Cancer Science最新文献

{"title":"Cancer-Type-Specific DNA Methylation Is a Source of Vulnerability in Liver Cancer Cells","authors":"Karen Minowa,&nbsp;Miho Seki,&nbsp;Yui Nagai,&nbsp;Satoshi Yamashita","doi":"10.1111/cas.70092","DOIUrl":"10.1111/cas.70092","url":null,"abstract":"<p>DNA methylation, a pivotal epigenetic mechanism, plays a critical role in various pathological conditions, including cancers. Notably, cancer-type-specific DNA methylation can be advantageous for survival only in specific environments while being disadvantageous in others. To investigate the role of cancer-type-specific methylation as a vulnerability in cancer cells, we bioinformatically profiled genome-wide DNA methylation in 1165 human cancer cell lines across 25 cancer types. The number of cancer-type-specific methylated cytosines varied significantly by organ, with exceptionally high numbers observed in blood cancers. A total of 73 genes were identified as potential liver cancer-specific methylation-silenced genes, and four genes, <i>ASNS</i>, <i>NQO1</i>, <i>FXYD5</i>, and BCAT2, were subjected to experimental further analysis. Silencing of <i>BCAT2</i> was found to contribute to the vulnerability of liver cancer cells to BCAT1 inhibition by gabapentin. Additionally, the silencing of the other three genes also rendered liver cancer cells vulnerable under different environmental conditions. These findings enhance our understanding of the biological and clinical significance of DNA methylation and provide a basis for developing diagnostic markers for cancer. (169 words).</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 7","pages":"2020-2031"},"PeriodicalIF":4.5,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70092","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144057948","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":"RETRACTION: miR-25-3p Reverses Epithelial-Mesenchymal Transition via Targeting Sema4C in Cisplatin-Resistance Cervical Cancer Cells","authors":"","doi":"10.1111/cas.70083","DOIUrl":"10.1111/cas.70083","url":null,"abstract":"<p><b>RETRACTION</b>: J. Song and Y. Li, “miR-25-3p Reverses Epithelial-Mesenchymal Transition via Targeting Sema4C in Cisplatin-Resistance Cervical Cancer Cells,” <i>Cancer Science</i> 108, no. 1 (2017): 23–31, https://doi.org/10.1111/cas.13104.</p><p>The above article, published online on 01 December 2016 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Masanori Hatakeyama; the Japanese Cancer Association; and John Wiley &amp; Sons Australia Ltd. The retraction has been agreed following an investigation into concerns raised by a third party, which revealed inappropriate duplication of image panels (Figures 1b, 2a, b and 3c) between this and several other articles published previously or in the same year by a different group of authors, in a different scientific context. Given the extent of the identified issues, the editors have lost confidence in the data presented and the article's conclusions can no longer be considered reliable. The authors and their institute have been informed of the concerns and the decision to retract but they remained unresponsive.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 7","pages":""},"PeriodicalIF":4.5,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70083","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144057896","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":"A Contrast-Enhanced Ultrasound Cine-Based Deep Learning Model for Predicting the Response of Advanced Hepatocellular Carcinoma to Hepatic Arterial Infusion Chemotherapy Combined With Systemic Therapies","authors":"Xu Han,&nbsp;Chuan Peng,&nbsp;Si-Min Ruan,&nbsp;Lingling Li,&nbsp;Minke He,&nbsp;Ming Shi,&nbsp;Bin Huang,&nbsp;Yudi Luo,&nbsp;Jingming Liu,&nbsp;Huiying Wen,&nbsp;Wei Wang,&nbsp;Jianhua Zhou,&nbsp;Minhua Lu,&nbsp;Xin Chen,&nbsp;Ruhai Zou,&nbsp;Zhong Liu","doi":"10.1111/cas.70089","DOIUrl":"10.1111/cas.70089","url":null,"abstract":"<p>Recently, a