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Tumor Endothelial Cells Induce M2 Macrophage Polarization via IL-4, Enhancing Tumor Growth in Hepatocellular Carcinoma. 肿瘤内皮细胞通过IL-4诱导M2巨噬细胞极化,促进肝癌肿瘤生长。
IF 4.3 2区 医学
Cancer Science Pub Date : 2025-08-27 DOI: 10.1111/cas.70179
Daijiro Matoba, Takehiro Noda, Shogo Kobayashi, Yoshihiro Sakano, Kenichi Matsumoto, Chihiro Yamanaka, Kazuki Sasaki, Shinichiro Hasegawa, Yoshifumi Iwagami, Daisaku Yamada, Yoshito Tomimaru, Hirofumi Akita, Hidenori Takahashi, Tadafumi Asaoka, Junzo Shimizu, Hisashi Wada, Yuichiro Doki, Hidetoshi Eguchi
{"title":"Tumor Endothelial Cells Induce M2 Macrophage Polarization via IL-4, Enhancing Tumor Growth in Hepatocellular Carcinoma.","authors":"Daijiro Matoba, Takehiro Noda, Shogo Kobayashi, Yoshihiro Sakano, Kenichi Matsumoto, Chihiro Yamanaka, Kazuki Sasaki, Shinichiro Hasegawa, Yoshifumi Iwagami, Daisaku Yamada, Yoshito Tomimaru, Hirofumi Akita, Hidenori Takahashi, Tadafumi Asaoka, Junzo Shimizu, Hisashi Wada, Yuichiro Doki, Hidetoshi Eguchi","doi":"10.1111/cas.70179","DOIUrl":"https://doi.org/10.1111/cas.70179","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs) and tumor endothelial cells (TECs) are important components in tumor microenvironments. This study examined the interaction between TECs and TAMs in hepatocellular carcinoma (HCC). The aim of this study is to clarify the mechanism of immune suppression and cancer progression mediated by the M2 polarization of TAMs. TECs were isolated from subcutaneous HCC tumors using murine BNL-T cells, and normal endothelial cells (NECs) were isolated from murine liver. M0 macrophages were obtained from bone marrow after incubation with M-CSF. Conditioned medium from TECs (TEC CM) or NECs (NEC CM) was added to M0 macrophages, and the polarization to M2 macrophages was assessed. The percentage of iNOS<sup>-</sup>CD206<sup>+</sup> cells was increased in the TEC CM group than in the NEC CM group. The subcutaneous tumor model with co-injection of BNL-T and TECs or NECs was applied, and the ratio of M2 macrophages (CD206<sup>+</sup>iNOS<sup>-</sup>CD45<sup>+</sup>CD11b<sup>+</sup>F4/80<sup>+</sup> cells) was elevated in the BNL-T + TEC group. IL-4 expression in TECs was upregulated compared to NECs, and the secretion of IL-4 was increased in the TEC CM compared to the NEC CM. After IL-4 down-regulation in TECs, the ratio of iNOS<sup>-</sup>CD206<sup>+</sup> cells decreased. The double immunofluorescent staining of CD31 and CD163 was performed in human HCC tissue. The number of CD31<sup>+</sup> endothelial cells correlated positively with CD163<sup>+</sup> TAMs. The high CD163/CD31 group showed poor prognosis in overall and disease-free survival. TECs induce M2 macrophage polarization through IL-4 secretion, leading to immune suppression and cancer progression.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144975538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Nationwide Real-World Usage of Blood-Based (Liquid) Biomarker Testing in Japan. 日本血液(液体)生物标志物检测的全国实际使用情况。
IF 4.3 2区 医学
Cancer Science Pub Date : 2025-08-26 DOI: 10.1111/cas.70174
Yasushi Yatabe, Ryosuke Watanabe, Yuko Kotera, Shotaro Yasuoka, Daisuke Ennishi
