bulk RNA-seq was performed and analyzed. Results: Fifty-six samples including PT, PM were harvested from 10 humice and 11 NSG models and were analysed with whole transcriptome sequencing. All models with orthotopic inoculation were found to create PM while no gross PM were appreciated in models with flank inoculation. Principal component analysis mapping of samples demonstrated transcriptomic distinction between normal peritoneum from the flank humice model and adjacent normal samples in the orthotopic and intra-peritoneal humice model. Compared to adjacent peritoneum of the intra-peritoneal humanized mouse model, the orthotopic model appeared to be more tumorigenic with enriched epithelial mesenchymal transition (EMT), stromal and immune infiltration, inflammatory response (IL2-STAT5, IL6-JAK-STAT3, TGF-β signaling), IFN-γ response signatures. Enrichment scores of these pathways were likewise more pronounced in adjacent normal peritoneal samples in the orthotopic humanized mouse model when contrasted against other sample types. Higher expression of M2 macrophages, B cells and T regs, dendritic cells (activating and resting) was found in adjacent peritoneum in the orthotopic model. Collectively, these describe a phenomenon in which the adjacent uninvolved peritoneum has evolved into a tumorigenic environment to facilitate transcoelomic metastasis. These unique niche changes of the peritoneum were conversely not appreciated in the NSG model. Conclusion: We unveil novel insights that delve into the mechanistic role of the host immune system in orchestrating tumorigenic microenvironmental alterations to support peritoneal organotropism. These provide functional proof alluding to the phenomenon of peritoneal niche conditioning in GC PM. Citation Format: Joseph J. Zhao, Daryl Kai Ann Chia, Zhisheng Her, Haoran Ma, Xuewen Ong, Su Ting Tay, Jimmy Bok Yan So, Qingfeng Chen, Patrick Tan, Raghav Sundar. Humanized mouse model unveils niche conditioning in gastric cancer peritoneal metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1497.

Abstract 1491: The enhanced formation of neutrophil extracellular traps (NETs) may contribute to the exacerbation of peritoneal metastasis in a diabetic host

Abstract Background: Diabetes is associated with increased risk of cancer development and progression. Recent studies have shown that neutrophils in diabetic patients are prone to forming neutrophil extracellular traps (NETs) which have been reported to capture circulating cancer cells, leading to the promotion of liver and lung metastasis. This study aims to clarify the causative relationship between NETs and the peritoneal metastasis (PM) in diabetic condition. Methods: Outcome of the diabetic patients who received curative gastrectomy for gastric cancer from 2010 to 2021 in our institute was comparatively investigated with those without diabetes. Neutrophils were isolated from the bone marrow from C57BL/JHamSlc-ob/ob mouse (type 2 diabetes model) and wild type mouse using Ly6G-based positive immunomagnetic selection. The neutrophils were stimulated with 100nM of PMA for 4 hours and NETs formation was evaluated by the addition of Sytox Green under fluorescent microscope. A mouse gastric cancer cell, YTN16P (5 × 105 cells) was intraperitoneally (IP) injected, the number of metastatic nodules on mesentery was comparatively evaluated two weeks later. Results: Disease-free survival (p=0.004, HR=1.65) and overall survival (p=0.035, HR=1.46) of 203 diabetic patients were significantly worse those of 975 non-diabetic patients. Neutrophils isolated from ob/ob mice produced markedly increased NETs than that from wild-type mice. NETs produced by neutrophils obtained from the peritoneal cavity of ob/ob mice after IP injection of a 9% casein solution effectively captured many YTN16P in vitro. The concentration of double strand DNA (dsDNA) in plasma in ob/ob mice compared with their counterparts (676ng/mL vs 590ng/mL, p=0.036, n=3). The number of PM in ob/ob mice was significantly more than that in wild-type controls (39.1 vs 15.5, p=0.027, n=10). Conclusion: Enhanced NETs formation in diabetic conditions may be associated with an increased risk of PM in gastric cancer. Citation Format: Rei Takahashi, Hideyuki Ohzawa, Yuki Kaneko, Misaki Matsumiya, Yurie Futoh, Kohei Tamura, Kazuya Takahashi, Yuki Kimura, Akira Saito, Hideyo Miyato, Naohiro Sata, Joji Kitayama. The enhanced formation of neutrophil extracellular traps (NETs) may contribute to the exacerbation of peritoneal metastasis in a diabetic host [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1491.