hepatic arterial infusion chemotherapy (HAIC)-associated combination therapeutic regimen, comprising HAIC and systemic therapies (molecular targeted therapy plus immunotherapy), referred to as HAIC combination therapy, has demonstrated promising anticancer effects. Identifying individuals who may potentially benefit from HAIC combination therapy could contribute to improved treatment decision-making for patients with advanced hepatocellular carcinoma (HCC). This dual-center study was a retrospective analysis of prospectively collected data with advanced HCC patients who underwent HAIC combination therapy and pretreatment contrast-enhanced ultrasound (CEUS) evaluations from March 2019 to March 2023. Two deep learning models, AE-3DNet and 3DNet, along with a time-intensity curve-based model, were developed for predicting therapeutic responses from pretreatment CEUS cine images. Diagnostic metrics, including the area under the receiver-operating-characteristic curve (AUC), were calculated to compare the performance of the models. Survival analysis was used to assess the relationship between predicted responses and prognostic outcomes. The model of AE-3DNet was constructed on the top of 3DNet, with innovative incorporation of spatiotemporal attention modules to enhance the capacity for dynamic feature extraction. 326 patients were included, 243 of whom formed the internal validation cohort, which was utilized for model development and fivefold cross-validation, while the rest formed the external validation cohort. Objective response (OR) or non-objective response (non-OR) were observed in 63% (206/326) and 37% (120/326) of the participants, respectively. Among the three efficacy prediction models assessed, AE-3DNet performed superiorly with AUC values of 0.84 and 0.85 in the internal and external validation cohorts, respectively. AE-3DNet's predicted response survival curves closely resembled actual clinical outcomes. The deep learning model of AE-3DNet developed based on pretreatment CEUS cine performed satisfactorily in predicting the responses of advanced HCC to HAIC combination therapy, which may serve as a promising tool for guiding combined therapy and individualized treatment strategies.</p><p><b>Trial Registration:</b> NCT02973685.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 7","pages":"1930-1940"},"PeriodicalIF":4.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70089","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027329","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":"The C11orf24 Gene as a Useful Biomarker for Predicting Severe Neutropenia in Modified FOLFIRINOX for Pancreatic Cancer","authors":"Gen Kanesada,&nbsp;Ryouichi Tsunedomi,&nbsp;Yuki Nakagami,&nbsp;Hiroto Matsui,&nbsp;Yoshitaro Shindo,&nbsp;Shinobu Tomochika,&nbsp;Hirofumi Akita,&nbsp;Tatsuya Ioka,&nbsp;Hidenori Takahashi,&nbsp;Hiroaki Nagano","doi":"10.1111/cas.70087","DOIUrl":"10.1111/cas.70087","url":null,"abstract":"<p>Pancreatic cancer (PC) is an aggressive and lethal tumor with a poor prognosis. FOLFIRINOX improves the prognosis of patients with PC; however, despite <i>UGT1A1</i> screening, adverse events, such as severe neutropenia, occur frequently. This study aimed to identify the novel biomarkers of severe neutropenia in patients treated with modified FOLFIRINOX (mFFX) for PC. In this study, patients with PC treated with mFFX (<i>n</i> = 71) and gemcitabine plus nab-paclitaxel (GnP) (<i>n</i> = 92) and patients with colorectal cancer treated with FOLFOXIRI (<i>n</i> = 50) were included. Genome-wide screening using whole-exome sequencing was performed during the screening phase. Validation analysis was performed using polymerase chain reaction genotyping, the Cochran–Armitage trend test, and multivariate analysis. The diagnostic performance of combined risk factors for severe neutropenia was examined using logistic regression with leave-one-out