Neoplasia最新文献

{"title":"The Impact of Atorvastatin on Intraprostatic Biomarkers – Prognostic Value of 3LS-score – Follow-up of ESTO1-Trial","authors":"Eemil Lehtonen ,&nbsp;Maiju Vertanen ,&nbsp;Heimo Syvälä ,&nbsp;Teemu Tolonen ,&nbsp;Seppo Auriola ,&nbsp;Teuvo Tammela ,&nbsp;Aino Siltari ,&nbsp;Teemu Murtola","doi":"10.1016/j.neo.2025.101132","DOIUrl":"10.1016/j.neo.2025.101132","url":null,"abstract":"<div><h3>Background</h3><div>Prostate cancer (PCa) remains a global health burden, with limited reliable biomarkers beyond prostate-specific antigen (PSA). Statins have been associated with survival benefits in advanced Pca, potentially by modulating cholesterol metabolism and tumor biology. However, the causal mechanisms are not well understood. A distinct three-lipid signature (3LS) has previously been proposed as a prognostic biomarker for PCa.</div></div><div><h3>Objective</h3><div>This study investigates the effects of atorvastatin intervention on PCa tissue markers, long-term clinical outcomes, and the prognostic value of the 3LS derived from prostate tissue lipidome.</div></div><div><h3>Methods</h3><div>The ESTO1 trial randomized 158 statin-naïve PCa patients to receive high-dose atorvastatin (80 mg daily) or placebo before prostatectomy. Long term outcomes were assessed for 102 patients through medical records review. Prostate tissue samples were pathologically characterized, and lipidome quantified. Cox regression models were used to analyse clinical outcomes between the groups. The 3LS score was calculated by identifying the constituent lipids from the prostate lipidome.</div></div><div><h3>Findings</h3><div>Higher intraprostatic atorvastatin lactone concentrations were associated with reduced Ki67 expression and PSA levels. After a median follow-up of seven years, no significant differences were observed in biochemical recurrence, overall mortality, or initiation of hormonal therapy. However, the atorvastatin arm had a lower risk of major acute cardiovascular events (HR 0.11, 95% CI 0.01–1.01). The intraprostatic 3LS correlated with higher baseline tumor aggressiveness but did not predict subsequent outcomes.</div></div><div><h3>Conclusion</h3><div>Higher atorvastatin lactone concentrations in the prostate tissue were linked to improved pathological variables. Pre-surgery statin intervention reduced MACE risk but no impact on other clinical outcomes was observed. The 3LS from prostate tissue does not seem to be prognostic marker in localized Pca.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"61 ","pages":"Article 101132"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143268468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"YPEL2 regulates the efficacy of BRD4-EZH2 dual targeting in EZH2Y641mut germinal center-derived lymphoma","authors":"Aránzazu Chamorro-Jorganes ,&nbsp;Núria Profitós-Pelejà ,&nbsp;Clara Recasens-Zorzo ,&nbsp;Juan G Valero ,&nbsp;Diana Reyes-Garau ,&nbsp;Laura Magnano ,&nbsp;Ray Butler ,&nbsp;Antonio Postigo ,&nbsp;Patricia Pérez-Galán ,&nbsp;Marcelo Lima Ribeiro ,&nbsp;Gaël Roué","doi":"10.1016/j.neo.2025.101131","DOIUrl":"10.1016/j.neo.2025.101131","url":null,"abstract":"<div><div>A significant proportion of diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) cases harbor a gain-of-function, heterozygous somatic mutation of the methyltransferase gene EZH2. While this factor is known to cooperate with the proto-oncogene MYC during malignant B cell development, the effect of interfering with both factors remains underexplored. Here we undertook the simultaneous evaluation of two epigenetic drugs targeting EZH2 methyltransferase activity and BRD4-mediated control of <em>MYC</em> transcription, CPI169 and CPI203, using preclinical models of DLBCL and FL with distinct EZH2 mutational status. We observed a specific and synergistic antiproliferative effect of these compounds in EZH2-mutated cells and mouse xenograft models, that was related to the abrogation of MYC transcriptional program and to tumor cell proliferation blockade at the G1 cell cycle phase. Gene expression profile, exploratory data analysis, and siRNA screening identified the PI3K/AKT-regulated gene and mitosis regulator, YPEL2, as a crucial factor involved in the efficacy of MYC/EZH2 dual targeting both <em>in vitro</em> and <em>in vivo</em>. Altogether, our results provide first pre-clinical evidence that simultaneous targeting of MYC and EZH2 is a safe and efficient approach that can be monitored by specific biomarkers, in aggressive lymphoid tumors of germinal center origin.