Apatinib to enhance chemosensitivity of gastric cancer to paciltaxel and 5-fluorouracil.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15545-e15545
Author(s):  
Xiangdong Cheng ◽  
Zhiyuan Xu ◽  
Jiahui Chen ◽  
Chunli Zhang ◽  
Jianfa Yu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Late Stage ◽  
Zebrafish Embryo ◽  
Xenograft Model ◽  
Cytotoxic Agents ◽  
Pathological Examination ◽  
Conversion Surgery ◽  
Synergistic Interactions

e15545 Background: Patients (pts) with late-stage gastric cancer (GC) have a poor prognosis. Targeted agent combined with chemotherapy is expected to yield clinical benefits. Apatinib, a novel tyrosine kinase inhibitor targeting VEGFR-2, improves outcomes in patients with metastatic GC as a third line of treatment. Hence, we aimed to assess the efficacy and safety of apatinib plus chemotherapy in vivo and in vitro. Methods: The MGC803 cell viability was assessed by CCK-8 assay, and the interactions between apatinib and conventional cytotoxic agents revealed by combined index (CI) values were calculated using Calcusyn 2.0 software. We also used a zebrafish embryo xenograft model to validate the synergistic interactions. Furthermore, 4 pts with late-stage GC were enrolled to receive paclitaxel (PTX)/S1 chemotherapy plus apatinib in conversion surgery. Apatinib was administered 500 mg once a day continuously, PTX 130 mg/m2 was given on day 1, and S-1 was administered at 80 mg/m2for 14 consecutive days, followed by 7 days of rest. Treatment was administered for 3-5 cycles, but the last cycle did not include apatinib. Results: Apatinib showed synergistic interactions with both PTX and 5-Fu in vivo (CIs < 1). The zebrafish embryo xenograft model also demonstrated that addition of 0.25 µg/mL apatinib significantly enhanced the tumor growth inhibition effects of 25 (38.39% vs. 11.77%, P < 0.001) and 50 ng/fish (43.58% vs. 17.88%, P < 0.05) 5-Fu, as well as those of 0.75 ng/fish (53.62% vs. 35.22%, P < 0.001) and 1.5 ng/fish (59.71% vs.46.73%, P < 0.01) PTX. Apatinib plus S1/paclitaxel chemotherapy was well tolerable before surgery. Objective response to preoperative SPA treatment was achieved in all pts. No posteroperative bleeding event or wound-healing complication was observed. No postoperative mortality occurred and morbidity was encountered. Pathological examination showed that all pts had grade Ib pathological response. Conclusions: The experimental data suggested that apatinib improves the efficacy of PTX and 5-Fu both in vitro and in vivo. Clinical evidence showed that combination of PTX/S1 chemotherapy with apatinib has promising efficacy and acceptable safety profile in late-stage GC, especially in the conversion surgery.

scholarly journals NUSAP1 Promotes Gastric Cancer Progression Through Regulation of Yap Stability

2020 ◽  
Author(s):  
Hui Guo ◽  
Jianping Zou ◽  
Ling Zhou ◽  
Yan He ◽  
Miao Feng ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Progression ◽  
Target Genes ◽  
Hippo Pathway ◽  
Critical Role ◽  
Xenograft Model ◽  
Migration And Invasion

