Carcinogenesis最新文献

Integrative functional screen of genomic loci uncovers CCND2 and its genetic regulatory mechanism in colorectal cancer development.

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-12-16 DOI: 10.1093/carcin/bgae078

Bin Li, Mei Wu, Hui Geng, Yan Li, Zhirui Chen, Zequn Lu, Xu Chen, Qiuhong Wang, Shuxin Song, Xiangpan Li, Xu Zhu, Yongchang Wei, Ying Zhu, Xiaoping Miao, Jianbo Tian, Jiuyang Liu, Chaoqun Huang, Xiaojun Yang

{"title":"Integrative functional screen of genomic loci uncovers CCND2 and its genetic regulatory mechanism in colorectal cancer development.","authors":"Bin Li, Mei Wu, Hui Geng, Yan Li, Zhirui Chen, Zequn Lu, Xu Chen, Qiuhong Wang, Shuxin Song, Xiangpan Li, Xu Zhu, Yongchang Wei, Ying Zhu, Xiaoping Miao, Jianbo Tian, Jiuyang Liu, Chaoqun Huang, Xiaojun Yang","doi":"10.1093/carcin/bgae078","DOIUrl":"https://doi.org/10.1093/carcin/bgae078","url":null,"abstract":"Although genome-wide association studies (GWASs) have identified dozens of loci associated with colorectal cancer (CRC) susceptibility, the causal genes or risk variants within these loci and their biological functions often remain elusive. Recently, the genomic locus 12p13.32, with the tag SNP rs10774214, was identified as a crucial CRC risk locus in Asian populations. However, the functional mechanism of this region has not been fully elucidated. Here, we applied a high-throughput RNA interference (RNAi) approach in CRC cell lines to interrogate the function of genes in this genomic region. Multiple genes were found to affect cell functions, with CCND2 having the most significant effect as an oncogene. Moreover, overexpressed CCND2 could promote CRC cell proliferation. Subsequently, by integrating a fine-mapping analysis and multi-ancestry large-scale population cohorts consisting of 14,358 CRC cases and 34,251 healthy controls, we identified a regulatory variant rs4477507-T that contributed to an increased CRC risk in populations from China (OR = 1.16, 95%CI = 1.11-1.22, P = 4.45×10-10) and Europe (OR = 1.17, 95%CI = 1.12-1.21, P = 1.65×10-14). Functional characterization of the variant demonstrated that it could act as an allele-specific enhancer to distally facilitate the expression of CCND2 mediated by the transcription factor TEAD4. Overall, our study underscores the essential role of CCND2 in CRC development and delineates its regulatory mechanism mediated by rs4477507, establishing an epidemiological and biological link between genetic variation and CRC pathogenesis.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827500","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 role of Interleukin 17 (IL17) in cancer: A systematic review. 白细胞介素 17 (IL17) 在癌症中的作用：系统综述。

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-12-14 DOI: 10.1093/carcin/bgae079

Emir Begagic, Semir Vranic, Ajith Sominanda

引用次数: 0

Testicular sex cord-stromal tumors in mice with constitutive activation of PI3K and loss of Pten.

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-12-13 DOI: 10.1093/carcin/bgae077

Marija Dinevska, Lachlan Mcaloney, Samuel S Widodo, Gulay Filiz, Jeremy Anderson, Sebastian Dworkin, Simon P Windley, Dagmar Wilhelm, Theo Mantamadiotis

{"title":"Testicular sex cord-stromal tumors in mice with constitutive activation of PI3K and loss of Pten.","authors":"Marija Dinevska, Lachlan Mcaloney, Samuel S Widodo, Gulay Filiz, Jeremy Anderson, Sebastian Dworkin, Simon P Windley, Dagmar Wilhelm, Theo Mantamadiotis","doi":"10.1093/carcin/bgae077","DOIUrl":"https://doi.org/10.1093/carcin/bgae077","url":null,"abstract":"Testicular tumors are the most common malignancy of young men and tumors affecting the testis are caused by somatic mutations in germ or germ-like cells. The PI3K pathway is constitutively activated in about one third of testicular cancers. To investigate the role of the PI3K pathway in transforming stem-like cells in the testis, we investigated tumors derived from mice with post-natal, constitutive activation of PI3K signaling and homozygous deletion of tumor suppressor Pten, targeted to nestin expressing cells. Mice developed aggressive tumors, exhibiting heterogeneous histopathology and hemorrhaging. The tumors resemble the rare testis tumor type, testicular sex cord-stromal Leydig cell tumors. Single cell resolution spatial tissue analysis demonstrated that T-cells are the dominant tumor infiltrating immune cell type, with very few infiltrating macrophages observed in the tumor tissue, with CD8+ T-cells predominating. Further analysis showed that immune cells preferentially localize to or accumulate within stromal regions.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142821937","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

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

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

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