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"61 ","pages":"Article 101131"},"PeriodicalIF":4.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143129964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An open-label study to determine the maximum tolerated dose of oral ESK-440 administered as a single agent in patients with advanced or metastatic solid tumors","authors":"Russell J. Schilder ,&nbsp;Drew Rasco ,&nbsp;Manish R. Sharma","doi":"10.1016/j.neo.2025.101133","DOIUrl":"10.1016/j.neo.2025.101133","url":null,"abstract":"<div><h3>Purpose</h3><div>Anaplastic lymphoma kinase (ALK) dysregulation is implicated in numerous cancers. Tyrosine kinase inhibitors (TKIs) targeting ALK have improved disease outcomes, but resistance mechanisms are common. This first-in-human trial evaluates ESK-440, a dual inhibitor of ALK and focal adhesion kinase, as a novel strategy for cancers with resistance to ALK-targeting TKIs.</div></div><div><h3>Methods</h3><div>This phase 1, open-label, dose-finding study evaluated the maximum tolerated dose (MTD), safety, efficacy, and pharmacokinetics of ESK-440 in participants with advanced or metastatic solid tumors (ClinicalTrials.gov: NCT01922752). A 3 + 3 dose-escalation design, with daily doses ranging from 25 to 700 mg/day of ESK-440 for each 28-day treatment cycle (6 to 8 cycles) was utilized to identify the MTD. A phase 1b was planned to further evaluate ESK-440 safety and antitumor activity at the MTD but was not performed due to sponsor decision.</div></div><div><h3>Results</h3><div>32 participants were enrolled and 24 (75 %) completed cycle 1 of treatment. Three dose-limiting toxicities, all grade 3 nausea, were reported (<em>n</em> = 1, 500 mg; <em>n</em> = 2, 700 mg). The MTD was determined to be 500 mg daily. The most frequent adverse events (AEs) were fatigue and nausea (53 % each) and vomiting (38 %). Seven participants (22 %) withdrew from treatment due to AEs and 4 deaths occurred, none related to ESK-440. No participant had a complete or partial response; the best overall response was stable disease in 7 participants.</div></div><div><h3>Conclusions</h3><div><strong>ESK-440 was safe and tolerable with a maximum tolerated dose of 500</strong> <strong>mg daily</strong>; however, the study was terminated early based on sponsor decision.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"61 ","pages":"Article 101133"},"PeriodicalIF":4.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143267550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ZC3H15 suppression ameliorates bone cancer pain through inhibiting neuronal oxidative stress and microglial inflammation","authors":"Li-Quan Huang ,&nbsp;Ting-Xuan Yan ,&nbsp;Bao-Sheng Wang,&nbsp;Hao Li,&nbsp;Nai-Bao Zhou","doi":"10.1016/j.neo.2025.101123","DOIUrl":"10.1016/j.neo.2025.101123","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Patients with advanced-stage malignancies often endure unbearable pain, partly due to the incomplete understanding of its molecular mechanisms. Zinc finger CCCH-type containing 15 (ZC3H15) is a highly conserved eukaryotic protein involved in various cellular processes, including tumor growth and inflammation. However, its impact on cancer-induced pain, especially the underlying mechanisms, remains largely unknown.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;To evaluate the expression of ZC3H15 in cancer-induced pain, we used microcomputed tomography (MicroCT), immunoblotting, co-immunoprecipitation (Co-IP), behavior tests, quantitative real-time polymerase chain reaction (qRT-PCR), and immunofluorescence assays in this investigation. Additionally, we used CCK8, cloning, and migration tests to examine the proliferation and migration of cancer cells. We also used transplantation tumor mouse model to investigate the course of the cancer cell growth. Finally, we looked into the biological processes linked to ZC3H15 using in vivo and in vitro ubiquitination detection, which was later verified.