Abstract Background:Nucleolar and spindle associated protein (NUSAP1) is involved in tumor initiation, progression and metastasis. However, there are limited studies regarding the role of NUSAP1 in gastric cancer (GC). Methods: The expression profile and clinical significance of NUSAP1 in GC were analysed in online database using GEPIA, Oncomine and KM plotter, which was further confirmed in clinical specimens.The functional role of NUSAP1 were detected utilizing in vitro and in vivo assays. Western blotting, qRT-PCR, the cycloheximide-chase, immunofluorescence staining and Co-immunoprecipitaion (Co-IP) assays were performed to explore the possible molecular mechanism by which NUSAP1 stabilizes YAP protein. Results:In this study, we found that the expression of NUSAP1 was upregulated in GC tissues and correlates closely with progression and prognosis. Additionally, abnormal NUSAP1 expression promoted malignant behaviors of GC cells in vitro and in a xenograft model. Mechanistically, we discovered that NUSAP1 physically interacts with YAP and furthermore stabilizes YAP protein expression, which induces the transcription of Hippo pathway downstream target genes. Furthermore, the effects of NUSAP1 on GC cell growth, migration and invasion were mainly mediated by YAP. Conclusions:Our data demonstrates that the novel NUSAP1-YAP axis exerts an critical role in GC tumorigenesis and progression, and therefore could provide a novel therapeutic target for GC treatment.

scholarly journals Lycorine hydrochloride inhibits cell proliferation and induces apoptosis through promoting FBXW7-MCL1 axis in gastric cancer

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Chongyang Li ◽  
Chaowei Deng ◽  
Guangzhao Pan ◽  
Xue Wang ◽  
Kui Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Xenograft Model ◽  
Resistant Cell ◽  
Tumor Xenograft ◽  
Gastric Cancer Cells ◽  
Bcl2 Family ◽  
Ubiquitin E3 Ligase ◽  
Underlying Mechanisms

Abstract Background Lycorine hydrochloride (LH), an alkaloid extracted from the bulb of the Lycoris radiata, is considered to have anti-viral, anti-malarial, and anti-tumorous effects. At present, the underlying mechanisms of LH in gastric cancer remain unclear. MCL1, an anti-apoptotic protein of BCL2 family, is closely related to drug resistance of tumor. Therefore, MCL1 is considered as a potential target for cancer treatment. Methods The effect of LH on gastric cancer was assessed in vitro (by MTT, BrdU, western blotting…) and in vivo (by immunohistochemistry). Results In this study, we showed that LH has an anti-tumorous effect by down-regulating MCL1 in gastric cancer. Besides, we unveiled that LH reduced the protein stability of MCL1 by up-regulating ubiquitin E3 ligase FBXW7, arrested cell cycle at S phase and triggered apoptosis of gastric cancer cells. Meanwhile, we also demonstrated that LH could induce apoptosis of the BCL2-drug-resistant-cell-lines. Moreover, PDX (Patient-Derived tumor xenograft) model experiment proved that LH combined with HA14–1 (inhibitor of BCL2), had a more significant therapeutic effect on gastric cancer. Conclusions The efficacy showed in our data suggests that lycorine hydrochloride is a promising anti-tumor compound for gastric cancer.

scholarly journals LINC00152 down-regulated miR-193a-3p to enhance MCL1 expression and promote gastric cancer cells proliferation

2018 ◽  
Vol 38 (3) ◽  
Author(s):  
Yong Huang ◽  
Hui Luo ◽  
Fang Li ◽  
Yun’e Yang ◽  
Guangsheng Ou ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Xenograft Model ◽  
Cell Counting ◽  
Gastric Cancer Cells ◽  
Normal Tissues ◽  
Non Coding Rna ◽  
Mouse Xenograft Model ◽  
Vitro Effect

The present work aimed to probe into the effect of long non-coding RNA (lncRNA) LINC00152 on gastric cancer (GC) cells proliferation by regulating miR-193a-3p and its target gene MCL1. Transfected si-LINC00152 was used to down-regulate LINC00152, and cells proliferation was measured by the cell counting kit-8 (CCK-8) assay. Cell apoptosis and cell cycle were analyzed by flow cytometry (FCM). Besides, we also detected the potential functional effects of differential expression of LINC00152 in vivo using nude mouse xenograft model. We overexpressed and downexpressed miR-193a-3p to study the in vitro effect of miR-193a-3p on GC cells proliferation and vitality. And MCL1 was silenced by shRNA to investigate the effect of MCL1 on proliferation of GC cells. In this research, LINC00152 was proven to have a higher expression level in GC tissues than in the adjacent normal tissues. GC cells proliferation was inhibited after LINC00152 was down-regulated. LINC00152 inhibited the expression of miR-193a-3p, which negatively regulated MCL1. In addition, GC cells proliferation was inhibited by cell transfection with shRNA-MCL1, and enhanced by transfection with miR-193a-3p mimics. Our study suggested that LINC00152 was overexpressed in GC tissues, and it down-regulated miR-193a-3p to enhance MCL1 expression thereby promoting GC cells proliferation.

