Gastric Cancer

doi: 10.1007/s10120-022-01307-8pmid: 35661943

BackgroundLoss of E-cadherin expression is frequently observed in signet ring carcinoma (SRCC). People with germline mutations in CDH1, which encodes E-cadherin, develop diffuse gastric cancer at a higher rate. Loss of E-cadherin expression is thus assumed to trigger oncogenic development.MethodsTo investigate novel therapeutic targets for gastric SRCC, we engineered an E-cadherin-deficient SRCC model in vitro using a human gastric organoid (hGO) with CDH1 knockout (KO).ResultsCDH1 KO hGO cells demonstrated distinctive morphological changes similar to SRCC and high cell motility. RNA-sequencing revealed up-regulation of matrix metalloproteinase (MMP) genes in CDH1 KO hGO cells compared to wild type. MMP inhibitors suppressed cell motility of CDH1 KO hGO cells and SRCC cell lines in vitro. Immunofluorescent analysis with 95 clinical gastric cancer tissues revealed that MMP-3 was specifically abundant in E-cadherin-aberrant SRCC. In addition, CXCR4 molecules translocated onto the cell membrane after CDH1 KO. Addition of CXCL12, a ligand of CXCR4, to the culture medium prolonged cell survival of CDH1 KO hGO cells and was abolished by the inhibitor, AMD3100. In clinical SRCC samples, CXCL12-secreting fibroblasts showed marked infiltration into the cancer area.ConclusionsE-cadherin deficient SRCCs might gain cell motility through upregulation of MMPs. CXCL12-positive cancer-associated fibroblasts could serve to maintain cancer-cell survival as a niche. MMPs and the CXCL12/CXCR4 axis represent promising candidates as novel therapeutic targets for E-cadherin-deficient SRCC.

BackgroundCENPK is a novel oncogene which is aberrantly expression in some malignant tumors. However, the role and mechanisms of CENPK in gastric cancer have not been explored.MethodsIn this study, we use RT-PCR and IHC to study CENPK expression in gastric cancer cells and tissues. In addition, we constructed the two kinds of CENPK siRNA lentivirus to knock down CENPK. Then, we use High content living cell imaging System, Cell Counting Kit-8, colony formation, wound healing and Transwell assays to demonstrate the function of CENPK on gastric cancer cells AGS and MKN45. Meanwhile, we use flow cytometry assay to study CENPK function on gastric cancer cell apoptosis and cell cycle arrest. Subcutaneous tumorigenesis in nude mice was also performed to confirm CENPK function on gastric cancer. Finally, we use Co-IP, LC-MS and function rescue assay to study the downstream interaction molecular of CENPK.ResultsWe demonstrated that CENPK expression were up-regulated in GC cell lines. Poor differentiation and III-IV stage had more percentages of high CENPK expression. Knocking down CENPK could significantly suppress GC cells proliferation, migration and invasion, and induce GC cells apoptosis and G1/S phase transition arrest. Subcutaneous tumorigenesis confirmed the tumor-promoting effects of CENPK in vivo. Remarkably, we found for the first time that XRCC5 might be interacted with CENPK through Co-IP, LC-MS and rescue study.ConclusionCENPK promotes GC cell proliferation and migration via interacting with XRCC5 and may be a novel prognostic factor or therapeutic target for CENPK.

BackgroundSignet ring cell carcinoma (SRC) is a distinct subtype of gastric cancer (GC); however, the specific characteristics of cancer cell surface glycans and glycosylation remain unclear. In this study, we investigated SRC-specific glycans using lectin microarray and evaluated the potential applicability of a glycan-targeting therapy.MethodsSRC cell lines (NUGC-4 and KATO-III) and non-SRC (NSRC) cell lines (NCI-N87, SNU-1, and MKN-45) were subjected to lectin microarray analysis to identify the SRC-specific glycans. Additionally, we performed immunohistochemical lectin staining and evaluated the anti-tumor effects of lectin drug conjugates (LDCs) using high-affinity lectins for SRC.ResultsAmong the 96 lectins tested, 11 high-affinity and 8 low-affinity lectins were identified for SRC. Glycan-binding motifs varied in the high-affinity lectins, but 5 (62.5%) low-affinity lectins bound the same glycan structure, α2–6-linked sialic acids. The ratio of signal intensity in SRC to NSRC (SRC/NSRC) was highest in the rBC2LCN lectin (1.930-fold), followed by the BPL lectin (1.786-fold). rBC2LCN lectin showed high affinity for both SRC cell lines and one of the three NSRC cell lines (NCI-N87). The therapeutic effects of the LDC, rBC2LCN-PE38 (rBC2LCN, and Pseudomonas exotoxin A), showed cytocidal effects in vitro and tumor regression in in vivo mouse xenograft models.ConclusionWe reported specific glycan profiles in SRC cells, showing reduced α2–6-linked sialic acids. Additionally, we found a targeted therapy using rBC2LCN lectin might be applicable as an alternative treatment option for patients with SRC.