Nanocluster/metal-organic framework nanosheet-based confined ECL enhancement biosensor for the extracellular vesicle detection

Gastric cancer (GC) was one of the most common cancers with high mortality. The detection of GC peritoneal metastasis had important significance. In this work, we have developed the novel electrochemiluminescence (ECL) biosensor to detect microRNA in GC extracellular vesicle (EV). Firstly, in situ growth of Cu nanocluster (Cu NC) on the metal-organic frameworks (MOFs) nanosheet was achieved successfully. Due to the confinement effect, Cu NCs in the porous structure of Zn MOF possessed the high quantum yield and good stability. Meanwhile, Zn MOF provided good electrochemical activity for the ECL reaction. Furthermore, the nanosized MOFs did not only act as sensing platform to load Cu NCs and link biomolecules, but also reduce steric hindrance effect for biomolecular recognition. Additionally, Au NPs/MXene and phospholipid layer were prepared and modified on the electrode, which can regulate electron transfer and improve the target recognition efficiency. The Cu NCs/Zn MOF nanosheet-based ECL sensor was employed to detect miRNA-421 from 1 fM to 1 nM with a detection limit of 0.5 fM. Finally, extracellular vesicles form clinic GC patient ascites were extracted and analyzed. The results showed that the constructed biosensor can be used for the GC peritoneal metastasis diagnosis.

TGF-β-driven LIF expression influences neutrophil extracellular traps (NETs) and contributes to peritoneal metastasis in gastric cancer

Gastric cancer (GC), notorious for its poor prognosis, often advances to peritoneal dissemination, a crucial determinant of detrimental outcomes. This study intricately explores the role of the TGFβ-Smad-LIF axis within the tumor microenvironment in propagating peritoneal metastasis, with a specific emphasis on its molecular mechanism in instigating Neutrophil Extracellular Traps (NETs) formation and encouraging GC cellular functions. Through a blend of bioinformatics analyses, utilizing TCGA and GEO databases, and meticulous in vivo and in vitro experiments, LIF was identified as pivotally associated with GC metastasis, notably, enhancing the NETs formation through neutrophil stimulation. Mechanistically, TGF-β was substantiated to elevate LIF expression via the activation of the Smad2/3 complex, culminating in NETs formation and consequently, propelling peritoneal metastasis of GC. This revelation uncovers a novel potential therapeutic target, promising a new avenue in managing GC and mitigating its metastatic propensities.

Low-dose radiotherapy synergizes with iRGD-antiCD3-modified T cells by facilitating T cell infiltration

Background and purposePoor penetration of transferred T cells represents a critical factor impeding the development of adoptive cell therapy in solid tumors. We demonstrated that iRGD-antiCD3 modification promoted both T cell infiltration and activation in our previous work. Interest in low-dose radiotherapy has recently been renewed due to its immuno-stimulatory effects including T cell recruitment. This study aims to explore the synergistic effects between low-dose radiotherapy and iRGD-antiCD3-modified T cells. Materials and methodsFlow cytometry was performed to assess the expression of iRGD receptors and chemokines. T cell infiltration was evaluated by immunohistofluorescence and in vivo real-time fluorescence imaging and antitumor effects were investigated by in vivo bioluminescence imaging in the gastric cancer peritoneal metastasis mouse model. ResultsWe found that 2 Gy irradiation upregulated the expression of all three iRGD receptors and T-cell chemokines. The addition of 2 Gy low-dose irradiation boosted the accumulation and penetration of iRGD-antiCD3-modified T cells in peritoneal tumor nodules. Combining 2 Gy low-dose irradiation with iRGD-antiCD3-modified T cells significantly inhibited tumor growth and prolonged survival in the peritoneal metastasis mouse model with a favorable safety profile. ConclusionAltogether, we demonstrated that low-dose radiotherapy could improve the antitumor potency of iRGD-antiCD3-modified T cells by promoting T cell infiltration, providing a rationale for exploring low-dose radiotherapy in combination of other adoptive T cell therapies in solid tumors.

Nanomechanical Analysis of Living Small Extracellular Vesicles to Identify Gastric Cancer Cell Malignancy Based on a Biomimetic Peritoneum.

