Carcinogenesis最新文献_第8页

CD133-containing microvesicles promote cancer progression by inducing M2-like tumor-associated macrophage polarization in the tumor microenvironment of colorectal cancer. 含 CD133 的微囊泡通过诱导结直肠癌肿瘤微环境中的 M2 类肿瘤相关巨噬细胞极化来促进癌症进展。

IF 4.7 3区医学

Carcinogenesis Pub Date : 2024-05-19 DOI: 10.1093/carcin/bgad093

Sang Yun Kim, Sungyeon Park, Suhyun Kim, Jesang Ko

{"title":"CD133-containing microvesicles promote cancer progression by inducing M2-like tumor-associated macrophage polarization in the tumor microenvironment of colorectal cancer.","authors":"Sang Yun Kim, Sungyeon Park, Suhyun Kim, Jesang Ko","doi":"10.1093/carcin/bgad093","DOIUrl":"10.1093/carcin/bgad093","url":null,"abstract":"Tumor-associated macrophages (TAMs) are among the most abundant cell types in the tumor microenvironment (TME). The immunosuppressive TME formed by TAMs is an essential prerequisite for cancer progression. Tumor-derived microvesicles (MVs), a subtype of extracellular vesicle shed directly from the plasma membrane, are important regulators of intercellular communication and TME modulation during tumorigenesis. However, the exact mechanism by which tumor-derived MVs induce the generation of the immunosuppressive TME and polarization of TAMs remains unclear. Here, we investigated the role of CD133-containing MVs derived from colorectal cancer (CRC) cells in macrophage polarization and cancer progression. CD133-containing MVs from CRC cells were incorporated into macrophages, and M0 macrophages were morphologically transformed into M2-like TAMs. CD133-containing MVs were found to increase the mRNA expression of M2 macrophage markers. Additionally, cytokine array analysis revealed that M2-like TAMs induced by CD133-containing MVs increased the secretion of interleukin 6, which activated the STAT3 pathway in CRC cells. Furthermore, the conditioned medium of M2-like TAMs promoted cell motility, epithelial-mesenchymal transition, and cell proliferation. However, MVs from CD133-knockdown cells had little effect on TAM polarization and CRC progression. These results demonstrate that CD133-containing MVs induce M2-like TAM polarization and contribute to cancer progression by mediating crosstalk between tumor cells and TAMs in the TME of CRC.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"300-310"},"PeriodicalIF":4.7,"publicationDate":"2024-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138797640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An update on the formation in tobacco, toxicity and carcinogenicity of N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. 关于 N'-Nitrosonornicotine 和 4-(Methylnitrosamino)-1-(3-吡啶基)-1-丁酮在烟草中的形成、毒性和致癌性的最新情况。

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-05-19 DOI: 10.1093/carcin/bgae018

Lisa A Peterson, Stephen B Stanfill, Stephen S Hecht

{"title":"An update on the formation in tobacco, toxicity and carcinogenicity of N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.","authors":"Lisa A Peterson, Stephen B Stanfill, Stephen S Hecht","doi":"10.1093/carcin/bgae018","DOIUrl":"10.1093/carcin/bgae018","url":null,"abstract":"The tobacco-specific nitrosamines N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are considered 'carcinogenic to humans' by the International Agency for Research on Cancer (IARC) and are believed to be important in the carcinogenic effects of both smokeless tobacco and combusted tobacco products. This short review focuses on the results of recent studies on the formation of NNN and NNK in tobacco, and their carcinogenicity and toxicity in laboratory animals. New mechanistic insights are presented regarding the role of dissimilatory nitrate reductases in certain microorganisms involved in the conversion of nitrate to nitrite that leads to the formation of NNN and NNK during curing and processing of tobacco. Carcinogenicity studies of the enantiomers of the major NNK metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and the enantiomers of NNN are reviewed. Recent toxicity studies of inhaled NNK and co-administration studies of NNK with formaldehyde, acetaldehyde, acrolein and CO2, all of which occur in high concentrations in cigarette smoke, are discussed.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"275-287"},"PeriodicalIF":3.3,"publicationDate":"2024-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11102769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140027434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PTCH1 mutation as a potential predictive biomarker for immune checkpoint inhibitors in gastrointestinal cancer. PTCH1突变作为胃肠癌免疫检查点抑制剂的潜在预测生物标记物。