cross-validation. Three gene polymorphisms were selected from the screening phase and subjected to the validation phase. In the validation phase, a single nucleotide polymorphism in <i>C11orf24</i> (c.448C&gt;T, rs901827) was significantly correlated with ≥ Grade 3 neutropenia in mFFX and FOLFOXIRI but not in GnP. Multivariate analysis showed <i>C11orf24</i> and baseline neutrophil count as independent risk factors for ≥ Grade 3 neutropenia. The diagnostic performance of the neutropenia prediction model showed areas under the curve of 0.754 (sensitivity = 0.605, specificity = 0.848) and 0.856 (sensitivity = 0.800, specificity = 0.893) for ≥ Grade 3 and 4 neutropenia, respectively. The <i>C11orf24</i> gene and baseline neutrophil count may be useful biomarkers for predicting severe neutropenia following irinotecan-containing triplet chemotherapy.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 7","pages":"2008-2019"},"PeriodicalIF":4.5,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70087","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144023725","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":"CDX2 Promoter-Controlled Oncolytic Adenovirus Suppresses Tumor Growth and Liver Metastasis of Colorectal Cancer","authors":"Naohiko Nakamura,&nbsp;Mizuho Sato-Dahlman,&nbsp;Elise Travis,&nbsp;Kari Jacobsen,&nbsp;Masato Yamamoto","doi":"10.1111/cas.70063","DOIUrl":"10.1111/cas.70063","url":null,"abstract":"<p>Colorectal cancer (CRC) is the second leading cause of cancer death worldwide, and liver metastasis (CRLM) is the most common among its distant metastases. We have recently generated a CDX2 promoter-controlled oncolytic adenovirus (Ad5/3-pCDX2) that showed an anticancer effect for CDX2-positive upper gastrointestinal tumors. Here, we reported the anticancer effect of Ad5/3-pCDX2 for CDX2-positive CRC and CRLM, and its combination efficacy with 5-fluorouracil (5FU) in vitro and in vivo. We used HT29 as CDX2-positive, and LS174T and SW480 as CDX2-negative CRC cell lines. Without 5FU, Ad5/3-pCDX2 killed HT29 but not LS174T and SW480 cells. In vitro, 5FU exposure upregulated CDX2 mRNA levels in all three cell lines. The 5FU combination enhanced the cytocidal effect and virus replication of Ad5/3-pCDX2 in CDX2-negative LS174T. In mouse xenograft models, Ad5/3-pCDX2 monotherapy suppressed the HT29 subcutaneous tumor growth compared to the control group. The 5FU plus Ad5/3-pCDX2 combination therapy showed a remarkable antitumor effect over the efficacy of Ad5/3-pCDX2 monotherapy. In the LS174T subcutaneous tumor, although Ad5/3-pCDX2 monotherapy did not show an antitumor effect, the 5FU plus Ad5/3-pCDX2 combination therapy significantly suppressed the tumor growth compared to the Ad5/3-pCDX2 monotherapy. In mice with HT29 liver metastasis, intrasplenic injection of Ad5/3-pCDX2 induced virus replication in liver tumors and thus successfully attenuated tumor growth. In conclusion, Ad5/3-pCDX2 showed a significant anticancer effect that was enhanced by 5FU treatment in not only CDX2-positive but also negative CRCs. Ad5/3-pCDX2 is a promising therapeutic modality for metastatic CRC such as CRLM.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 7","pages":"1897-1907"},"PeriodicalIF":4.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70063","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144051453","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":"Pyrotinib and Nab-Paclitaxel in HER2-Positive Breast Cancer (PANHER Trial): A Prospective, Single-Arm, Phase II Trial","authors":"Huan Li,&nbsp;Min Yan,&nbsp;Zhaohui Li,&nbsp;Xiujie Cui,&nbsp;Xuening Ji,&nbsp;Fengqi Fang,&nbsp;Yuyang Zhang,&nbsp;Yan Wang,&nbsp;Xiangyu Guo,&nbsp;Mingxi Jing,&nbsp;Zhichao Gao,&nbsp;Hui Cao,&nbsp;Fangyuan Dong,&nbsp;Jie Wu,&nbsp;Cui Jiang,&nbsp;Yangyang Duan,&nbsp;Xiaorui Li,&nbsp;Yujun Jiang,&nbsp;Lei Jiang,&nbsp;Ying E,&nbsp;Yufeng Jia,&nbsp;Liang Zhang,&nbsp;Pai Peng,&nbsp;Tao