{"title":"Nationwide Real-World Usage of Blood-Based (Liquid) Biomarker Testing in Japan.","authors":"Yasushi Yatabe, Ryosuke Watanabe, Yuko Kotera, Shotaro Yasuoka, Daisuke Ennishi","doi":"10.1111/cas.70174","DOIUrl":"https://doi.org/10.1111/cas.70174","url":null,"abstract":"<p><p>Despite the advances in precision oncology through biomarker testing, not all patients are able to benefit from treatment decisions guided by tissue-based testing like comprehensive genomic profiling (CGP). However, the application and integration of liquid biopsy testing into clinical practice has not been fully defined in Japan. Clinical records were retrieved from the data repository of the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan. All records related to FoundationOne Liquid tests were evaluated from the database's inception in June 2019 to June 2023. Outcomes of interest included treatment patterns before and after testing, as well as mutations of interest. The seven most frequent tumor types (pancreas, prostate, biliary tract, bowel, lung, stomach and ovary) were stratified as part of subgroup analyses. Of 7461 patient records, the most prevalent cancers were pancreatic (24.5%), prostate (15.8%), and biliary tract (11.2%) cancers. Following molecular tumor board (MTB) review, 5.8% of cases received new treatments, predominantly targeted therapy (41.7%) and chemotherapy (40.9%), with 2.1% participating in clinical trials. Median durations from specimen collection to post-MTB treatment were 63 days. Tests for patients with bowel cancer (70/796; 8.8%) and lung cancer (57/695; 8.2%) received genotype-matched treatment most frequently, followed by tests for patients with prostate cancer (92/1182; 7.8%). Access to CGP in Japan appears more limited compared to other high-income countries. While CGP may be valuable for certain cancers, such as bowel, biliary, and prostate cancer, its benefit for other cancer types remains unclear.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144975455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Cystathionine as a Potential Urinary Marker for Diagnosing and Assessing Pretreatment Risk in Neuroblastoma. 半胱硫氨酸作为诊断和评估神经母细胞瘤预处理风险的潜在尿液标志物。
IF 4.3 2区 医学
Cancer Science Pub Date : 2025-08-25 DOI: 10.1111/cas.70169
Hizuru Amano, Yoshiharu Hayashi, Kazuharu Harada, Atsushi Narita, Shigehisa Fumino, Yuji Yamada, Shuhei Karakawa, Minoru Sakairi, Chiyoe Shirota, Takahisa Tainaka, Kazuki Yokota, Satoshi Makita, Daiki Kato, Hiroki Ishii, Kyoichi Deie, Makiko Mori, Yuichi Mitani, Yutaka Tomioka, Masataka Taguri, Katsuyoshi Koh, Tatsuro Tajiri, Motohiro Kato, Kimikazu Matsumoto, Yoshiyuki Takahashi, Tomoko Iehara, Akinari Hinoki, Hiroo Uchida
{"title":"Cystathionine as a Potential Urinary Marker for Diagnosing and Assessing Pretreatment Risk in Neuroblastoma.","authors":"Hizuru Amano, Yoshiharu Hayashi, Kazuharu Harada, Atsushi Narita, Shigehisa Fumino, Yuji Yamada, Shuhei Karakawa, Minoru Sakairi, Chiyoe Shirota, Takahisa Tainaka, Kazuki Yokota, Satoshi Makita, Daiki Kato, Hiroki Ishii, Kyoichi Deie, Makiko Mori, Yuichi Mitani, Yutaka Tomioka, Masataka Taguri, Katsuyoshi Koh, Tatsuro Tajiri, Motohiro Kato, Kimikazu Matsumoto, Yoshiyuki Takahashi, Tomoko Iehara, Akinari Hinoki, Hiroo Uchida","doi":"10.1111/cas.70169","DOIUrl":"https://doi.org/10.1111/cas.70169","url":null,"abstract":"<p><p>Urinary homovanillic acid (HVA) and vanillylmandelic acid (VMA) are widely used diagnostic markers for neuroblastoma, but urinary markers for risk assessment prior to invasive biopsy are lacking. We hypothesized that cystathionine (CTN) may be a new neuroblastoma biomarker and evaluated its utility for diagnosis and pretreatment risk assessment. 