Talaporfin-mediated photodynamic therapy for peritoneal metastasis of gastric cancer in an in vivo mouse model: Drug distribution and efficacy studies

Abstract Background Peritoneal metastasis (PM) in gastric cancer (GC) is characterized by diffusely infiltrating and proliferating cancer cells accompanied by extensive stromal fibrosis in the peritoneal space. The prognosis of GC with PM is still poor regardless of the various current treatments. In order to elucidate the cause of difficulties in PM treatment, we compared the tumor immune microenvironment (TME) in primary and PM lesions in GC. In addition, a PM model with fibrous stroma was constructed using immunocompetent mice to determine whether its TME was similar to that in patients. MethodsImmuno-histochemical analyses of infiltrating immune cells were performed in paired primary and PM lesions from 28 patients with GC. A C57BL/6J mouse model with PM was established using the mouse GC cell line YTN16 either with or without co-inoculation of mouse myofibroblast cell line LmcMF with a-SMA expression. The resected PM from each mouse model was analyzed the immunocompetent cells using immunohistochemistry.ResultsThe number of CD8+ cells was significantly lower in PM lesions than in primary lesions (P<0.01). Conversely, the number of CD163+ cells (M2 macrophages) was significantly higher in PM lesions than in primary lesions (P=0.016). Azan staining revealed that YTN16 and LmcMF co-inoculated tumors were more fibrous than tumor with YTN16 alone (P<0.05). Co-inoculated fibrous tumor also showed an invasive growth pattern and higher progression than tumor with YTN16 alone (P=0.045). Additionally, YTN16 and LmcMF co-inoculated tumors showed lower infiltration of CD8+ cells and higher infiltration of M2 macrophages than tumors with YTN16 alone (P<0.05, P<0.05). These results indicate that LmcMF plays as cancer-associated fibroblasts (CAFs) by crosstalk with YTN16 and CAFs contribute tumor progression, invasion, fibrosis, and immune suppression.ConclusionsThis model is the first immunocompetent mouse model similar to TME of human clinical PM with fibrosis. By using this model, new treatment strategies for PM, such as anti-CAFs therapies, may be developed.

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Indole-2-Carboxamides Are Active against Mycobacterium abscessus in a Mouse Model of Acute Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02245-18 ◽

2019 ◽

Vol 63 (3) ◽

Cited By ~ 10

Author(s):

Amit N. Pandya ◽

Pavan K. Prathipati ◽

Pooja Hegde ◽

Wei Li ◽

Kyle F. Graham ◽

...

Keyword(s):

Mouse Model ◽

Oral Administration ◽

Infected Mouse ◽

Mouse Models ◽

Nontuberculous Mycobacteria ◽

Acute Infection ◽

Mycobacterium Abscessus ◽

Content Type ◽

Efficacy Studies

ABSTRACT Nontuberculous mycobacteria (NTM) pathogens particularly infect patients with structural lung disorders. We previously reported novel indole-2-carboxamides (ICs) that are active against a wide panel of NTM pathogens. This study discloses in vivo data for two lead molecules (compounds 5 and 25) that were advanced for efficacy studies in Mycobacterium abscessus-infected mouse models. Oral administration of the lead molecules showed a statistically significant reduction in the bacterial loads in lung and spleen of M. abscessus-infected mice.

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Established fibrous peritoneal metastasis in an immunocompetent mouse model similar to clinical immune microenvironment of gastric cancer

BMC Cancer ◽

10.1186/s12885-020-07477-x ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Daisuke Fujimori ◽

Jun Kinoshita ◽

Takahisa Yamaguchi ◽

Yusuke Nakamura ◽

Katsuya Gunjigake ◽

...

