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

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 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.

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

BMC Cancer ◽  
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.

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

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.

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

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.

scholarly journals Risk Factors for Metachronous Isolated Peritoneal Metastasis after Preoperative Chemotherapy and Potentially Curative Gastric Cancer Resection: Results from the CRITICS Trial

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4626
Author(s):  
Irene A. Caspers ◽  
Karolina Sikorska ◽  
Astrid E. Slagter ◽  
Romy M. van Amelsfoort ◽  
Elma Meershoek-Klein Kranenbarg ◽  
...  
Keyword(s):  
Risk Factors ◽  
Gastric Cancer ◽  
Lymph Node ◽  
Preoperative Chemotherapy ◽  
Peritoneal Metastasis ◽  
Risk Model ◽  
Treatment Strategies ◽  
Histological Subtype ◽  
Multivariable Analyses ◽  
Independent Risk Factors

Gastric cancer (GC) patients at high risk of developing peritoneal metastasis (PM) as a single site of metastasis after curative treatment may be candidates for adjuvant prophylactic strategies. Here we investigated risk factors for metachronous isolated PM in patients who were treated in the CRITICS trial (NCT00407186). Univariable and multivariable analyses on both metachronous isolated PM and ‘other events’, i.e., (concurrent) distant metastasis, locoregional recurrence or death, were performed using a competing risk model and summarized by cumulative incidences. Isolated PM occurred in 64 of the 606 (11%) included patients. Diffuse or mixed histological subtype, ypT4 tumor stage and LNhigh (ypN3 lymph node stage or a lymph node ratio >20%) were independent risk factors for isolated PM in both univariable and multivariable analyses. Likewise, LNhigh was an independent risk factor for ‘other events’. Patients with tumors who were positive for all three independent risk factors had the highest two-year cumulative incidence of 43% for isolated PM development. In conclusion, diffuse or mixed histological subtype, ypT4 and LNhigh were identified as independent risk factors for isolated PM in patients treated with preoperative chemotherapy followed by surgical resection. The combination of these factors may identify a subgroup that may benefit from PM-preventing treatment strategies.

scholarly journals The Pyroptosis-Related Signature Predicts Prognosis and Indicates Immune Microenvironment Infiltration in Gastric Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Wei Shao ◽  
Zongcheng Yang ◽  
Yue Fu ◽  
Lixin Zheng ◽  
Fen Liu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cox Regression ◽  
Treatment Strategies ◽  
Future Research ◽  
Consensus Clustering ◽  
Immune Microenvironment ◽  
Chemotherapy Drugs ◽  
Response To Chemotherapy ◽  
Prognosis Model ◽  
Cox Analysis

Gastric cancer (GC) is one of the leading causes of cancer-related deaths and shows high levels of heterogeneity. The development of a specific prognostic model is important if we are to improve treatment strategies. Pyroptosis can arise in response to H. pylori, a primary carcinogen, and also in response to chemotherapy drugs. However, the prognostic evaluation of GC to pyroptosis is insufficient. Consensus clustering by pyroptosis-related regulators was used to classify 618 patients with GC from four GEO cohorts. Following Cox regression with differentially expressed genes, our prognosis model (PS-score) was built by LASSO-Cox analysis. The TCGA-STAD cohort was used as the validation set. ESTIMATE, CIBERSORTx, and EPIC were used to investigate the tumor microenvironment (TME). Immunotherapy cohorts by blocking PD1/PD-L1 were used to investigate the treatment response. The subtyping of GC based on pyroptosis-related regulators was able to classify patients according to different clinical traits and TME. The difference between the two subtypes identified in this study was used to develop a prognosis model which we named “PS-score.” The PS-score could predict the prognosis of patients with GC and his/her overall survival time. A low PS-score implies greater inflammatory cell infiltration and better response of immunotherapy by PD1/PD-L1 blockers. Our findings provide a foundation for future research targeting pyroptosis and its immune microenvironment to improve prognosis and responses to immunotherapy.

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