80 participants provided 202 urine samples: 32 from 32 control participants, 29 from 29 patients with primary neuroblastoma, and 141 from 30 patients with residual tumors, 11 of whom had primary neuroblastoma. Urinary CTN and HVA/VMA concentrations were measured using liquid chromatography/mass spectrometry. The area under the receiver operating characteristic curve (ROC-AUC) was used to evaluate diagnostic and pretreatment risk assessment performance according to the International Neuroblastoma Risk Group (INRG) pretreatment risk classification and the revised 2021 Children's Oncology Group (COG) neuroblastoma risk classification. Associations with prognostic factors were also evaluated. The AUC values for diagnosis were 0.920, 0.903, and 0.946 for HVA, VMA, and CTN, respectively. For pretreatment risk assessment (high-risk versus intermediate- and low-risk, and high- and intermediate-risk versus low-risk) the AUCs according to the INRG classification were 0.576 and 0.578 for HVA, 0.524 and 0.513 for VMA, and 0.852 and 0.708 for CTN, respectively, whereas they were 0.530 and 0.741 for HVA, 0.510 and 0.796 for VMA, and 0.758 and 0.981 for CTN, respectively, according to the COG classification. The values for MYCN status were 0.844 for HVA, 0.844 for VMA, and 0.942 for CTN. CTN may be a useful urinary marker for neuroblastoma diagnosis and pretreatment risk assessment.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144975002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Head and Neck Cancer Immunotherapy: Overcoming Limitations and Enhancing Efficacy. 头颈部肿瘤免疫治疗:克服局限性,提高疗效。
IF 4.3 2区 医学
Cancer Science Pub Date : 2025-08-23 DOI: 10.1111/cas.70176
Hirofumi Shibata, Masashi Kuroki, Ryo Kawaura, Tatsuhiko Yamada, Ryota Iinuma, Hiromasa Ishihara, Hiroshi Okuda, Kenichi Mori, Takenori Ogawa
{"title":"Head and Neck Cancer Immunotherapy: Overcoming Limitations and Enhancing Efficacy.","authors":"Hirofumi Shibata, Masashi Kuroki, Ryo Kawaura, Tatsuhiko Yamada, Ryota Iinuma, Hiromasa Ishihara, Hiroshi Okuda, Kenichi Mori, Takenori Ogawa","doi":"10.1111/cas.70176","DOIUrl":"https://doi.org/10.1111/cas.70176","url":null,"abstract":"<p><p>Head and neck cancers (HNCs) are a heterogeneous group of malignancies, including head and neck squamous cell carcinoma (HNSCC), thyroid carcinoma, and salivary gland carcinoma. Despite multidisciplinary treatment approaches, outcomes for advanced HNCs remain poor. Among these, HNSCC has been the most extensively studied in the field of immunotherapy. Immune checkpoint inhibitors (ICIs), particularly anti-PD-1 antibodies, have demonstrated survival benefits in R/M HNSCC, but response rates remain modest at 15%-20%, highlighting the need for more effective strategies. Recent advances include the use of neoadjuvant and adjuvant immunotherapy in locally advanced HNSCC, which may improve pathological response rates and long-term survival. Additionally, novel immunotherapeutic approaches such as tumor antigen-targeted cancer vaccines and T-cell receptor-engineered T-cell (TCR-T) therapy are emerging. These strategies aim to enhance tumor-specific immunity, especially in tumors lacking targetable driver mutations. The tumor microenvironment (TME) in HNSCC plays a pivotal role in modulating immune response and therapeutic efficacy. Immunomodulatory agents such as HDAC inhibitors, TLR agonists, and VEGF inhibitors have shown promise in enhancing ICI responsiveness by altering the immunosuppressive TME. Moreover, the identification of predictive biomarkers, including PD-L1 expression, tumor mutational burden, and tertiary lymphoid structures, is crucial for patient selection and response prediction. This review provides a comprehensive overview of the current landscape and future directions of immunotherapy for HNCs, with a particular focus on HNSCC. We highlight ongoing clinical challenges and discuss emerging strategies aimed at overcoming resistance and improving clinical outcomes.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144975517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