IF 4.7 3区医学

Carcinogenesis Pub Date : 2024-05-19 DOI: 10.1093/carcin/bgae007

Shuangya Deng, Haoran Gu, ZongYao Chen, Yaqin Liu, Qin Zhang, Dongsheng Chen, Shengen Yi

{"title":"PTCH1 mutation as a potential predictive biomarker for immune checkpoint inhibitors in gastrointestinal cancer.","authors":"Shuangya Deng, Haoran Gu, ZongYao Chen, Yaqin Liu, Qin Zhang, Dongsheng Chen, Shengen Yi","doi":"10.1093/carcin/bgae007","DOIUrl":"10.1093/carcin/bgae007","url":null,"abstract":"Immune checkpoint inhibitors (ICIs) have become prominent therapies for gastrointestinal cancer (GC). However, it is urgent to screen patients who can benefit from ICIs. Protein patched homolog 1 (PTCH1) is a frequently altered gene in GC. We attempt to explore the association between PTCH1 mutation and immunotherapy efficacy. The Memorial Sloan Kettering Cancer Center (MSKCC) cohort (n = 236) with GC (esophageal, gastric and colorectal cancers) patients receiving ICIs was used for discovery and the Peking University Cancer Hospital (PUCH) GC cohort (n = 92) was used for validation. Overall survival (OS) and tumor mutational burden (TMB) of the PTCH1 mutant-type (PTCH1-MUT) and PTCH1 wild-type (PTCH1-WT) groups were compared. Furthermore, GC data were collected from The Cancer Genome Atlas to assess the potential mechanisms. In the MSKCC cohort, PTCH1-MUT group showed significantly better OS (P = 0.017) and higher TMB. Multivariate analysis showed that PTCH1 mutation was associated with better OS. In the PUCH cohort, PTCH1-MUT group showed significantly longer OS (P = 0.036) and progression-free survival, and higher durable clinical benefit and TMB. Immune cell infiltration analysis revealed that PTCH1-MUT group had significantly higher distributions of CD8 T cells, CD4 T cells, NK cells, mast cells and M1 cells. The PTCH1-MUT group showed significantly higher expression of most immune-related genes. Gene set enrichment analysis showed that the PTCH1-MUT group had enriched INF-γ response, INF-α response, glycolysis and reactive oxygen species pathway gene sets. PTCH1 mutation may represent a potential biomarker for predicting ICIs response in GC. Nevertheless, prospective cohort studies should be performed to further validate our results.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"351-357"},"PeriodicalIF":4.7,"publicationDate":"2024-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139680712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

LncRNA CARD8-AS1 suppresses lung adenocarcinoma progression by enhancing TRIM25-mediated ubiquitination of TXNRD1. LncRNA CARD8-AS1 通过增强 TRIM25 介导的 TXNRD1 泛素化抑制肺腺癌的进展。

IF 4.7 3区医学

Carcinogenesis Pub Date : 2024-05-19 DOI: 10.1093/carcin/bgad097

Cheng Pan, Qi Wang, Hongshun Wang, Xiaheng Deng, Liang Chen, Zhihua Li

{"title":"LncRNA CARD8-AS1 suppresses lung adenocarcinoma progression by enhancing TRIM25-mediated ubiquitination of TXNRD1.","authors":"Cheng Pan, Qi Wang, Hongshun Wang, Xiaheng Deng, Liang Chen, Zhihua Li","doi":"10.1093/carcin/bgad097","DOIUrl":"10.1093/carcin/bgad097","url":null,"abstract":"Long non-coding RNAs (lncRNAs) play crucial roles in the tumorigenesis and progression of lung adenocarcinoma (LUAD). However, little was known about the role of lncRNAs in high-risk LUAD subtypes: micropapillary-predominant adenocarcinoma (MPA) and solid-predominant adenocarcinoma (SPA). In this study, we conducted a systematic screening of differentially expressed lncRNAs using RNA sequencing in 10 paired MPA/SPA tumor tissues and adjacent normal tissues. Consequently, 110 significantly up-regulated lncRNAs and 288 aberrantly down-regulated lncRNAs were identified (|Log2 Foldchange| ≥ 1 and corrected P < 0.05). The top 10 lncRNAs were further analyzed in 89 MPA/SPA tumor tissues and 59 normal tissues from The Cancer Genome Atlas database. Among them, CARD8-AS1 showed the most significant differential expression, and decreased expression of CARD8-AS1 was significantly associated with a poorer prognosis. Functionally, CARD8-AS1 overexpression remarkably suppressed the proliferation, migration and invasion of LUAD cells both in vitro and in vivo. Conversely, inhibition of CARD8-AS1 yielded opposite effects. Mechanistically, CARD8-AS1 acted as a scaffold to facilitate the interaction between TXNRD1 and E3 ubiquitin ligase TRIM25, thereby promoting the degradation of TXNRD1 through the ubiquitin-proteasome pathway. Additionally, TXNRD1 was found to promote LUAD cell proliferation, migration and invasion in vitro. Furthermore, the suppressed progression of LUAD cells resulting from CARD8-AS1 overexpression could be significantly reversed by simultaneous overexpression of TXNRD1. In conclusion, this study revealed that the lncRNA CARD8-AS1 played a suppressive role in the progression of LUAD by enhancing TRIM25-mediated ubiquitination of TXNRD1. The CARD8-AS1-TRIM25-TXNRD1 axis may represent a promising therapeutic target for LUAD.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"311-323"},"PeriodicalIF":4.7,"publicationDate":"2024-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139048365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction to: (-)-Epigallocatechin-3-gallate and DZNep reduce polycomb protein level via a proteasome-dependent mechanism in skin cancer cells. 更正：(-)-表没食子儿茶素-3-棓酸盐和 DZNep 通过蛋白酶体依赖机制降低皮肤癌细胞中多聚体蛋白的水平。