scholarly journals Stmn1 up-regulates Cdx2 expression and participates in gastric intestinal metaplasia in vitro and in vivo: a randomized controlled trial

2020 ◽  
Author(s):  
Xuan Chen ◽  
Lizuan Chen ◽  
Zeming Ren ◽  
Yeling Tong ◽  
Guanhai Dai ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Line ◽  
Precancerous Lesion ◽  
Expression Level ◽  
Pathological Examination ◽  
Gastric Cell ◽  
Potential Biomarker ◽  
Im Model

Abstract BACKGROUND AND PURPOSE: Stmn1 is over-expressed in almost all pathological stages during gastric cancer development, such as chronic atrophic gastritis, dysplasia, and gastric cancer. IM is an important precancerous lesion of gastric cancer, however, whether Stmn1 was up-regulated or down-regulated in this stage is still unknown. We aimed to evaluate the expression level of Stmn1 in IM in vivo and its relationship with important gene of IM named Cdx2 in vitro.EXPERIMENTAL APPROACH: Wistar rats (n=12, sex in half) were gavaged with MNNG (167μg/ml) to induce IM model in stomach. After pathological examination with AB staining to confirm that the model was successful, relative expression level of Stmn1 was detected between normal group and model group using RT-qPCR. Human gastric cell line GES-1 was used to investigate whether Stmn1 influence expression level of IM essential gene Cdx2 by over-expressing or down-expressing experiments, RT-qPCR and western blot.KEY RESULTS: We have demonstrated that Stmn1 was up-regulated in IM model induced by MNNG in rats in vivo, and it could significantly up-regulate Cdx2 expression level in human gastric cell line GES-1 in vitro.CONCLUSIONS AND IMPLICATIONS: We demonstrated that Stmn1 was involved in IM in this model and it could up-regulating Cdx2 in human gastric cell line GES-1 in vitro. These results suggested that Stmn1 might be a potential biomarker or candidate treatment target of IM in stomach.

scholarly journals Lycorine hydrochloride inhibits cell proliferation and induces apoptosis through promoting FBXW7-MCL1 axis in gastric cancer

2020 ◽  
Author(s):  
Chongyang Li ◽  
Chaowei Deng ◽  
Guangzhao Pan ◽  
Xue Wang ◽  
Kui Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Xenograft Model ◽  
Resistant Cell ◽  
Tumor Xenograft ◽  
Gastric Cancer Cells ◽  
Bcl2 Family ◽  
Ubiquitin E3 Ligase ◽  
Underlying Mechanisms

Abstract Background: Lycorine hydrochloride (LH), an alkaloid extracted from the bulb of the Lycoris radiata, is considered to have anti-viral, anti-malarial, and anti-tumorous effects. At present, the underlying mechanisms of LH in gastric cancer remain unclear. MCL1, an anti-apoptotic protein of BCL2 family, is closely related to drug resistance of tumor. Therefore, MCL1 is considered as a potential target for cancer treatment. Methods: The effect of LH on gastric cancer was assessed in vitro (by MTT, BrdU, western blotting…) and in vivo (by immunohistochemistry).Results: In this study, we showed that LH has an anti-tumorous effect by down-regulating MCL1 in gastric cancer. Besides, we unveiled that LH reduced the protein stability of MCL1 by up-regulating ubiquitin E3 ligase FBXW7, arrested cell cycle at S phase and triggered apoptosis of gastric cancer cells. Meanwhile, we also demonstrated that LH could induce apoptosis of the BCL2-drug-resistant-cell-lines. Moreover, PDX (Patient-Derived tumor xenograft) model experiment proved that LH combined with HA14-1 (inhibitor of BCL2), had a more significant therapeutic effect on gastric cancer. Conclusions: Together, the efficacy showed in our data suggests that lycorine hydrochloride is a promising anti-tumorous compound for gastric cancer.