Gastric cancer is one of the most prevalent digestive malignancies. The lack of effective in vitro peritoneal models has hindered the exploration of the potential mechanisms behind gastric cancer's peritoneal metastasis. An accumulating body of research indicates that small extracellular vesicles (sEVs) play an indispensable role in peritoneal metastasis of gastric cancer cells. In this study, a biomimetic peritoneum was constructed. The biomimetic model is similar to real peritoneum in internal microstructure, composition, and primary function, and it enables the recurrence of peritoneal metastasis process in vitro. Based on this model, the association between the mechanical properties of sEVs and the invasiveness of gastric cancer was identified. By performing nanomechanical analysis on sEVs, we found that the Young's modulus of sEVs can be utilized to differentiate between malignant clinical samples (ascites) and nonmalignant clinical samples (peritoneal lavage). Furthermore, patients' ascites-derived sEVs were verified to stimulate the mesothelial-to-mesenchymal transition, thereby promoting peritoneal metastasis. In summary, nanomechanical analysis of living sEVs could be utilized for the noninvasive diagnosis of malignant degree and peritoneal metastasis of gastric cancer. This finding is expected to contribute future treatments.

Unveiling the oncogenic role of CLDN11-secreting fibroblasts in gastric cancer peritoneal metastasis through single-cell sequencing and experimental approaches

BackgroundFibroblasts are necessary to the progression of cancer. However, the role of fibroblasts in peritoneal metastasis (PM) of gastric cancer (GC) remains elusive. In this study, we would explore the role of fibroblasts mediated cell interaction in PM of GC. MethodsSingle-cell sequencing data from public database GSE183904 was used to explore the specific fibroblast cluster. Fibroblasts were extracted from PM and GC tissues. The expression level of CXCR7 was verified by western blot, immunohistochemistry. The role of CLDN11 was investigate through in vitro and in vivo study. Multiple immunohistochemistry was used to characterize the tumor microenvironment. ResultsCXCR7-positive fibroblasts were significantly enriched in PM of GC. CXCR7 could promote the expression of CLDN11 through activation of the AKT pathway in fibroblasts. Fibroblasts promote the GC proliferation and peritoneal metastasis by secreting CLDN11 in vitro and in vivo. Furthermore, it was revealed that CXCR7-positive fibroblasts were significantly associated with M2-type macrophages infiltration in tissues. ConclusionCXCR7-positive fibroblasts play an essential role in PM of GC via CLDN11. Therapy targeting CXCR7-positive fibroblasts or CLDN11 may be helpful in the treatment of GC with PM.

G-protein-coupled estrogen receptor 1 promotes peritoneal metastasis of gastric cancer through nicotinamide adenine dinucleotide kinase 1-mediated redox modulation.

Adipose tissue is the second most important site of estrogen production, where androgens are converted into estrogen by aromatase. While gastric cancer patients often develop adipocyte-rich peritoneal metastasis, the underlying mechanism remains unclear. In this study, we identified the G-protein-coupled estrogen receptor (GPER1) as a promoter of gastric cancer peritoneal metastasis. Functional invitro studies revealed that β-Estradiol (E2) or the GPER1 agonist G1 inhibited anoikis in gastric cancer cells. Additionally, genetic overexpression or knockout of GPER1 significantly inhibited or enhanced gastric cancer cell anoikis invitro and peritoneal metastasis invivo, respectively. Mechanically, GPER1 knockout disrupted the NADPH pool and increased reactive oxygen species (ROS) generation. Conversely, overexpression of GPER1 had the opposite effects. GPER1 suppressed nicotinamide adenine dinucleotide kinase 1(NADK1) ubiquitination and promoted its phosphorylation, which were responsible for the elevated expression of NADK1 at protein levels and activity, respectively. Moreover, genetic inhibition of NADK1 disrupted NADPH and redox homeostasis, leading to high levels of ROS and significant anoikis, which inhibited lung and peritoneal metastasis in cell-based xenograft models. In summary, our study suggests that inhibiting GPER1-mediated NADK1 activity and its ubiquitination may be a promising therapeutic strategy for peritoneal metastasis of gastric cancer.

N6-methyladenosine-modified MIB1 promotes stemness properties and peritoneal metastasis of gastric cancer cells by ubiquitinating DDX3X.