ROS-Driven PKCζ Signaling as a Widely Involved Mechanism for Cancer Cell Motility and Metastasis. ros驱动的PKCζ信号传导作为癌细胞运动和转移的广泛参与机制。
IF 4.3 2区 医学
Cancer Science Pub Date : 2025-08-20 DOI: 10.1111/cas.70165
Yasushi Sato, Maki Tanaka, Naoko Kitamura, Naoko Araki, Wataru Kurata, Akiko Sasaki, Yukimi Seo, Kageaki Kuribayashi, Shuzo Kobayashi, Yoshiro Niitsu
{"title":"ROS-Driven PKCζ Signaling as a Widely Involved Mechanism for Cancer Cell Motility and Metastasis.","authors":"Yasushi Sato, Maki Tanaka, Naoko Kitamura, Naoko Araki, Wataru Kurata, Akiko Sasaki, Yukimi Seo, Kageaki Kuribayashi, Shuzo Kobayashi, Yoshiro Niitsu","doi":"10.1111/cas.70165","DOIUrl":"https://doi.org/10.1111/cas.70165","url":null,"abstract":"<p><p>The enhancement of cell motility by bioactive molecules such as growth factors, hormones, and tissue factors is pivotal in cancer invasion and metastasis. However, the molecular mechanisms underlying this enhancement remain incompletely understood. In this study, we demonstrate that hepatoblastoma HepG2 cell motility is significantly increased following hepatocyte growth factor (HGF) treatment, as assessed by phagokinetic track assays, Transwell assays, and scratch assays. This enhancement is mediated by reactive oxygen species (ROS), which activate the PKCζ/Rho GTPase signaling pathway. Notably, the motility increase is markedly suppressed by superoxide dismutase (SOD), N-acetylcysteine (NAC), diphenyleneiodonium (DPI), and the PKCζ inhibitory peptide MyrPKCζ. Similar patterns of motility enhancement and its inhibition by MyrPKCζ were observed in HGF-treated colon cancer HCT116 cells, epidermal growth factor (EGF)-treated HepG2 and HCT116 cells, and transforming growth factor-β (TGF-β)-treated HepG2 cells, as evaluated using Transwell assays. Additionally, estradiol enhances the motility of breast cancer MDA-MB-231-luc cells via ROS generation and activation of the PKCζ/Rho GTPase signaling pathway, with this effect significantly suppressed by MyrPKCζ in Transwell assays. The inhibitory effect of MyrPKCζ was further confirmed in vivo, where it suppressed peritoneal invasion of HCT116 cells in NOD-SCID mice. Furthermore, in NOD-SCID mice injected with MDA-MB-231-luc cells carrying shRNA targeting PKCζ into the tail vein, doxycycline-induced shRNA expression resulted in marked suppression of pulmonary metastasis. These findings indicate that the ROS/PKCζ/Rho GTPase signaling cascade is a pivotal regulator of cancer cell motility and suggest that PKCζ represents a promising therapeutic target for preventing cancer invasion and metastasis.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144975526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Comparison of the Efficacy of Different First-Line Therapies for EGFR L858R-Mutated NSCLC Patients With Brain Metastases. 不同一线治疗方法对EGFR l858r突变非小细胞肺癌脑转移患者疗效的比较
IF 4.3 2区 医学
Cancer Science Pub Date : 2025-08-15 DOI: 10.1111/cas.70175
Jing Chen, Yin Pan, Baishen Zhang, Meichen Li, Hui Yu, Mingjie Yu, Likun Chen