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-05-19 DOI: 10.1093/carcin/bgad045

引用次数: 0

E3 ubiquitin ligase RNF148 functions as an oncogene in colorectal cancer by ubiquitination-mediated degradation of CHAC2. E3泛素连接酶RNF148通过泛素化介导的CHAC2降解在结直肠癌中发挥癌基因的功能。

IF 4.7 3区医学

Carcinogenesis Pub Date : 2024-04-12 DOI: 10.1093/carcin/bgae002

Shuiping Liu, Lvjia Zhuo, Lu Chen, Ying He, Xudong Chen, Hao Zhang, Yuan Zhou, Ziheng Ni, Shujuan Zhao, Xiaotong Hu

{"title":"E3 ubiquitin ligase RNF148 functions as an oncogene in colorectal cancer by ubiquitination-mediated degradation of CHAC2.","authors":"Shuiping Liu, Lvjia Zhuo, Lu Chen, Ying He, Xudong Chen, Hao Zhang, Yuan Zhou, Ziheng Ni, Shujuan Zhao, Xiaotong Hu","doi":"10.1093/carcin/bgae002","DOIUrl":"10.1093/carcin/bgae002","url":null,"abstract":"We previously reported that RNF148 was involved in the ubiquitination-mediated degradation of CHAC2. However, its molecular mechanism was not determined. In this study, we investigated the role and mechanism of RNF148 in the progression of colorectal cancer (CRC), especially in the process of ubiquitination-mediated degradation of CHAC2. Our results revealed that RNF148 was upregulated in most CRC tissues, and its expression significantly correlated with the 3-year overall survival rate and most clinicopathological parameters of CRC patients. Furthermore, RNF148 served as an independent prognostic biomarker of CRC and promoted CRC cell proliferation and migration while inhibiting cell apoptosis and sensitivity to 5-FU. Mechanistically, RNF148 used its protease-associated domain to bind to the CHAC domain of CHAC2 and target it for degradation. In addition, we identified two phosphorylation and three ubiquitination residues of CHAC2 and identified Y118 and K102 as the critical phosphorylation and ubiquitination residues, respectively. We also identified CHAC2's and RNF148's interacting proteins and discovered their potential interaction network. In conclusion, our current study unveiled the role of RNF148 in CRC and the mechanism of RNF148 in the ubiquitination-mediated degradation of CHAC2, which shed light on providing potential prognostic biomarkers and molecular targets for CRC patients.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"247-261"},"PeriodicalIF":4.7,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139402014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MAGP1 maintains tumorigenicity and angiogenesis of laryngeal cancer by activating Wnt/β-catenin/MMP7 pathway. MAGP1 通过激活 Wnt/β-catenin/MMP7 通路维持喉癌的致瘤性和血管生成。

IF 4.7 3区医学

Carcinogenesis Pub Date : 2024-04-12 DOI: 10.1093/carcin/bgad003

Fei Lv, Xiaoqi Li, Ying Wang, Liying Hao

引用次数: 0

ITGA2 as a prognostic factor of glioma promotes GSCs invasion and EMT by activating STAT3 phosphorylation. ITGA2 是胶质瘤的一个预后因子，它通过激活 STAT3 磷酸化促进 GSCs 的侵袭和 EMT。