Keyword(s):

Gastric Cancer ◽

Mouse Model ◽

Cell Line ◽

Peritoneal Metastasis ◽

Treatment Strategies ◽

M2 Macrophages ◽

Immunocompetent Mouse ◽

Immune Microenvironment ◽

Fibrous Stroma ◽

Immunocompetent Mice

Abstract Background Peritoneal metastasis (PM) in gastric cancer (GC) is characterized by diffusely infiltrating and proliferating cancer cells accompanied by extensive stromal fibrosis in the peritoneal space. The prognosis of GC with PM is still poor regardless of the various current treatments. In order to elucidate the cause of difficulties in PM treatment, we compared the tumor immune microenvironment (TME) in primary and PM lesions in GC. In addition, a PM model with fibrous stroma was constructed using immunocompetent mice to determine whether its TME was similar to that in patients. Methods Immuno-histochemical analyses of infiltrating immune cells were performed in paired primary and PM lesions from 28 patients with GC. A C57BL/6 J mouse model with PM was established using the mouse GC cell line YTN16 either with or without co-inoculation of mouse myofibroblast cell line LmcMF with α-SMA expression. The resected PM from each mouse model was analyzed the immunocompetent cells using immunohistochemistry. Results The number of CD8+ cells was significantly lower in PM lesions than in primary lesions (P < 0.01). Conversely, the number of CD163+ cells (M2 macrophages) was significantly higher in PM lesions than in primary lesions (P = 0.016). Azan staining revealed that YTN16 and LmcMF co-inoculated tumors were more fibrous than tumor with YTN16 alone (P < 0.05). Co-inoculated fibrous tumor also showed an invasive growth pattern and higher progression than tumor with YTN16 alone (P = 0.045). Additionally, YTN16 and LmcMF co-inoculated tumors showed lower infiltration of CD8+ cells and higher infiltration of M2 macrophages than tumors with YTN16 alone (P < 0.05, P < 0.05). These results indicate that LmcMF plays as cancer-associated fibroblasts (CAFs) by crosstalk with YTN16 and CAFs contribute tumor progression, invasion, fibrosis, and immune suppression. Conclusions This model is the first immunocompetent mouse model similar to TME of human clinical PM with fibrosis. By using this model, new treatment strategies for PM, such as anti-CAFs therapies, may be developed.

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Inhibition of the peritoneal metastasis of human gastric cancer cells by dextran sulphate in vivo and in vitro

Oncology Letters ◽

10.3892/ol.2016.4234 ◽

2016 ◽

Vol 11 (4) ◽

pp. 2384-2390 ◽

Cited By ~ 2

Author(s):

YUANYI XU ◽

YUNNING HUANG ◽

HONGHONG WANG ◽

YONG LIU

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Peritoneal Metastasis ◽

Human Gastric Cancer ◽

Dextran Sulphate ◽

Gastric Cancer Cells

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STAT3 promotes peritoneal metastasis of gastric cancer by enhancing mesothelial-mesenchymal transition

Biological Chemistry ◽

10.1515/hsz-2021-0120 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Hongkui Yang ◽

Wenjun Xu

Keyword(s):

Gastric Cancer ◽

Peritoneal Metastasis ◽

Metastatic Potential ◽

Mesenchymal Transition ◽

Tumor Tissues ◽

Inducing Factors ◽

Transcription 3 ◽

Xenograft Tumor Growth

Abstract Signal transducer and activator of transcription 3 (STAT3) is a widely-reported oncogene in many human cancers, but its role in the peritoneal metastasis of gastric cancer (GC) has yet to be studied. The expression level of STAT3 in GC patient tissues was assessed. Stable shRNA knockdown (KD) of STAT3 was established in GC cell line AGS, followed by examination of its effect on AGC cell viability and proliferation, xenograft tumor growth, metastatic potential, mesothelial-to-mesenchymal transition (MMT)-related properties and peritoneal metastasis in a mouse model. The specific STAT3 inhibitor BP1-102 was also employed to verify findings from STAT3 KD experiments. Expression of activated STAT3 was upregulated in GC patient tumor tissues, and further elevated among patients diagnosed with peritoneal metastasis. STAT3 deactivation suppressed viability and proliferation of GC cells in vitro, as well as GC tumorigenesis in vivo. Furthermore, the metastatic properties and production of MMT-inducing factors of GC cells in vitro were also dependent on STAT3 activation. Importantly, STAT3 KD significantly compromised peritoneal metastasis of GC in vivo. STAT3 activation contributes to peritoneal metastasis of GC by promoting MMT, warranting further investigation to explore its potential for GC treatment, in particular among peritoneal metastasis patients.