Peritoneal metastasis (PM), one of the most typical forms of metastasis in advanced gastric cancer (GC), indicates a poor prognosis. Exploring the potential molecular mechanism of PM is urgently necessary, as it has not been well studied. E3 ubiquitin ligase has been widely established to exert a biological function in various cancers, but its mechanism of action in GC with PM remains unknown. The effect of MIB1 on PM of GC was confirmed in vitro and in vivo. Co-immunoprecipitation (Co-IP) and mass spectrometry demonstrated the association between MIB1 and DDX3X. Western blot, flow cytometry and immunofluorescence determined that DDX3X was ubiquitylated by MIB1 and promoted stemness. We further confirmed that METTL3 promoted the up-regulation of MIB1 by RNA immunoprecipitation (RIP), luciferase reporter assay and other experiments. We observed that the E3 ubiquitin ligase Mind bomb 1 (MIB1) was highly expressed in PMs, and patients with PM with high MIB1 expression showed a worse prognosis than those with low MIB1 expression. Mechanistically, our study demonstrated that the E3 ubiquitin ligase MIB1 promoted epithelial-mesenchymal transition (EMT) progression and stemness in GC cells by degrading DDX3X. In addition, METTL3 mediated m6A modification to stabilize MIB1, which required the m6A reader IGF2BP2. Our study elucidated the specific molecular mechanism by which MIB1 promotes PM of GC, and suggested that targeting the METTL3-MIB1-DDX3X axis may be a promising therapeutic strategy for GC with PM.

Macrophages reprogramming improves immunotherapy of IL-33 in peritoneal metastasis of gastric cancer

Peritoneal metastasis (PM) has a suppressive tumor immune microenvironment (TIME) that limits the effects of immunotherapy. This study aimed to investigate the immunomodulatory effects of intraperitoneal administration of IL-33, a cytokine that is reported to potentiate antitumor immunity and inhibit metastasis. We found survival was significantly prolonged in patients with high IL-33 mRNA expression. In immunocompetent mice, intraperitoneal administration of IL-33 could induce a celiac inflammatory environment, activate immunologic effector cells, and reverse the immunosuppressive tumor microenvironment, which effectively delayed tumor progression and PM of gastric cancer. Mechanistically, IL-33 could induce M2 polarization by activating p38-GATA-binding protein 3 signaling. IL-33 combined with anti-CSF1R or p38 inhibitor to regulate tumor-associated macrophages (TAMs) had a synergistic antitumor effect. Inducing a local inflammatory milieu by IL-33 administration provided a novel approach for treating peritoneal metastasis, which, when combined with TAM reprogramming to reshape TIME, can achieve better treatment efficacy.

MiR-1286, a Tumor Suppressor of Gastric Cancer, Serves as a Promising Biomarker for Screening Gastric Cancer from Gastritis.

Gastric cancer (GC) is one of the crucial causes of cancer-associated death worldwide. This study aimed to investigate the biological function of miR-1286 in GC progression in vitro, evaluate the clinical value of serum miR-1286 to screen GC patients and explore its relationship with helicobacter pylori (HP) infection and peritoneal metastasis in GC patients. Expression of miR-1286 was measured by RT-qPCR. Cell Counting Kit-8 assay was utilized for measuring GC cell proliferation ability. The migration and invasion abilities of GC cells were measured using Transwell assays. Serum samples were obtained from 108 GC patients, 62 gastritis cases and 62 healthy volunteers. The diagnostic performance of miR-1286 was assessed using ROC analysis, and the predictive value of miR-1286 for peritoneal metastasis onset was analyzed using logistic regression analysis. miR-1286 played as a tumor suppressor in GC progression by inhibiting GC cell proliferation, migration and invasion. In GC patients, significantly decreased miR-1286 was observed compared to gastritis and healthy controls, and had considerable diagnostic accuracy to distinguish GC from the controls. A significant association was found between miR-1286 expression and HP infection, peritoneal metastasis and TNM stage. Moreover, miR-1286 was lowly expressed in GC patients with peritoneal metastasis, and independently predicted the occurrence of peritoneal metastasis in GC. miR-1286 acts as a tumor suppressor and a biomarker in GC, and is closely associated with HP infection and peritoneal metastasis onset. The methods to regulate miR-1286 may be novel strategies to improve the treatment of GC.

Blocking EGR1/TGF-β1 and CD44s/STAT3 Crosstalk Inhibits Peritoneal Metastasis of Gastric Cancer.