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;In this study, we established a bone cancer pain (BCP) murine mouse model that impairs patients’ quality of life. Initially, we observed a significant increase in the expression of ZC3H15 in dorsal horn spinal cord tissues of BCP mice, along with severe oxidative stress and inflammation. Subsequently, we found that adeno-associated virus (AAV) expressing ZC3H15 short hairpin RNA (shRNA) (AAV-shZC3H15) to silence ZC3H15 in vivo significantly alleviated the progression of BCP in mice, improving nociceptive behaviors, independent of tumor burden and bone destruction. Subsequently, we made a novel discovery that ZC3H15 knockdown mice with BCP displayed improved neuronal oxidative stress and reactive oxygen species (ROS) generation in spinal cord tissues, which was confirmed in H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt;-treated mouse spinal cord neurons primarily through mediating the kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor, erythroid 2-like transcription factor 2 (NRF2) pathway. Mechanistically, immunoblotting analysis revealed that ZC3H15 could maintain KEAP1 stability and thereby promote NRF2 ubiquitination and degradation under oxidative stress. Furthermore, the suppression of oxidative damage in neurons by ZC3H15 knockdown was significantly abolished upon the deletion of NRF2 expression, identifying the necessity of NRF2 for ZC3H15 in the mediation of BCP progression. Additionally, microglial activation and inflammatory response in spinal cord tissues of BCP mice were also attenuated by AAV-shZC3H15, which was verified in LPS-treated microglial cells &lt;em&gt;in vitro&lt;/em&gt; by blocking the inhibitory protein κBα (IκBα)/nuclear factor κB (NF-κB) signaling pathway.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Our results provide evidence that suppressing ZC3H15 can alleviate BCP by restricting neuronal oxidative ","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"61 ","pages":"Article 101123"},"PeriodicalIF":4.8,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143129963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SLC31A1 promotes chemoresistance through inducing CPT1A-mediated fatty acid oxidation in ER-positive breast cancer","authors":"Xudong Li ,&nbsp;Jingjing Ge ,&nbsp;Mengdi Wan ,&nbsp;Tongtong Feng ,&nbsp;Xiaoqian Li ,&nbsp;Haibo Zhang ,&nbsp;Zhangyan Wang ,&nbsp;Yongsheng Gao ,&nbsp;Meiting Chen ,&nbsp;Fei Pan","doi":"10.1016/j.neo.2025.101125","DOIUrl":"10.1016/j.neo.2025.101125","url":null,"abstract":"<div><div>Over 60% of breast cancer cases are diagnosed with estrogen-receptor (ER) positive. Tamoxifen (TAM), a commonly employed medication for ER-positive breast cancer, often yields suboptimal therapeutic outcomes due to the emergence of TAM resistance, leading to the recurrence and a poor prognosis. The copper transporter, solute carrier family 31 member 1 (SLC31A1), has been associated with tumor aggressiveness and unfavorable outcomes in various types of tumors. In our current study, we found high expression of SLC31A1 that predicted poor survival in patients with breast cancer. Significantly, ER-positive breast cancer tissues in patients with recurrence post-TAM treatment exhibited considerably stronger SLC31A1 expression levels. <em>In vitro</em> experiments verified that TAM-resistant ER-positive breast cancer cell lines expressed notably higher SLC31A1 levels compared to the parental cell lines. Of great significance, SLC31A1 depletion notably rescued TAM sensitivity in chemoresistant ER-positive breast cancer cells, as demonstrated by the attenuated cell proliferative and invasive capabilities. Conversely, promoting SLC31A1 significantly facilitated the proliferation and invasion of wild-type breast cancer cells. Subsequently, we detected reduced copper levels in TAM-resistant breast cancer cells with SLC31A1 depletion. Mechanistically, we observed that in chemoresistant breast cancer cell lines, SLC31A1 knockdown resulted in a substantial decrease in the expression of carnitine palmitoyltransferase 1A (CPT1A), a rate-limiting enzyme of fatty acid oxidation (FAO). RNA-Seq analysis indicated that FAO might be implicated in SLC31A1-mediated breast cancer