BackgroundCirculating tumor DNA (ctDNA) has predictive and prognostic value in localized and metastatic cancer. This study analyzed the prognostic value of baseline and on-treatment ctDNA in metastatic gastroesophageal cancer (mGEC) using a region-specific next generation sequencing (NGS) panel.MethodsCell free DNA was isolated from plasma of patients before start of first-line palliative systemic treatment and after 9 and 18 weeks. Two NGS panels were designed comprising the most frequently mutated genes and targetable mutations in GEC. Tumor-derived mutations in matched metastatic biopsies were used to validate that the sequencing panels assessed true tumor-derived variants. Tumor volumes were calculated from baseline CT scans and correlated to variant allele frequency (VAF). Survival analyses were performed using univariable and multivariable Cox-regression analyses.ResultsctDNA was detected in pretreatment plasma in 75% of 72 patients and correlated well with mutations in metastatic biopsies (86% accordance). The VAF correlated with baseline tumor volume (Pearson’s R 0.53, p < 0.0001). Detection of multiple gene mutations at baseline in plasma was associated with worse overall survival (OS, HR 2.16, 95% CI 1.10–4.28; p = 0.027) and progression free survival (PFS, HR 2.71, 95% CI 1.28–5.73; p = 0.009). OS and PFS were inferior in patients with residual detectable ctDNA after 9 weeks of treatment (OS: HR 4.95, 95% CI 1.53–16.04; p = 0.008; PFS: HR 4.08, 95% CI 1.31–12.75; p = 0.016).ConclusionBased on our NGS panel, the number of ctDNA mutations before start of first-line chemotherapy has prognostic value. Moreover, residual ctDNA after three cycles of systemic treatment is associated with inferior survival.

doi: 10.1007/s10120-022-01303-ypmid: 35622240

BackgroundThe risk of bleeding after gastric endoscopic submucosal dissection (ESD) in antithrombotic agent users has increased, and its management remains a problem. Second-look endoscopy (SLE) following gastric ESD in antithrombotic agent users may be effective in preventing delayed bleeding, but this requires elucidation. Therefore, this study aimed to investigate the efficacy of SLE in reducing bleeding after gastric ESD in patients receiving antithrombotic agents.MethodsThis retrospective cohort study was conducted at 19 referral hospitals in Japan. A total of 1,245 patients who were receiving antithrombotic agents underwent gastric ESD between January 2013 and July 2018. The incidence of delayed bleeding was compared between SLE and non-SLE groups using propensity score matching analysis.ResultsOverall, 858 patients (SLE group, 657 patients; non-SLE group, 201 patients) were analyzed. After matching, 198 pairs were created. Delayed bleeding occurred in 10 patients (5.1%) in the SLE group and 16 patients (8.1%) in the non-SLE group [odds ratio (OR) 0.605, 95% confidence interval (CI) 0.23–1.46, p = 0.310]. In the subgroup analysis, SLE reduced the incidence of delayed bleeding in patients receiving heparin bridging therapy (6.3% and 40.0%, respectively; p = 0.004). In the SLE group, prophylactic coagulation did not significantly reduce delayed bleeding compared to the no treatment group (14.6% and 8.6%, respectively; p = 0.140).ConclusionsSLE was ineffective in reducing bleeding after gastric ESD in antithrombotic agent users, overall. A prospective comparative study is warranted to definitively evaluate the effectiveness of SLE in reducing bleeding in high-risk patients.

doi: 10.1007/s10120-022-01327-4pmid: 35907049

ObjectiveEndoscopic resection (ER) is an effective treatment method for gastric submucosal tumors (G-SMTs), but endoscopic resection failure requires emergency surgery. The purpose of this study was to assess potential risk factors for endoscopic resection failure.MethodsA total of 1041 patients with G-SMT undergoing endoscopic resection were enrolled. Twenty-five patients in whom endoscopic resection failed, requiring a transition to surgery midway through the operation, were included in the failed group, and 1016 patients who received successful endoscopic resection were included in the successful endoscopic resection group. Baseline and lesion characteristics were recorded, and the differences in tumor characteristics and risk factors for resection failure of G-SMT were analyzed. Sensitivity analysis was performed to detect the stability of the indicator.ResultsOf the 1041cases included, there were 25 cases (2.4%) of failed endoscopic resection. Binary logistic analysis showed that the independent risk factors included tumors originating from deep muscularis propria(OR = 14.42, 95% CI 4.47–46.52), size > 3 cm (OR = 7.75, 95% CI 2.64–22.70), exophytic growth pattern (OR = 4.98, 95% CI 1.62–15.29), endoscopist with less experience (OR = 5.99, 95% CI 1.07–12.19), and irregular borders (OR = 4.13, 95% CI 1.40–12.19). The stable risk factors were tumors size, tumor origin and growth pattern according to sensitivity analysis.ConclusionsTumors originating from the deep muscularis propria, tumor size > 3 cm, endoscopists with less experience, an exophytic growth pattern, and irregular boundaries were found to be independent risk factors for endoscopic resection failure. To reduce the risk of endoscopic resection failure, physicians should carefully evaluate G-SMT characteristics preoperative.