{"title":"Comparison of the Efficacy of Different First-Line Therapies for EGFR L858R-Mutated NSCLC Patients With Brain Metastases.","authors":"Jing Chen, Yin Pan, Baishen Zhang, Meichen Li, Hui Yu, Mingjie Yu, Likun Chen","doi":"10.1111/cas.70175","DOIUrl":"https://doi.org/10.1111/cas.70175","url":null,"abstract":"<p><p>Compared to exon 19 deletions, the epidermal growth factor receptor (EGFR) exon 21 L858R (21L858R) mutation is associated with a poorer prognosis in non-small cell lung cancer (NSCLC), particularly in patients with brain metastases (BMs). However, there is a notable lack of prospective or retrospective clinical studies focusing on this specific population. This study aims to evaluate the efficacy of different first-line treatment strategies using EGFR-tyrosine kinase inhibitors (TKIs) in NSCLC patients harboring the 21L858R mutation and BMs while providing insights into concurrent mutations and resistance mechanisms. We analyzed clinical data from 331 patients diagnosed with the EGFR 21L858R mutation and BMs who received first-line EGFR-TKI treatment at Sun Yat-sen University Cancer Center between April 2014 and June 2023 (ID: GASTO-1027). The efficacy was evaluated through intracranial progression-free survival (iPFS), PFS, and overall survival (OS). Compared to the first-generation and second-generation cohorts, the third-generation EGFR-TKI cohort demonstrated significant improvements in iPFS (p = 0.002), PFS (p < 0.001), and OS (p = 0.016). Within the third-generation EGFR-TKI group, the combination chemotherapy cohort exhibited the most favorable outcomes, with marked extensions in both iPFS (p = 0.037) and PFS (p = 0.049). Multivariate analyses identified the treatment regimen of third-generation TKIs combined with chemotherapy as an independent prognostic factor for improved iPFS. Compared to treatment regimens containing first-generation or second-generation EGFR-TKIs, patients with TP53 mutations derived greater benefit from treatment regimens containing third-generation EGFR-TKIs. The combination of third-generation EGFR-TKIs with chemotherapy shows enhanced efficacy in patients with EGFR 21L858R mutations and BMs compared to other treatments. Future prospective clinical trials are essential to assess this combination's effects in this population.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
SOX10 Regulates Melanoma Metastasis Through the IRF1-ITGA3/EphA2-FAK Pathway. SOX10通过IRF1-ITGA3/EphA2-FAK通路调控黑色素瘤转移。
IF 4.3 2区 医学
Cancer Science Pub Date : 2025-08-13 DOI: 10.1111/cas.70173
Ryuya Kaminaka, Nana Takahashi, Mayu Nishizawa, Soichiro Sasaki, Yuichiro Sugihara, Minoru Matsumoto, Ryoma Taniguchi, Yue Zhou, Yoshihiro Hayakawa, Hiroaki Sakurai, Satoru Yokoyama
{"title":"SOX10 Regulates Melanoma Metastasis Through the IRF1-ITGA3/EphA2-FAK Pathway.","authors":"Ryuya Kaminaka, Nana Takahashi, Mayu Nishizawa, Soichiro Sasaki, Yuichiro Sugihara, Minoru Matsumoto, Ryoma Taniguchi, Yue Zhou, Yoshihiro Hayakawa, Hiroaki Sakurai, Satoru Yokoyama","doi":"10.1111/cas.70173","DOIUrl":"https://doi.org/10.1111/cas.70173","url":null,"abstract":"<p><p>Melanoma heterogeneity contributes to increased metastatic potential. Although a subpopulation characterized by MITF<sup>low</sup>/AXL<sup>high</sup> has been linked to invasiveness, the underlying mechanisms remain unclear. In this study, we identified cell migration-related gene sets as significantly enriched after the knockdown of SOX10 in melanoma. Both in silico analysis and in vitro analysis identified ITGA3 and EPHA2 as downstream effectors of SOX10-mediated migration, essential for cell adhesion and random motility, respectively. Moreover, the oncogenic activation of