scholarly journals Circular RNA MCTP2 inhibits cisplatin resistance in gastric cancer by miR-99a-5p-mediated induction of MTMR3 expression

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Guangli Sun ◽  
Zheng Li ◽  
Zhongyuan He ◽  
Weizhi Wang ◽  
Sen Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Xenograft Model ◽  
Circular Rna ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Mouse Xenograft Model ◽  
Mirna Sponges ◽  
High Level

Abstract Background Cisplatin (CDDP) is the first-line chemotherapy for gastric cancer (GC). The poor prognosis of GC patients is partially due to the development of CDDP resistance. Circular RNAs (circRNAs) are a subclass of noncoding RNAs that function as microRNA (miRNA) sponges. The role of circRNAs in CDDP resistance in GC has not been evaluated. Methods RNA sequencing was used to identify the differentially expressed circRNAs between CDDP-resistant and CDDP-sensitive GC cells. qRT-PCR was used to detect the expression of circMCTP2 in GC tissues. The effects of circMCTP2 on CDDP resistance were investigated in vitro and in vivo. Pull-down assays and luciferase reporter assays were performed to confirm the interactions among circMCTP2, miR-99a-5p, and myotubularin-related protein 3 (MTMR3). The protein expression levels of MTMR3 were detected by western blotting. Autophagy was evaluated by confocal microscopy and transmission electron microscopy (TEM). Results CircMCTP2 was downregulated in CDDP-resistant GC cells and tissues compared to CDDP-sensitive GC cells and tissues. A high level of circMCTP2 was found to be a favorable factor for the prognosis of patients with GC. CircMCTP2 inhibited proliferation while promoting apoptosis of CDDP-resistant GC cells in response to CDDP treatment. CircMCTP2 was also found to reduce autophagy in CDDP-resistant GC cells. MiR-99a-5p was verified to be sponged by circMCTP2. Inhibition of miR-99a-5p could sensitize GC cells to CDDP. MTMR3 was confirmed to be a direct target of miR-99a-5p. Knockdown of MTMR3 reversed the effects of circMCTP2 on the proliferation, apoptosis and autophagy of CDDP-resistant GC cells. CircMCTP2 was also confirmed to inhibit CDDP resistance in vivo in a nude mouse xenograft model. Conclusions CircMCTP2 sensitizes GC to CDDP through the upregulation of MTMR3 by sponging miR-99a-5p. Overexpression of CircMCTP2 could be a new therapeutic strategy for counteracting CDDP resistance in GC.

scholarly journals Knockdown of Kremen2 Inhibits Tumor Growth and Migration in Gastric Cancer

2021 ◽  
Vol 10 ◽  
Author(s):  
Beibei Chen ◽  
Sai-Qi Wang ◽  
Jinxi Huang ◽  
Weifeng Xu ◽  
Huifang Lv ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Xenograft Model ◽  
Gastric Cancer Cells ◽  
And Migration ◽  
Induced Apoptosis ◽  
Gastric Cancer Patients

