Carcinogenesis最新文献_第5页

Macropinocytosis inhibits alkaliptosis in pancreatic cancer cells through fatty acid uptake. 大吞噬作用通过脂肪酸摄取抑制胰腺癌细胞的碱中毒。

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-12-30 DOI: 10.1093/carcin/bgae045

Fangquan Chen, Hu Tang, Junhao Lin, Limin Xiang, Yanjiao Lu, Rui Kang, Daolin Tang, Jiao Liu

{"title":"Macropinocytosis inhibits alkaliptosis in pancreatic cancer cells through fatty acid uptake.","authors":"Fangquan Chen, Hu Tang, Junhao Lin, Limin Xiang, Yanjiao Lu, Rui Kang, Daolin Tang, Jiao Liu","doi":"10.1093/carcin/bgae045","DOIUrl":"10.1093/carcin/bgae045","url":null,"abstract":"Alkaliptosis, a form of regulated cell death, is characterized by lysosomal dysfunction and intracellular pH alkalinization. The pharmacological induction of alkaliptosis using the small molecule compound JTC801 has emerged as a promising anticancer strategy in various types of cancers, particularly pancreatic ductal adenocarcinoma (PDAC). In this study, we investigate a novel mechanism by which macropinocytosis, an endocytic process involving the uptake of extracellular material, promotes resistance to alkaliptosis in human PDAC cells. Through lipid metabolomics analysis and functional studies, we demonstrate that the inhibition of alkaliptosis by fatty acids, such as oleic acid, is not dependent on endogenous synthetic pathways but rather on exogenous uptake facilitated by macropinocytosis. Consequently, targeting macropinocytosis through pharmacological approaches (e.g. using EIPA or EHoP-016) or genetic interventions (e.g. RAC1 knockdown) effectively enhances JTC801-induced alkaliptosis in human PDAC cells. These findings provide compelling evidence that the modulation of macropinocytosis can increase the sensitivity of cancer cells to alkaliptosis inducers.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"953-964"},"PeriodicalIF":3.3,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141615959","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

EIF2S2 transcriptionally upregulates HIF1α to promote gastric cancer progression via activating PI3K/AKT/mTOR pathway. EIF2S2 通过激活 PI3K/AKT/mTOR 通路，转录上调 HIF1α 以促进胃癌进展。

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-12-30 DOI: 10.1093/carcin/bgae043

Zhiyong Wang, Yingyi Zhang, Yingwei Xue, Wei Huang, Hongfeng Zhang

{"title":"EIF2S2 transcriptionally upregulates HIF1α to promote gastric cancer progression via activating PI3K/AKT/mTOR pathway.","authors":"Zhiyong Wang, Yingyi Zhang, Yingwei Xue, Wei Huang, Hongfeng Zhang","doi":"10.1093/carcin/bgae043","DOIUrl":"10.1093/carcin/bgae043","url":null,"abstract":"Eukaryotic translation initiation factor 2 subunit beta (EIF2S2) is a protein that controls protein synthesis under various stress conditions and is abnormally expressed in several cancers. However, there is limited insight regarding the expression and molecular role of EIF2S2 in gastric cancer. In this study, we identified the overexpression of EIF2S2 in gastric cancer by immunohistochemical staining and found a positive correlation between EIF2S2 expression and shorter overall survival and disease-free survival. Functionally, we revealed that EIF2S2 knockdown suppressed gastric cancer cell proliferation and migration, induced cell apoptosis, and caused G2 phase cell arrest. Additionally, EIF2S2 is essential for in vivo tumor formation. Mechanistically, we demonstrated that EIF2S2 transcriptionally regulated hypoxia-inducible factor-1 alpha (HIF1α) expression by NRF1. The promoting role of EIF2S2 in malignant behaviors of gastric cancer cells depended on HIF1α expression. Furthermore, the PI3K/AKT/mTOR signaling was activated upon EIF2S2 overexpression in gastric cancer. Collectively, EIF2S2 exacerbates gastric cancer progression via targeting HIF1α, providing a fundamental basis for considering EIF2S2 as a potential therapeutic target for gastric cancer patients.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"916-927"},"PeriodicalIF":3.3,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141751182","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