MAPK was necessary for increased random motility through EphA2 phosphorylation at the Ser 897 residue. We also identified IRF1 as an upstream regulator of both ITGA3 and EphA2 after the knockdown of SOX10. Notably, IRF1 suppression or the treatment with the FAK inhibitor, defactinib, significantly reduced melanoma metastasis in vivo. These findings demonstrate that the reduced expression of SOX10 promotes melanoma metastasis through the IRF1-ITGA3/EphA2-FAK pathway and highlight FAK inhibition as a potential therapeutic strategy.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144849464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Mitochondrial DNA-Mediated Intercellular Communication via Extracellular Vesicles Under Hypoxic Stress to Drive HCC Progression. 缺氧胁迫下通过细胞外囊泡介导的线粒体dna介导的细胞间通讯驱动HCC进展。
IF 4.3 2区 医学
Cancer Science Pub Date : 2025-08-13 DOI: 10.1111/cas.70172
Jiaying Fu, Qingqing Liu, Yuan Yuan, Runyuan Li, Jian Wang, Yuanxin Zhao, Xiaoyu Yan, Jing Su
{"title":"Mitochondrial DNA-Mediated Intercellular Communication via Extracellular Vesicles Under Hypoxic Stress to Drive HCC Progression.","authors":"Jiaying Fu, Qingqing Liu, Yuan Yuan, Runyuan Li, Jian Wang, Yuanxin Zhao, Xiaoyu Yan, Jing Su","doi":"10.1111/cas.70172","DOIUrl":"https://doi.org/10.1111/cas.70172","url":null,"abstract":"<p><p>Immunotherapy has opened new opportunities for the therapy of hepatocellular carcinoma (HCC), but is limited by the immunosuppressive microenvironment. Recent studies have reported that abnormal mitochondrial DNA (mtDNA) stress in tumor cells acts as an intercellular communication signal capable of affecting the tumor itself as well as the microenvironment, but the pathways by which mtDNA drives this process are currently unknown. In this study, we found that mtDNA is involved in hypoxia-derived EVs-mediated macrophage M2 phenotypic polarization promoting HCC progression. In vitro and in vivo experiments demonstrated that hypoxia promotes mtDNA release by enhancing mitochondrial quality control (MQC) signaling and subsequent exocytosis to macrophage via EVs. EVs carrying mtDNA activate macrophage cGAS/STING/NF-κB pathway and promote M2 phenotypic polarization. In addition, we have modified the drug by using a nanodelivery system to make it tumor-targeted and effective in inhibiting tumor growth in vivo. Taken together, our study reveals a critical role for EVs-mtDNA in the formation of the immunosuppressive microenvironment in HCC under hypoxia and provides new evidence and solutions to improve sensitivity to immunotherapy for HCC.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144849463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Single-Cell Transcriptomics Identifies Novel Prognostic Signatures in HNSCC Immunotherapy Response. 单细胞转录组学鉴定HNSCC免疫治疗反应的新预后特征。
IF 4.3 2区 医学
Cancer Science Pub Date : 2025-08-12 DOI: 10.1111/cas.70171
Kankui Wu, Xiuzhen Chen, Qiaobin Wu, Bin Liu, Fei Peng, Na Zhang, Yinhong Li, Jing Meng, Mingyu Liu
{"title":"Single-Cell Transcriptomics Identifies Novel Prognostic Signatures in HNSCC Immunotherapy Response.","authors":"Kankui Wu, Xiuzhen Chen, Qiaobin Wu, Bin Liu, Fei Peng, Na Zhang, Yinhong Li, Jing Meng, Mingyu Liu","doi":"10.1111/cas.70171","DOIUrl":"https://doi.org/10.1111/cas.70171","url":null,"abstract":"<p><p>Head and neck squamous cell carcinoma (HNSCC) poses a major therapeutic challenge. In this study, we aimed to analyze tumor immune microenvironment changes and develop a prognostic model based on immunotherapy response. We analyzed