Kremen2 (Krm2) plays an important role in embryonic development, bone formation, and tumorigenesis as a crucial regulator of classical Wnt/β-catenin signaling pathway. However, the role of Krm2 in gastric cancer is not clear. The aim of this study was to explore the regulatory role of Krm2 in the tumorigenesis and metastasis of gastric cancer. It was demonstrated that, compared to para-cancerous tissues, Krm2 was significantly up-regulated in gastric cancer tissues and was positively correlated with the pathological grade of gastric cancer patients. Given that Krm2 is abundantly expressed in most tested gastric cancer cell lines, Krm2 knockdown cell models were established and further used to construct mice xenograft model. After knocking down Krm2, both the cell survival in vitro and tumorigenesis in vivo of gastric cancer cells were inhibited. At the same time, knockdown of Krm2 induced apoptosis, cell cycle arrest at G2/M phase and repression of migration in gastric cancer cells in vitro. Mechanistically, we found that knockdown of Krm2 suppressed PI3K/Akt pathway. Therefore, we revealed the novel role and the molecular mechanism of Krm2 in promoting the tumorigenesis and metastasis in gastric cancer. Krm2 can be a potent candidate for designing of targeted therapy.

scholarly journals Calmodulin 2 Facilitates Angiogenesis and Metastasis of Gastric Cancer via STAT3/HIF-1A/VEGF-A Mediated Macrophage Polarization

2021 ◽  
Vol 11 ◽  
Author(s):  
Ganggang Mu ◽  
Yijie Zhu ◽  
Zehua Dong ◽  
Lang Shi ◽  
Yunchao Deng ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Growth ◽  
Lung Metastasis ◽  
Macrophage Polarization ◽  
Xenograft Model ◽  
Migration And Invasion ◽  
Tubule Formation ◽  
Set Up

BackgroundTumor-associated macrophages (TAMs) are indispensable to mediating the connections between cells in the tumor microenvironment. In this study, we intended to research the function and mechanism of Calmodulin2 (CALM2) in gastric cancer (GC)-TAM microenvironment.Materials and methodsCALM2 expression in GC tissues and GC cells was determined through quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC). The correlation between CALM2 level and the survival rate of GC patients was assessed. The CALM2 overexpression or knockdown model was constructed to evaluate its role in GC cell proliferation, migration, and invasion. THP1 cells or HUVECs were co-cultured with the conditioned medium of GC cells. Tubule formation experiment was done to examine the angiogenesis of endothelial cells. The proliferation, migration, and polarization of THP1 cells were measured. A xenograft model was set up in BALB/c male nude mice to study CALM2x’s effects on tumor growth and lung metastasis in vivo. Western Blot (WB) checked the profile of JAK2/STAT3/HIF-1/VEGFA in GC tissues and cells.ResultsIn GC tissues and cell lines, CALM2 expression was elevated and positively relevant to the poor prognosis of GC patients. In in-vitro experiments, CALM2 overexpression or knockdown could facilitate or curb the proliferation, migration, invasion, and angiogenesis of HUVECs and M2 polarization of THP1 cells. In in-vivo experiments, CALM2 boosted tumor growth and lung metastasis. Mechanically, CALM2 could arouse the JAK2/STAT3/HIF-1/VEGFA signaling. It was also discovered that JAK2 and HIF-1A inhibition could attenuate the promoting effects of CALM2 on GC, HUVECs cells, and macrophages.ConclusionCALM2 modulates the JAK2/STAT3/HIF-1/VEGFA axis and bolsters macrophage polarization, thus facilitating GC metastasis and angiogenesis.

Establishment of esophagogastric xenografts: A model for characterizing disease heterogeneity.

2012 ◽  
Vol 30 (30_suppl) ◽  
pp. 95-95
Author(s):  
Yelena Yuriy Janjigian ◽  
Christopher M. Gromisch ◽  
Gregory Carbonetti ◽  
Laura H. Tang ◽  
David Paul Kelsen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Rational Design ◽  
Single Agent ◽  
Cytotoxic Agents ◽  
Her2 Positive ◽  
Disease Heterogeneity ◽  
Esophagogastric Cancer ◽  
Xenograft Models

