Carcinogenesis最新文献_第9页

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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098012/pdf/","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":"OA","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 2.9 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":2.9,"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 2.9 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

CAFomics: convergence to translation for precision stroma approaches. CAFomics：精准基质方法的转化。

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-11-22 DOI: 10.1093/carcin/bgae063

Ian C McCabe, Xianlu L Peng, Joseph F Kearney, Jen Jen Yeh

{"title":"CAFomics: convergence to translation for precision stroma approaches.","authors":"Ian C McCabe, Xianlu L Peng, Joseph F Kearney, Jen Jen Yeh","doi":"10.1093/carcin/bgae063","DOIUrl":"10.1093/carcin/bgae063","url":null,"abstract":"A noticeable characteristic of pancreatic ductal adenocarcinoma (PDAC) tumors is a dense tumor microenvironment with abundant and dense, desmoplastic stroma woven tightly with both cellular and matrix components. The high stromal density is associated with higher intratumor pressures which, until the last decade, was largely assumed to be tumor protective, confirmed by early studies demonstrating that altering the stroma was effective in genetically engineered models of PDAC. However, clinical trials using these approaches have been disappointing. There is increasing recognition that stroma heterogeneity is much greater than initially thought with an explosion of investigation into cancer-associated fibroblast (CAF) subpopulations led by experimental and single-cell transcriptomic studies. This review summarizes and attempts to harmonize the current transcriptomic data of CAF subpopulations. Understanding the heterogeneity of CAFs, the matrix, and other tumor microenvironment features will be critical to developing effective therapeutic approaches. Identifying model systems that best recapitulate the clinical behavior and treatment response of human PDAC will be important. Examining subpopulations as defined by clinical outcome will remain a critical step in defining clinically impactful CAF subtypes in larger clinical cohorts. The future of precision oncology in PDAC will depend on the integration of precision tumor epithelial and precision stroma approaches.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"817-822"},"PeriodicalIF":3.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602972","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

BRAF V600E-induced distinct DNA damage response defines the therapeutic potential of p53 activation for TP53 wild-type colorectal cancer. BRAF V600E 诱导的独特 DNA 损伤反应决定了 p53 激活对 TP53 野生型结直肠癌的治疗潜力。

IF 3.3 3区医学

Carcinogenesis Pub Date : 2024-11-22 DOI: 10.1093/carcin/bgae040

Shinji Tokuyama, Hisakazu Kato, Hidekazu Takahashi, Kyoko Ueda, Asami Arita, Ryuta Ueda, Hiroto Seto, Yuki Sekido, Tsuyoshi Hata, Atsushi Hamabe, Takayuki Ogino, Norikatsu Miyoshi, Mamoru Uemura, Ken Matsuoka, Osamu Tsukamoto, Hirofumi Yamamoto, Yuichiro Doki, Hidetoshi Eguchi, Seiji Takashima

{"title":"BRAF V600E-induced distinct DNA damage response defines the therapeutic potential of p53 activation for TP53 wild-type colorectal cancer.","authors":"Shinji Tokuyama, Hisakazu Kato, Hidekazu Takahashi, Kyoko Ueda, Asami Arita, Ryuta Ueda, Hiroto Seto, Yuki Sekido, Tsuyoshi Hata, Atsushi Hamabe, Takayuki Ogino, Norikatsu Miyoshi, Mamoru Uemura, Ken Matsuoka, Osamu Tsukamoto, Hirofumi Yamamoto, Yuichiro Doki, Hidetoshi Eguchi, Seiji Takashima","doi":"10.1093/carcin/bgae040","DOIUrl":"10.1093/carcin/bgae040","url":null,"abstract":"BRAF V600E, one of the most frequent mutations in the MAPK pathway, confers poor prognosis to colorectal cancers (CRCs), partly because of chemotherapeutic resistance. Oncogene-induced DNA damage responses (DDRs) that primarily activate p53 are important mechanistic barriers to the malignant transformation of cells; however, the mechanism underlying this impairment in cancer remains unknown. Here, we evaluated the responses of BRAFV600E-induced DDRs in two CRC cell lines, SW48 and LIM1215, both of which harbor wild-type TP53, KRAS, and BRAF. BRAFV600E transduction exhibited distinct phenotypes in these cells: SW48 cell proliferation markedly decreased, whereas that of LIM1215 increased. BRAFV600E expression induced the activation of oncogene-induced DDR signaling in SW48 cells, but not in LIM1215 cells, whereas chemotherapeutic agents similarly activated DDRs in both cell lines. Knockdown experiments revealed that these responses in SW48 cells were mediated by p53-p21 pathway activation. Comet assay (both alkaline and neutral) revealed that BRAFV600E increased single-strand breaks to the same extent in both cell lines; however, in the case of LIM1215 cells, it only facilitated double-strand breaks. Furthermore, the proliferation of LIM1215 cells, wherein no oncogene-induced DDRs occurred, was synergistically inhibited upon MDM2 inhibitor-mediated p53 activation combined with MEK inhibition. Taken together, these distinct DDR signaling responses highlight the novel characteristics of BRAFV600E-mutated CRC cells and define the therapeutic potential of p53 activation combined with MAPK inhibition against TP53 wild-type CRC harboring a BRAFV600E mutation.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":"857-867"},"PeriodicalIF":3.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141310122","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