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Computational Drug Repositioning and Experimental Validation of Ivermectin in Treatment of Gastric Cancer

Frontiers in Pharmacology ◽

10.3389/fphar.2021.625991 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hanne-Line Rabben ◽

Gøran Troseth Andersen ◽

Aleksandr Ianevski ◽

Magnus Kringstad Olsen ◽

Denis Kainov ◽

...

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Cell Proliferation ◽

Mouse Model ◽

Signaling Pathways ◽

In Silico ◽

Drug Repositioning ◽

Human And Mouse

Objective: The aim of the present study was repositioning of ivermectin in treatment of gastric cancer (GC) by computational prediction based on gene expression profiles of human and mouse model of GC and validations with in silico, in vitro and in vivo approaches.Methods: Computational drug repositioning was performed using connectivity map (cMap) and data/pathway mining with the Ingenuity Knowledge Base. Tissue samples of GC were collected from 16 patients and 57 mice for gene expression profiling. Additional seven independent datasets of gene expression of human GC from the TCGA database were used for validation. In silico testing was performed by constructing interaction networks of ivermectin and the downstream effects in targeted signaling pathways. In vitro testing was carried out in human GC cell lines (MKN74 and KATO-III). In vivo testing was performed in a transgenic mouse model of GC (INS-GAS mice).Results: GC gene expression “signature” and data/pathway mining but not cMAP revealed nine molecular targets of ivermectin in both human and mouse GC associated with WNT/β-catenin signaling as well as cell proliferation pathways. In silico inhibition of the targets of ivermectin and concomitant activation of ivermectin led to the inhibition of WNT/β-catenin signaling pathway in “dose-depended” manner. In vitro, ivermectin inhibited cell proliferation in time- and concentration-depended manners, and cells were arrested in the G1 phase at IC50 and shifted to S phase arrest at >IC50. In vivo, ivermectin reduced the tumor size which was associated with inactivation of WNT/β-catenin signaling and cell proliferation pathways and activation of cell death signaling pathways.Conclusion: Ivermectin could be recognized as a repositioning candidate in treatment of gastric cancer.

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Established fibrous peritoneal metastasis in an immunocompetent mouse model accurately reflects the real clinical immune microenvironment of gastric cancer

10.21203/rs.3.rs-41049/v1 ◽

2020 ◽

Author(s):

Daisuke Fujimori ◽

Jun Kinoshita ◽

Takahisa Yamaguchi ◽

Yusuke Nakamura ◽

Katsuya Gunjigake ◽

...

Keyword(s):

Gastric Cancer ◽

Mouse Model ◽

Cell Line ◽

Peritoneal Metastasis ◽

Treatment Strategies ◽

M2 Macrophages ◽

Immunocompetent Mouse ◽

Immune Microenvironment ◽

Fibrous Stroma ◽

Immunocompetent Mice

Abstract Background Peritoneal metastasis (PM) in gastric cancer (GC) is characterized by diffusely infiltrating and proliferating cancer cells accompanied by extensive stromal fibrosis in the peritoneal space. The prognosis of GC with PM is still poor regardless of the various current treatments. In order to elucidate the cause of difficulties in PM treatment, we compared the tumor immune microenvironment (TME) in primary and PM lesions in GC. In addition, a PM model with fibrous stroma was constructed using immunocompetent mice to determine whether its TME was similar to that in patients. MethodsImmuno-histochemical analyses of infiltrating immune cells were performed in paired primary and PM lesions from 28 patients with GC. A C57BL/6J mouse model with PM was established using the mouse GC cell line YTN16 either with or without co-inoculation of mouse myofibroblast cell line LmcMF with a-SMA expression. The resected PM from each mouse model was analyzed the immunocompetent cells using immunohistochemistry.ResultsThe number of CD8+ cells was significantly lower in PM lesions than in primary lesions (P<0.01). Conversely, the number of CD163+ cells (M2 macrophages) was significantly higher in PM lesions than in primary lesions (P=0.016). Azan staining revealed that YTN16 and LmcMF co-inoculated tumors were more fibrous than tumor with YTN16 alone (P<0.05). Co-inoculated fibrous tumor also showed an invasive growth pattern and higher progression than tumor with YTN16 alone (P=0.045). Additionally, YTN16 and LmcMF co-inoculated tumors showed lower infiltration of CD8+ cells and higher infiltration of M2 macrophages than tumors with YTN16 alone (P<0.05, P<0.05). These results indicate that LmcMF plays as cancer-associated fibroblasts (CAFs) by crosstalk with YTN16 and CAFs contribute tumor progression, invasion, fibrosis, and immune suppression.ConclusionsThis model is the first immunocompetent mouse model to accurately reflect the TME of human clinical PM. By using this model, new treatment strategies for PM, such as anti-CAFs therapies, may be developed.