95 Background: Gastric cancer is a heterogeneous disease that may be subdivided into distinct subtypes—proximal/gastroesophageal (GE) junction, diffuse/signet ring type, and distal gastric cancer/intestinal type—based on histopathologic and anatomic criteria. Each subtype is associated with unique epidemiology and gene expression. Human epidermal growth factor receptor (HER2) is a validated treatment target in gastric cancer. For patients with metastatic disease, the available cytotoxic agents are applied indiscriminately to all disease subtypes, and with only modest success. The purpose of this study is to establish xenograft models from gastric cancer subtypes to improve our understanding of disease heterogeneity and develop therapies geared for each subtype of gastric cancer. Methods: Fresh specimens obtained from resected primary or metastatic tumors under aseptic conditions. 1 g tumor samples injected SQ into flanks of NSG mice. Xenografts established after 5 passages and maintained by serial transplantation into new mice. Cell cultures established after 5 in vitro passages; cell lines after 15 passages Results: To date, 66 tumor samples have been implanted from which 16 xenografts have been established. The table below summarizes the results. Single-agent afatinib (pan-ErbB inhibitor) demonstrated antitumor activity in an HER2-positive xenograft established from MSKCC patient’s tumor harvested from a skin metastasis. Conclusions: We have established xenograft models of gastric cancer. In vivo testing of afatinib showed a reduction of tumor growth of HER2-positive gastric cancer. These models provide a platform to study potential therapeutics for esophagogastric cancer to further validate difference in their biology and guide rational design of clinical trials. [Table: see text]

scholarly journals CircC6orf132 Facilitates Proliferation, Migration, Invasion, and Glycolysis of Gastric Cancer Cells Under Hypoxia by Acting on the miR-873-5p/PRKAA1 Axis

2021 ◽  
Vol 12 ◽  
Author(s):  
Weizhi Chen ◽  
Yanhong Ji
Keyword(s):  
Gastric Cancer ◽  
Lactate Production ◽  
Xenograft Model ◽  
Hypoxic Condition ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Gastric Cancer Cells ◽  
Mouse Xenograft Model

Background: Hypoxia is a crucial factor in the progression of various tumors, including gastric cancer (GC). Circular RNAs (circRNAs) are important regulators in GC, and this study focused on researching circC6orf132 in GC progression under hypoxia.Methods:In vitro experiments were performed in GC cells under hypoxia (1% O2). CircC6orf132, microRNA-873-5p (miR-873-5p), and protein kinase AMP-activated alpha 1 catalytic subunit (PRKAA1) levels were examined by real-time polymerase chain reaction (qRT-PCR). Colony formation assay and transwell assay were used for detecting cell proliferation and migration or invasion. Glycolytic metabolism was evaluated using lactate production, glucose uptake, and adenosine triphosphate (ATP) level and extracellular acidification rate (ECAR). Western blotting was performed for determining protein expression. The target interaction was analyzed by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. In vivo assay was conducted via mouse xenograft model.Results: The expression of circC6orf132 was significantly high in GC cells under hypoxia. Hypoxia-induced GC proliferation, migration, invasion, and glycolysis were reversed by silencing circC6orf132. CircC6orf132 targeted miR-873-5p; and the inhibition of circC6orf132 knockdown for the effects of hypoxia on GC cells was abrogated by miR-873-5p inhibitor. PRKAA1 was validated as a downstream gene of miR-873-5p, and miR-873-5p functioned as an anticancer molecule in GC cells under hypoxia by downregulating PRKAA1 level. CircC6orf132 could regulate PRKAA1 by sponging miR-873-5p. CircC6orf132/miR-873-5p/PRKAA1 axis could regulate GC progression under the hypoxic condition. CircC6orf132 downregulation reduced tumorigenesis in vivo through affecting the miR-873-5p/PRKAA1 axis.Conclusion: CircC6orf132 has been affirmed to promote proliferation, migration, invasion, and glycolysis in GC under hypoxia, partly by depending on the regulation of miR-873-5p/PRKAA1 axis.

Sign in / Sign up

Export Citation Format

Share Document