IF 4.7 3区医学

Carcinogenesis Pub Date : 2024-04-12 DOI: 10.1093/carcin/bgad096

Jin Zhang, Ruinan Li, Haibin Zhang, Shanshan Wang, Yuanli Zhao

{"title":"ITGA2 as a prognostic factor of glioma promotes GSCs invasion and EMT by activating STAT3 phosphorylation.","authors":"Jin Zhang, Ruinan Li, Haibin Zhang, Shanshan Wang, Yuanli Zhao","doi":"10.1093/carcin/bgad096","DOIUrl":"10.1093/carcin/bgad096","url":null,"abstract":"Glioma is the most common malignant brain tumor in adults with a high mortality and recurrence rate. Integrin alpha 2 (ITGA2) is involved in cell adhesion, stem cell regulation, angiogenesis and immune cell function. The role of ITGA2 in glioma malignant invasion remains unknown. The function and clinical relevance of ITGA2 were analysed by bioinformatics databases. The expression of ITGA2 in parent cells and GSCs was detected by flow cytometry and immunofluorescence double staining. The role of ITGA2 on the malignant phenotype of GSCs and epithelial-mesenchymal transition (EMT) was identified by stem cell function assays and Western blot. The effect of ITGA2 on glioma progression in vivo was determined by the intracranial orthotopic xenograft model. Immunohistochemistry, Spearman correlation and Kaplan-Meier were used to analyse the relationship of ITGA2 with clinical features and glioma prognosis. Biological analysis showed that ITGA2 might be related to cell invasion and migration. ITGA2, enriched in GSCs and co-expressed with SOX2, promoted the invasion and migration of GSCs by activating STAT3 phosphorylation and enhancing EMT. ITGA2 knockout suppressed the intracranial orthotopic xenograft growth and prolonged the survival of xenograft mice. In addition, the expression level of ITGA2 was significantly correlated to the grade of malignancy, N-cadherin and Ki67. High expression of ITGA2 indicated a worse prognosis of glioma patients. As a biomarker for the prediction of prognosis, ITGA2 promotes the malignant invasion of GSCs by activating STAT3 phosphorylation and enhancing EMT, leading to tumor recurrence and poor prognosis.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"235-246"},"PeriodicalIF":4.7,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139032183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Functional genetic variants of the disulfidptosis-related INF2 gene predict survival of hepatitis B virus-related hepatocellular carcinoma. 二硫化相关 INF2 基因的功能性遗传变异可预测乙型肝炎病毒相关肝细胞癌的存活率。

IF 4.7 3区医学

Carcinogenesis Pub Date : 2024-04-12 DOI: 10.1093/carcin/bgae003

Junjie Wei, Qiuping Wen, Shicheng Zhan, Ji Cao, Yanji Jiang, Jiawei Lian, Yuejiao Mai, Moqin Qiu, Yingchun Liu, Peiqin Chen, Qiuling Lin, Xiaoxia Wei, Yuying Wei, Qiongguang Huang, Ruoxin Zhang, Songqing He, Guandou Yuan, Qingyi Wei, Zihan Zhou, Hongping Yu