progression. CPT1A was also overexpressed in TAM-resistant breast cancer cells, accompanied by enhanced FAO rates and ATP levels. Suppressing CPT1A significantly enhanced the chemosensitivity of TAM-resistant breast cancer cells in response to TAM treatments. Intriguingly, copper exposure dose-dependently increased CPT1A expression in chemoresistant breast cancer cells, but this could be abolished upon SLC31A1 knockdown, along with enhanced apoptosis, which elucidated that copper uptake contributed to CPT1A expression. Furthermore, SLC31A1 overexpression significantly augmented CPT1A expression in parental breast cancer cells, accompanied by facilitated copper levels, FAO rates, and ATP levels, while being notably diminished upon CPT1A suppression. Finally, our <em>in vivo</em> studies confirmed that SLC31A1 deficiency re-sensitized TAM-resistant breast cancer cells to TAM treatment and abolished tumor growth. Collectively, all our studies demonstrated that SLC31A1/copper suppression could enhance TAM responses for chemoresistant ER-positive breast cancer cells through constraining the CPT1A-mediated FAO process.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"61 ","pages":"Article 101125"},"PeriodicalIF":4.8,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143129931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High p16INK4A expression in glioblastoma is associated with senescence phenotype and better prognosis","authors":"Soon Sang Park ,&nbsp;Tae Hoon Roh ,&nbsp;Yoshiaki Tanaka ,&nbsp;Young Hwa Kim ,&nbsp;So Hyun Park ,&nbsp;Tae-Gyu Kim ,&nbsp;So Yeong Eom ,&nbsp;Tae Jun Park ,&nbsp;In-Hyun Park ,&nbsp;Se-Hyuk Kim ,&nbsp;Jang-Hee Kim","doi":"10.1016/j.neo.2024.101116","DOIUrl":"10.1016/j.neo.2024.101116","url":null,"abstract":"<div><div>Glioblastoma, isocitrate dehydrogenase (IDH)-wildtype (GBM), is the most malignant brain tumor in adults, with limited therapeutic intervention. Previous studies have identified a few prognostic markers for GBM, including the methylation status of O⁶-methylguanine-DNA methyltransferase (<em>MGMT</em>) promoter, <em>TERT</em> promoter mutation, <em>EGFR</em> amplification, and <em>CDKN2A/2B</em> deletion. However, the classification of GBM remains incomplete, necessitating a comprehensive analysis. In this study, we investigated the impact of p16^INK4A expression in GBM and found that p16^INK4A-high GBM exhibits distinct characteristics compared to p16^INK4A-low GBM. Specifically, tumor cells with p16^INK4A-high expression display a senescent phenotype and are correlated with higher intra-tumoral immune cell infiltration. Furthermore, an association was observed between elevated p16^INK4A expression in GBM and extended overall survival of patients. Our <em>in vivo</em> and <em>in vitro</em> studies revealed that CCL13 is predominantly expressed by p16^INK4A-high GBM cells. The released CCL13 enhances the infiltration of T cells within the tumor, potentially contributing to the improved prognosis observed in patients with high p16^INK4A expression. These findings suggest that tumor cells with a senescence phenotype in GBM, through the secretion of chemokines such as CCL13, may augment immune cell infiltration and potentially enhance patient outcomes by creating a more immunologically active tumor microenvironment.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101116"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729681/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial profiling of endoplasmic reticulum stress markers in tumor associated cells predicts patient outcomes in pancreatic cancer","authors":"Georgia Porter ,&nbsp;Murray D. Norris ,&nbsp;Minoti Apte ,&nbsp;Angelica M. Merlot","doi":"10.1016/j.neo.2024.101115","DOIUrl":"10.1016/j.neo.2024.101115","url":null,"abstract":"<div><h3>Introduction</h3><div>The impact of endoplasmic reticulum (ER) stress in tumor-associated cells, such as cancer associated fibroblasts (CAFs), immune cells and endothelial cells, on patient outcomes in clinical specimens have not been examined. For the first time, we characterized the expression and spatial locations of ER stress markers, BiP and CHOP, in tumor-associated cells and assessed their prognostic significance in a panel of pancreatic ductal adenocarcinoma (PDAC) patient samples.