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MiR495- and miR551a-mediated down-regulation of PRL-3 expression inhibits peritoneal metastasis in a mouse model of gastric cancer

World Chinese Journal of Digestology ◽

10.11569/wcjd.v21.i18.1693 ◽

2013 ◽

Vol 21 (18) ◽

pp. 1693

Author(s):

Mu Xu ◽

Yi Cao ◽

Meng-Meng Jiang ◽

Zhi-Gang Jie ◽

Zheng-Rong Li

Keyword(s):

Gastric Cancer ◽

Mouse Model ◽

Peritoneal Metastasis ◽

Down Regulation

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Established fibrous peritoneal metastasis in an immunocompetent mouse model similar to clinical immune microenvironment of gastric cancer

10.21203/rs.3.rs-41049/v2 ◽

2020 ◽

Author(s):

Daisuke Fujimori ◽

Jun Kinoshita ◽

Takahisa Yamaguchi ◽

Yusuke Nakamura ◽

Katsuya Gunjigake ◽

...

Keyword(s):

Gastric Cancer ◽

Mouse Model ◽

Cell Line ◽

Peritoneal Metastasis ◽

Treatment Strategies ◽

M2 Macrophages ◽

Immunocompetent Mouse ◽

Immune Microenvironment ◽

Fibrous Stroma ◽

Immunocompetent Mice

Abstract Background Peritoneal metastasis (PM) in gastric cancer (GC) is characterized by diffusely infiltrating and proliferating cancer cells accompanied by extensive stromal fibrosis in the peritoneal space. The prognosis of GC with PM is still poor regardless of the various current treatments. In order to elucidate the cause of difficulties in PM treatment, we compared the tumor immune microenvironment (TME) in primary and PM lesions in GC. In addition, a PM model with fibrous stroma was constructed using immunocompetent mice to determine whether its TME was similar to that in patients. Methods Immuno-histochemical analyses of infiltrating immune cells were performed in paired primary and PM lesions from 28 patients with GC. A C57BL/6J mouse model with PM was established using the mouse GC cell line YTN16 either with or without co-inoculation of mouse myofibroblast cell line LmcMF with a-SMA expression. The resected PM from each mouse model was analyzed the immunocompetent cells using immunohistochemistry.Results The number of CD8+ cells was significantly lower in PM lesions than in primary lesions (P<0.01). Conversely, the number of CD163+ cells (M2 macrophages) was significantly higher in PM lesions than in primary lesions (P=0.016). Azan staining revealed that YTN16 and LmcMF co-inoculated tumors were more fibrous than tumor with YTN16 alone (P<0.05). Co-inoculated fibrous tumor also showed an invasive growth pattern and higher progression than tumor with YTN16 alone (P=0.045). Additionally, YTN16 and LmcMF co-inoculated tumors showed lower infiltration of CD8+ cells and higher infiltration of M2 macrophages than tumors with YTN16 alone (P<0.05, P<0.05). These results indicate that LmcMF plays as cancer-associated fibroblasts (CAFs) by crosstalk with YTN16 and CAFs contribute tumor progression, invasion, fibrosis, and immune suppression.Conclusions This model is the first immunocompetent mouse model to accurately reflect the similar to TME of human clinical PM with fibrosis. By using this model, new treatment strategies for PM, such as anti-CAFs therapies, may be developed.

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