From precursor to cancer: decoding the intrinsic and extrinsic pathways of pancreatic intraepithelial neoplasia progression. 从前驱体到癌症：胰腺上皮内瘤发展的内在和外在途径解码。

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-11-22 DOI: 10.1093/carcin/bgae064

Sarah Graham, Mariia Dmitrieva, Debora Barbosa Vendramini-Costa, Ralph Francescone, Maria A Trujillo, Edna Cukierman, Laura D Wood

{"title":"From precursor to cancer: decoding the intrinsic and extrinsic pathways of pancreatic intraepithelial neoplasia progression.","authors":"Sarah Graham, Mariia Dmitrieva, Debora Barbosa Vendramini-Costa, Ralph Francescone, Maria A Trujillo, Edna Cukierman, Laura D Wood","doi":"10.1093/carcin/bgae064","DOIUrl":"10.1093/carcin/bgae064","url":null,"abstract":"This review explores the progression of pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma through a dual lens of intrinsic molecular alterations and extrinsic microenvironmental influences. PanIN development begins with Kirsten rat sarcoma viral oncogene (KRAS) mutations driving PanIN initiation. Key additional mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein p53 (TP53), and mothers against decapentaplegic homolog 4 (SMAD4) disrupt cell cycle control and genomic stability, crucial for PanIN progression from low-grade to high-grade dysplasia. Additional molecular alterations in neoplastic cells, including epigenetic modifications and chromosomal alterations, can further contribute to neoplastic progression. In parallel with these alterations in neoplastic cells, the microenvironment, including fibroblast activation, extracellular matrix remodeling, and immune modulation, plays a pivotal role in PanIN initiation and progression. Crosstalk between neoplastic and stromal cells influences nutrient support and immune evasion, contributing to tumor development, growth, and survival. This review underscores the intricate interplay between cell-intrinsic molecular drivers and cell-extrinsic microenvironmental factors, shaping PanIN predisposition, initiation, and progression. Future research aims to unravel these interactions to develop targeted therapeutic strategies and early detection techniques, aiming to alleviate the severe impact of pancreatic cancer by addressing both genetic predispositions and environmental influences.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"801-816"},"PeriodicalIF":3.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602998","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

Call for Applications. 征集申请。

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-11-22 DOI: 10.1093/carcin/bgae068

引用次数: 0

Exogenous or in situ vaccination to trigger clinical responses in pancreatic cancer. 外源性或原位疫苗接种引发胰腺癌临床反应。

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-11-22 DOI: 10.1093/carcin/bgae065

Gregory L Beatty, Elizabeth M Jaffee

{"title":"Exogenous or in situ vaccination to trigger clinical responses in pancreatic cancer.","authors":"Gregory L Beatty, Elizabeth M Jaffee","doi":"10.1093/carcin/bgae065","DOIUrl":"10.1093/carcin/bgae065","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDA) is a lethal disease for which remarkable therapeutic resistance is the norm. Conventional immunotherapies, like immune checkpoint inhibitors, show limited efficacy in PDA due to a remarkably immunosuppressive tumor microenvironment (TME) and systemic inflammation. This review discusses the potential of both exogenous and in situ vaccination strategies to overcome these barriers and enhance anti-tumor immunity in PDA. Exogenous vaccines, including whole-cell, dendritic cell, peptide, and nucleic acid-based vaccines, have shown varying degrees of promise but face challenges related to antigen selection, production complexities, and patient-specific factors. In contrast, in situ vaccination strategies leverage conventional cytotoxic therapies, such as chemotherapy and radiation therapy, to induce immunogenic cell death and modulate the TME with the aim to stimulate anti-tumor immunity. While preclinical studies support the use of in situ vaccination, balancing the stimulatory and inhibitory effects is likely fundamental to eliciting productive anti-tumor responses in patients. Ongoing research seeks to identify new innovative strategies that can harness the endogenous immune response and trigger in situ vaccination. Overall, while both vaccination approaches offer significant potential, further research and clinical trials will be needed to optimize these strategies for improving patient outcomes in PDA.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"826-835"},"PeriodicalIF":3.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11584293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602979","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