</div></div><div><h3>Methods</h3><div>Multiplex immunofluorescence was performed on tumor microarrays and images were analyzed using HALO AI software.</div></div><div><h3>Results</h3><div>BiP and CHOP were upregulated in CAFs and endothelial cells in PDAC sections relative to non-neoplastic pancreas sections. High BiP expression in CAFs and endothelial cells was associated with greater vascular invasion and in immune cells was correlated with increased tumor size. High CHOP expression in immune cells correlated with poor patient survival. CAFs and immune cells were more likely to express BiP or CHOP when located close (&lt; 20 μm) to tumor cells. High expression of CHOP in CAFs close to tumor cells correlated with improved patient survival.</div></div><div><h3>Conclusion</h3><div>For the first time, this study demonstrated that ER stress occurs in CAFs and immune cells predominantly in proximity to tumor cells in PDAC patient tissue. The correlation of high ER stress in immune cells with poor patient survival highlights the importance of the TME and the use of spatial analysis for the identification of novel biomarkers.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101115"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pancreatic cancer cells infiltrate nerves through TGFbeta1-driven perineural epithelial-to-mesenchymal-like transdifferentiation","authors":"Theresa Krauss ,&nbsp;Ibrahim Halil Gürcinar ,&nbsp;Ulrike Bourquain ,&nbsp;Maren Hieber ,&nbsp;Evelyn N. Krohmer ,&nbsp;Nan Wu ,&nbsp;Sergey Tokalov ,&nbsp;Rüdiger Goess ,&nbsp;Carmen Mota Reyes ,&nbsp;Dieter Saur ,&nbsp;Helmut Friess ,&nbsp;Güralp O. Ceyhan ,&nbsp;Ihsan Ekin Demir ,&nbsp;Okan Safak","doi":"10.1016/j.neo.2025.101126","DOIUrl":"10.1016/j.neo.2025.101126","url":null,"abstract":"<div><div>Neural invasion is a prognostic hallmark of pancreatic ductal adenocarcinoma (PDAC), yet the underlying mechanisms behind the disruption of perineural barriers and access of cancer cells into intrapancreatic nerves remain poorly understood. This study aimed to investigate the role of epithelial-mesenchymal transformation (EMT) in perineural epithelial cells during neural invasion.Histopathological analysis of human and murine primary tumors using perineurium-specific GLUT1 antibody revealed a reduction in perineural integrity, which positively correlated with the extent of neural invasion in human PDAC cases. Human pancreatic cancer cell lines were found to secrete TGFbeta1, which induced EMT of perineural epithelial cells, characterized by the loss of epithelial markers (CK19-9) and the acquisition of mesenchymal markers (alphaSMA, N-Cadherin). Additionally, these transitioning perineural epithelial cells demonstrated increased matrix-degrading capabilities through the upregulation of matrix-metalloproteases 3 and 9 via SMAD2. In an autochthonous mouse model with elevated endogenous TGFbeta1 levels in addition to oncogenic Kras activation (<em>Ptf1a^Cre/+, LSL-Kras^G12D/+, LSL-R26^Tgfβ/+</em>), decreased perineural integrity could be reproduced <em>in vivo</em>.Collectively, these findings underscore the role played by TGFbeta1-overexpressing pancreatic cancer cells in the dismantling of perineural barriers during neural invasion.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101126"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11763858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143025417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"True cancer stem cells exhibit relative degrees of dormancy and genomic stability","authors":"Sanford H. Barsky ,&nbsp;Krista Mcphail ,&nbsp;Justin Wang ,&nbsp;Jordan Dillard ,&nbsp;Crystal J. Beard ,&nbsp;Yin Ye","doi":"10.1016/j.neo.2025.101127","DOIUrl":"10.1016/j.neo.2025.101127","url":null,"abstract":"<div><h3>Background</h3><div>Cancer stem cells in human tumors have been defined by stem cell markers, embryonal signaling pathways and characteristic biology, ie., namely the ability to repopulate the proliferating population. However, even if these properties can be demonstrated within a tumor cell subpopulation, it does not mean that they are truly hierarchical stem cells because they could have been derived from the proliferating population in a reversible manner.