single-cell RNA sequencing data from three HNSCC patients receiving TLR8 agonist and anti-PD1 combination therapy, identified cell subpopulations before and after treatment with a focus on six major immune cell types, and developed a LASSO-Cox risk stratification model using combined single-cell and bulk RNA sequencing data. We identified 19 pre-treatment and 13 post-treatment cell subpopulations. Analysis of six major immune cell types revealed differential gene expression patterns. Based on treatment-induced differential genes, we developed a LASSO-Cox model with 51 survival-associated genes, which showed robust predictive performance (AUC: 0.749-0.800) across different timepoints for both HPV-positive and HPV-negative patients. High-risk groups had elevated MDSCs and CAFs, decreased immune cell infiltration (except Th2 CD4+ T cells and common lymphoid progenitors), and increased expression of ICB-related genes. In conclusion, our model effectively captures patients' immune status and provides insights for optimizing HNSCC immunotherapy strategies.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144823022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Machine Learning-Based Predictive Modeling Maximizes the Efficacy of mTOR/p53 Co-Targeting Therapy Against AML. 基于机器学习的预测模型最大化mTOR/p53联合靶向治疗AML的疗效
IF 4.3 2区 医学
Cancer Science Pub Date : 2025-08-11 DOI: 10.1111/cas.70170
Jingmei Li, Emi Sugimoto, Keita Yamamoto, Yutong Dai, Wenyu Zhang, Yu-Hsuan Chang, Jakushin Nakahara, Tomohiro Yabushita, Toshio Kitamura, Sung-Joon Park, Kenta Nakai, Susumu Goyama
{"title":"Machine Learning-Based Predictive Modeling Maximizes the Efficacy of mTOR/p53 Co-Targeting Therapy Against AML.","authors":"Jingmei Li, Emi Sugimoto, Keita Yamamoto, Yutong Dai, Wenyu Zhang, Yu-Hsuan Chang, Jakushin Nakahara, Tomohiro Yabushita, Toshio Kitamura, Sung-Joon Park, Kenta Nakai, Susumu Goyama","doi":"10.1111/cas.70170","DOIUrl":"https://doi.org/10.1111/cas.70170","url":null,"abstract":"<p><p>Although mTOR signaling plays a key role in acute myeloid leukemia (AML), mTOR inhibitors have shown limited efficacy against AML in clinical trials. In this study, we found that the anti-leukemic effect of mTOR inhibition was mediated in part through the TP53 pathway. mTOR inhibition by rapamycin and TP53 activation by DS-5272 collaboratively induced the downregulation of MYC and MCL1 partly through miR-34a, thereby inducing cell cycle arrest and apoptosis in AML cells. Joint non-negative matrix factorization (JNMF) and statistical regression analysis using public AML databases revealed that monocytic AMLs with distinctive gene expression profiles were highly sensitive to mTOR inhibition, leading to the generation of an 11-gene score (Rapa-11) to predict the rapamycin sensitivity of each monocytic AML. Consistent with our in silico prediction, mouse AML cells expressing MLL-AF9, the monocytic AML with a low Rapa-11 score, were highly sensitive to rapamycin, whereas those expressing RUNX1-ETO or SETBP1/ASXL1 mutations were not. Co-treatment with rapamycin and DS-5272 had a dramatic in vivo effect on MLL-AF9-driven AML, curing 85% of the leukemic mice. Thus, machine learning-based predictive approaches identified monocytic AML with wild-type TP53 and low Rapa-11 score as a rapamycin-sensitive AML subtype and an ideal target for mTOR/p53 co-targeting therapy.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144818026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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