ADRA2A promotes the classical/progenitor subtype and reduces disease aggressiveness of pancreatic cancer. ADRA2A 可促进胰腺癌的经典/祖细胞亚型并降低疾病的侵袭性。

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-11-22 DOI: 10.1093/carcin/bgae056

Paloma Moreno, Yuuki Ohara, Amanda J Craig, Huaitian Liu, Shouhui Yang, Tiffany H Dorsey, Lin Zhang, Gatikrushna Panigrahi, Helen Cawley, Azadeh Azizian, Jochen Gaedcke, Michael Ghadimi, Nader Hanna, S Perwez Hussain

{"title":"ADRA2A promotes the classical/progenitor subtype and reduces disease aggressiveness of pancreatic cancer.","authors":"Paloma Moreno, Yuuki Ohara, Amanda J Craig, Huaitian Liu, Shouhui Yang, Tiffany H Dorsey, Lin Zhang, Gatikrushna Panigrahi, Helen Cawley, Azadeh Azizian, Jochen Gaedcke, Michael Ghadimi, Nader Hanna, S Perwez Hussain","doi":"10.1093/carcin/bgae056","DOIUrl":"10.1093/carcin/bgae056","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) manifests diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, with the latter known for its aggressiveness. We employed integrative transcriptome and metabolome analyses to identify potential genes contributing to the molecular subtype differentiation and its metabolic features. Our comprehensive analysis revealed that adrenoceptor alpha 2A (ADRA2A) was downregulated in the basal-like/squamous subtype, suggesting its potential role as a candidate suppressor of this subtype. Reduced ADRA2A expression was significantly associated with a high frequency of lymph node metastasis, higher pathological grade, advanced disease stage, and decreased survival among PDAC patients. In vitro experiments demonstrated that ADRA2A transgene expression and ADRA2A agonist inhibited PDAC cell invasion. Additionally, ADRA2A-high condition downregulated the basal-like/squamous gene expression signature, while upregulating the classical/progenitor gene expression signature in our PDAC patient cohort and PDAC cell lines. Metabolome analysis conducted on the PDAC cohort and cell lines revealed that elevated ADRA2A levels were associated with suppressed amino acid and carnitine/acylcarnitine metabolism, which are characteristic metabolic profiles of the classical/progenitor subtype. Collectively, our findings suggest that heightened ADRA2A expression induces transcriptome and metabolome characteristics indicative of classical/progenitor subtype with decreased disease aggressiveness in PDAC patients. These observations introduce ADRA2A as a candidate for diagnostic and therapeutic targeting in PDAC.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"845-856"},"PeriodicalIF":3.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11584292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970675","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

Redefining pancreatic cancer management with tumor-agnostic precision medicine. 用肿瘤诊断精准医学重新定义胰腺癌治疗。

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-11-22 DOI: 10.1093/carcin/bgae066