{"title":"Functional genetic variants of the disulfidptosis-related INF2 gene predict survival of hepatitis B virus-related hepatocellular carcinoma.","authors":"Junjie Wei, Qiuping Wen, Shicheng Zhan, Ji Cao, Yanji Jiang, Jiawei Lian, Yuejiao Mai, Moqin Qiu, Yingchun Liu, Peiqin Chen, Qiuling Lin, Xiaoxia Wei, Yuying Wei, Qiongguang Huang, Ruoxin Zhang, Songqing He, Guandou Yuan, Qingyi Wei, Zihan Zhou, Hongping Yu","doi":"10.1093/carcin/bgae003","DOIUrl":"10.1093/carcin/bgae003","url":null,"abstract":"Disulfidptosis is a novel form of programmed cell death involved in migration and invasion of cancer cells, but few studies investigated the roles of genetic variants in disulfidptosis-related genes in survival of patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). We used Cox proportional hazards regression analyses, Kaplan-Meier curves and receiver operating characteristic curves to assess effects of genetic variants in 14 disulfidptosis-related genes on overall survival of 866 HBV-HCC patients. The Bayesian false discovery probability was used for multiple testing corrections. We also investigated biological mechanisms of the significant variants through expression quantitative trait loci analyses using the data from publicly available databases, luciferase reporter assays and differential expression analyses. As a result, we identified two independently functional single nucleotide polymorphisms (SNPs) (INF2 rs4072285 G > A and INF2 rs4444271 A > T) that predicted overall survival of HBV-HCC patients, with adjusted hazard ratios of 1.60 (95% CI = 1.22-2.11, P = 0.001) and 1.50 (95% CI = 1.80-1.90, P < 0.001), respectively, after multiple testing correction. Luciferase reporter assays indicated that both INF2 rs4072285 A and INF2 rs4444271 T alleles increased INF2 mRNA expression levels (P < 0.001) that were also higher in HCC tumor tissues than in adjacent normal tissues (P < 0.001); such elevated INF2 expression levels were associated with a poorer survival of HBV-HCC patients (P < 0.001) in the TCGA database. In summary, this study supported that INF2 rs4072285 and INF2 rs4444271 may be novel biomarkers for survival of HBV-HCC patients.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"199-209"},"PeriodicalIF":4.7,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139545760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sitravatinib combined with PD-1 blockade enhances cytotoxic T-cell infiltration by M2 to M1 tumor macrophage repolarization in esophageal adenocarcinoma. 西拉瓦替尼联合阻断PD1可增强食管癌中M2 - M1肿瘤巨噬细胞的细胞毒性t细胞浸润。

IF 4.7 3区医学

Carcinogenesis Pub Date : 2024-04-12 DOI: 10.1093/carcin/bgad087

Ryan Sweeney, Ashten N Omstead, John T Fitzpatrick, Ping Zheng, Anastasia Gorbunova, Erin E Grayhack, Arul Goel, Alisha F Khan, Juliann E Kosovec, Patrick L Wagner, Blair A Jobe, Ronan J Kelly, Ali H Zaidi

{"title":"Sitravatinib combined with PD-1 blockade enhances cytotoxic T-cell infiltration by M2 to M1 tumor macrophage repolarization in esophageal adenocarcinoma.","authors":"Ryan Sweeney, Ashten N Omstead, John T Fitzpatrick, Ping Zheng, Anastasia Gorbunova, Erin E Grayhack, Arul Goel, Alisha F Khan, Juliann E Kosovec, Patrick L Wagner, Blair A Jobe, Ronan J Kelly, Ali H Zaidi","doi":"10.1093/carcin/bgad087","DOIUrl":"10.1093/carcin/bgad087","url":null,"abstract":"Esophageal adenocarcinoma (EAC) is a leading cause of cancer-related mortality. Sitravatinib is a novel multi-gene tyrosine kinase inhibitor (TKI) that targets tumor-associated macrophage (TAM) receptors, VEGF, PDGF and c-Kit. Currently, sitravatinib is actively being studied in clinical trials across solid tumors and other TKIs have shown efficacy in combination with immune checkpoint inhibitors (ICI) in cancer models. In this study, we investigated the anti-tumor activity of sitravatinib alone and in combination with PD-1 blockade in an EAC rat model. Treatment response was evaluated by mortality, pre- and post-treatment MRI, gene expression, immunofluorescence and immunohistochemistry. Our results demonstrated adequate safety and significant tumor shrinkage in animals treated with sitravatinib, and more profoundly, sitravatinib and PD-1 inhibitor, AUNP-12 (P < 0.01). Suppression of TAM receptors resulted in increased gene expression of pro-inflammatory cytokines and decreased expression of anti-inflammatory cytokines, enhanced infiltration of CD8+ T cells, and M2 to M1 macrophage phenotype repolarization in the tumor microenvironment of treated animals (P < 0.01). Moreover, endpoint immunohistochemistry staining corroborated the anti-tumor activity by downregulation of Ki67 and upregulation of Caspase-3 in the treated animals. Additionally, pretreatment gene expression of TAM receptors and PD-L1 were significantly higher in major responders compared with the non-responders, in animals that received sitravatinib and AUNP-12 (P < 0.02), confirming that TAM suppression enhances the efficacy of PD-1 blockade. In conclusion, this study proposes a promising immunomodulatory strategy using a multi-gene TKI to overcome developed resistance to an ICI in EAC, establishing rationale for future clinical development.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"210-219"},"PeriodicalIF":4.7,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138457987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0