</div></div><div><h3>Methods</h3><div>Using a human PDX, Mary-X, that overall expressed a strong cancer stem cell phenotype, the study conducted both GPP-labelled retroviral transfection and fluorescent microsphere uptake studies to distinguish proliferating from dormant cells and array CGH to identify regions of amplifications (gains) and deletions (losses) on the overall Mary-X population and then applied derived probes by FISH on individual cells to identify a genomically stable subpopulation.</div></div><div><h3>Results</h3><div>Whereas 97-99 % of the cells expressed retroviral GFP and not fluorescent particles and showed numerous gene amplifications and deletions, approximately 1-3 % of the cells showed the opposite. The subpopulation with the retained fluorescent microspheres and exhibiting genomic stability was significantly smaller in size than their GFP-expressing and genomically unstable counterparts. Sorting Mary-X spheroids on the basis of either CD133 or ALDH positivity further enriched for this subpopulation.</div></div><div><h3>Conclusions</h3><div>These studies indicate that a truly biological cancer stem cell subpopulation exists that exhibits both dormancy and genomic stability. This subpopulation could not have been derived from the proliferating and resulting genomically unstable population and therefore represents a truly hierarchical stem cell subpopulation capable of only unidirectional differentiation.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101127"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimal radiation dose to induce an abscopal effect by combining carbon-ion radiotherapy and anti-CTLA4 antibody","authors":"Liqiu Ma ,&nbsp;Yang Li ,&nbsp;Yoshimitsu Sakamoto ,&nbsp;Lin Xie ,&nbsp;Saaya Suzuki ,&nbsp;Yukari Yoshida ,&nbsp;Li Sui ,&nbsp;Gang Guo ,&nbsp;Jialing Wen ,&nbsp;Wangcai Ren ,&nbsp;Kazuhiro Kakimi ,&nbsp;Kensuke Osada ,&nbsp;Akihisa Takahashi ,&nbsp;Takashi Shimokawa","doi":"10.1016/j.neo.2024.101099","DOIUrl":"10.1016/j.neo.2024.101099","url":null,"abstract":"<div><h3>Background and purpose</h3><div>Although carbon-ion radiotherapy (CIRT) has led to good outcomes, controlling metastasis is still crucial for improving overall survival. This study aimed to evaluate the effectiveness of by two combinations, one of CIRT and anti-CTLA4 antibody, the other of CIRT and anti-PD-1 antibody, applied at different radiation doses for distal tumour and metastasis suppression.</div></div><div><h3>Materials and methods</h3><div>Murine cancer cells (colon carcinoma Colon-26 cells for experiments and osteosarcoma LM8 cells for verification) were grafted into both sides of the hind legs of syngeneic mice. Right-side tumours were irradiated with 3 Gy or 10 Gy CIRT while the left-side tumours were not irradiated, followed by the administration of the anti-CTLA4 antibody or anti-PD-1 antibody. The diameter of the tumours in both legs was measured 3 times per week after irradiation. The number of pulmonary metastases was evaluated within 3 weeks after irradiation.</div></div><div><h3>Results</h3><div>Compared with the control group, the high-dose group showed promising anti-cancer benefits in terms of both irradiated tumours and lung metastasis, but neither 10 Gy CIRT combined with the anti-CTLA4 antibody nor 10 Gy CIRT combined with the anti-PD-1 antibody suppressed the growth of distant unirradiated tumours. In the low-dose group, the effect on primary tumour control was slightly weaker than that in the high-dose treatment group, but significant suppressive effects on both distant unirradiated tumours and metastases were observed following 3 Gy CIRT combined with anti-CTLA4 antibody treatment. Specifically, the volume of distant unirradiated tumours decreased by 40 % compared with that of the control group, and no lung metastasis was observed.</div></div><div><h3>Conclusion</h3><div>Our findings suggest that there is an optimal dose range for the abscopal effect generated with the CIRT combined with anti-CTLA4 antibody, and it highlights a new opportunity for increased induction efficiency of the abscopal effect of combination therapy.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101099"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}