Neha K Reddy, Vivek Subbiah

{"title":"Redefining pancreatic cancer management with tumor-agnostic precision medicine.","authors":"Neha K Reddy, Vivek Subbiah","doi":"10.1093/carcin/bgae066","DOIUrl":"10.1093/carcin/bgae066","url":null,"abstract":"Precision oncology and tumor-agnostic drug development provide hope for enhancing outcomes among patients with pancreatic cancer. Tumor-agnostic therapies have emerged across various tumor types, driven by insights into shared biomarkers. In the case of pancreatic cancer, the prevalence of the KRAS gene mutation is noteworthy. However, there exist other actionable alterations, such as BRCA1/2 mutations and fusion genes (BRAF, FGFR2, RET, NTRK, NRG1, and ALK), which present potential targets for therapy. Notably, tumor-agnostic drugs have demonstrated efficacy in specific subsets of pancreatic cancer patients who harbor these genetic alterations. Despite the rarity of NTRK fusions in pancreatic cancer, larotrectinib and entrectinib have exhibited effectiveness in NTRK fusion-positive pancreatic cancers. Additionally, repotrectinib, a next-generation NTRK inhibitor, has shown promising activity in NTRK positive pancreatic cancer patients who have developed acquired resistance to previous NTRK inhibitors. Immune checkpoint inhibitors, such as pembrolizumab and dostarlimab, have proven to be effective in dMMR/MSI-H pancreatic cancers. Moreover, targeted therapies for BRAF V600, RET fusions, and HER2/neu overexpression have displayed promising results in specific subsets of pancreatic cancer patients. Emerging targets like NRG fusions, FGFR2 fusions, TP53 mutations, and KRAS G12C mutations present potential avenues for targeted therapy. Tumor-agnostic therapies have the potential to revolutionize pancreatic cancer treatment by focusing on specific genetic alterations. It is crucial to continue implementing comprehensive screening strategies that encompass the ability to detect all these tumor-agnostic biomarkers. This will be essential in identifying pancreatic cancer patients who may benefit from these therapies.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"836-844"},"PeriodicalIF":3.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603006","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

The interplay of DNA damage and repair, gene expression, and mutagenesis in mammalian cells during oxidative stress. 氧化应激过程中哺乳动物细胞中 DNA 损伤与修复、基因表达和诱变的相互作用。

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-11-22 DOI: 10.1093/carcin/bgae046

Ahmad Besaratinia, Andrew W Caliri, Stella Tommasi

{"title":"The interplay of DNA damage and repair, gene expression, and mutagenesis in mammalian cells during oxidative stress.","authors":"Ahmad Besaratinia, Andrew W Caliri, Stella Tommasi","doi":"10.1093/carcin/bgae046","DOIUrl":"10.1093/carcin/bgae046","url":null,"abstract":"We investigated the interplay among oxidative DNA damage and repair, expression of genes encoding major base excision repair (BER) enzymes and bypass DNA polymerases, and mutagenesis in mammalian cells. Primary mouse embryonic fibroblasts were challenged with oxidative stress induced by methylene blue plus visible light, and formation and repair of DNA damage, changes in gene expression, and mutagenesis were determined at increasing intervals posttreatment (0-192 hours). Significant formation of oxidative DNA damage together with upregulation of Ogg1, Polβ, and Polκ, and no changes in Mutyh and Nudt1 expression were found in treated cells. There was a distinct interconnection between Ogg1 and Polβ expression and DNA damage formation and repair whereby changes in expression of these two genes were proportionate to the levels of oxidative DNA damage, once a 3-plus hour lag time passed (P < .05). Equally notable was the matching pattern of Polκ expression and kinetics of oxidative DNA damage and repair (P < .05). The DNA damage and gene expression data were remarkably consistent with mutagenicity data in the treated cells; the induced mutation spectrum is indicative of erroneous bypass of oxidized DNA bases and incorporation of oxidized deoxynucleoside triphosphates during replication of the genomic DNA. Our findings support follow-up functional studies to elucidate how oxidation of DNA bases and the nucleotide pool, overexpression of Polκ, delayed upregulation of Ogg1 and Polβ, and inadequate expression of Nudt1 and Mutyh collectively affect mutagenesis consequent to oxidative stress.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"868-879"},"PeriodicalIF":3.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11584291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632699","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

Editorial: special issue on the latest advances and challenges in pancreas cancer research in memory of S. Perwez Hussain. 编辑：纪念 S. Perwez Hussain 的胰腺癌研究最新进展与挑战特刊。

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-11-22 DOI: 10.1093/carcin/bgae069

Christine Alewine, Curtis C Harris, Anirban Maitra, Sharon R Pine, David Tuveson

引用次数: 0

The evolving role for surgery in pancreatic cancer. 外科手术在胰腺癌中不断演变的角色。

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-11-22 DOI: 10.1093/carcin/bgae062

David Tuveson, Peter Allen

引用次数: 0