Peritoneal metastasis (PM) continues to limit the clinical efficacy of gastric cancer (GC). Early growth response 1 (EGR1) plays an important role in tumor cell proliferation, angiogenesis and invasion. However, the role of EGR1 derived from the tumor microenvironment in reshaping the phenotypes of GC cells and its specific molecular mechanisms in increasing the potential for PM are still unclear. In this study, we reported that EGR1 was significantly up-regulated in mesothelial cells from GC peritoneal metastases, leading to enhanced epithelial-mesenchymal transformation (EMT) and stemness phenotypes of GC cells under co-culture conditions. These phenotypes were achieved through the transcription and secretion of TGF-β1 by EGR1 in mesothelial cells, which could regulate the expression and internalization of CD44s. After being internalized into the cytoplasm, CD44s interacted with STAT3 to promote STAT3 phosphorylation and activation, and induced EMT and stemness gene transcription, thus positively regulating the metastasis of GC cells. Moreover, TGF-β1 secretion in the PM microenvironment was significantly increased compared with the matched primary tumor. The blocking effect of SHR-1701 on TGF-β1 was verified by inhibiting peritoneal metastases in xenografts. Collectively, the interplay of EGR1/TGF-β1/CD44s/STAT3 signaling between mesothelial cells and GC cells induces EMT and stemness phenotypes, offering potential as a therapeutic target for PM of GC.

Analysis of circulating tumor DNA identifies distinct therapeutic response to intraperitoneal and intravenous paclitaxel plus S-1 in gastric cancer patients with peritoneal metastasis.

Circulating tumor DNA (ctDNA) is a promising technique for predicting curative effects and monitoring tumor recurrence. The utility of ctDNA for gastric cancer with peritoneal dissemination remains elusive. To assess the feasibility of ctDNA in predicting tumor response to chemotherapy in gastric cancer with peritoneal dissemination. This was a prospective study. We enrolled 30 patients with gastric cancer peritoneal metastasis, treated with intraperitoneal and intravenous paclitaxel plus S-1. Peripheral blood samples of patients were prospectively collected at baseline, after treatment initiation accompanied by computed tomography scan and disease progression. Mutational profiles from ctDNA were analyzed to evaluate its association with chemotherapeutic response. Tumor protein 53 (TP53) was the most frequently altered gene at baseline blood samples. Although baseline TP53 mutation was not related to therapeutic response, patients with TP53 mutation had worse progression-free survival (PFS) and overall survival (OS). Additionally, baseline ctDNA content fraction (CCF) was found to be significantly lower in responders than non-responders. Meanwhile, patients with high CCF had a trend of worse PFS and OS. Combining TP53 alteration and CCF, the prognosis of TP53-wt patients could be further stratified. Patients with CCF-low_TP53-wt had markedly longer survival than those with CCF-high_TP53-wt. Our study highlighted the significance of ctDNA in predicting potential clinical outcomes in gastric cancer patients during chemotherapy. ChiCTR-IIR-16009802 (Chinese Clinical Trial Registry).

ESM1 Interacts with c-Met to Promote Gastric Cancer Peritoneal Metastasis by Inducing Angiogenesis.

The peritoneum is the most common metastatic site of advanced gastric cancer and is associated with extremely poor prognosis. Endothelial-specific molecule 1 (ESM1) was found to be significantly associated with gastric cancer peritoneal metastasis (GCPM); however, the biological functions and molecular mechanisms of ESM1 in regulating GCPM remain unclear. Herein, we demonstrated that ESM1 expression was significantly upregulated in gastric cancer tissues and positively correlated with platelet endothelial cell adhesion molecule-1 (CD31) levels. Moreover, clinical validation, in in vitro and in vivo experiments, confirmed that ESM1 promoted gastric cancer angiogenesis, eventually promoting gastric cancer peritoneal metastasis. Mechanistically, ESM1 promoted tumor angiogenesis by binding to c-Met on the vascular endothelial cell membrane. In addition, our results confirmed that ESM1 upregulated VEGFA, HIF1α, and MMP9 expression and induced angiogenesis by activating the MAPK/ERK pathway. In conclusion, our findings identified the role of ESM1 in gastric cancer angiogenesis and GCPM, thus providing insights into the diagnosis and treatment of advanced gastric cancer.

Retracted: Levels and Significance of Tumor Markers and Cytokines in Serum and Peritoneal Lavage Fluid of Patients with Peritoneal Metastasis of Gastric Cancer.

[This retracts the article DOI: 10.1155/2022/9528444.].