Sun","doi":"10.1111/cas.70086","DOIUrl":"10.1111/cas.70086","url":null,"abstract":"<p>Trastuzumab and pertuzumab combined with chemotherapy represent the standard therapy for first-line treatment of HER2-positive metastatic breast cancer (BC). Due to challenges related to availability and cost in China, it is necessary to explore treatments involving tyrosine kinase inhibitors (TKIs). In this multicenter, single-arm, open-label phase II trial, patients with HER2-positive BC were enrolled from seven hospitals in China. Patients received oral pyrotinib 400 mg once daily and intravenous nab-paclitaxel 125 mg/m² on days 1, 8, and 15 of each 28-day cycle until disease progression or intolerable toxicity. The primary endpoint was the objective response rate (ORR). Between December 2019 and December 2021, 51 patients were enrolled. Among all enrolled patients, 48 had at least one response evaluation. Of these evaluable patients, 39 patients achieved responses, resulting in a positive study outcome. The ORR was 76.5% (95% CI, 62.5%–87.2%), and the disease control rate was 94.1% (95% CI, 83.8–98.8). As of January 24, 2024, the median follow-up duration was 29.2 months (IQR, 24.9–33.2). The median progression-free survival was 14.6 months (95% CI, 8.0–24.2), and the median overall survival was not reached. Forty-nine patients (96.1%) developed grade ≥ 3 adverse events (AEs). The most common grade ≥ 3 AEs were decreased neutrophil count (43.1%), decreased white blood cell count (43.1%), and diarrhea (23.5%). Pyrotinib combined with nab-paclitaxel demonstrated promising efficacy for HER2-positive advanced breast cancer, with an acceptable safety profile.</p><p><b>Trial Registration:</b> chictr.org, ChiCTR1900023653</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 7","pages":"1920-1929"},"PeriodicalIF":4.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70086","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144053577","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":"In Vivo Reprogramming Highlights Epigenetic Regulation That Shapes Cancer Hallmarks","authors":"Yosuke Yamada,&nbsp;Nao Sankoda,&nbsp;Yasuhiro Yamada","doi":"10.1111/cas.70067","DOIUrl":"10.1111/cas.70067","url":null,"abstract":"<p>Douglas Hanahan added “non-mutational epigenetic reprogramming” and “unlocking phenotypic plasticity” as new hallmarks of cancer, proposing that cancer cells possess fundamental features that are not directly linked to their genetic abnormalities. In vivo reprogramming studies have demonstrated that non-mutational epigenetic regulation can cause cellular reprogramming, leading to cancer development at the organismal level. Given that epigenetic regulation functions as an interface between the cellular environment and gene expression, these results suggest that intercellular communications in the tumor microenvironment play a critical role in cancer development. This review first introduces genetic aberrations that cause cancer development. Then, it illustrates the impact of epigenetic abnormalities in cancer, especially with reference to studies that use in vivo reprogramming technologies. Finally, it discusses the importance of histological evaluations of tumor tissue to understand non-cell-autonomous epigenetic regulation that establishes cancer hallmarks.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 7","pages":"1807-1814"},"PeriodicalIF":4.5,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70067","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035935","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":"Impact of Vitamin C on Immune Response and Edema Following Near-Infrared Photoimmunotherapy (NIR-PIT)","authors":"Hiroshi Yamamoto,&nbsp;Aki Furusawa,&nbsp;Hiroshi Fukushima,&nbsp;Seiichiro Takao,&nbsp;Motofumi Suzuki,&nbsp;Makoto Kano,&nbsp;Miyu Kano,&nbsp;Shuhei Okuyama,&nbsp;Ko Kitamura,&nbsp;Peter L. Choyke,&nbsp;Hisataka Kobayashi","doi":"10.1111/cas.70070","DOIUrl":"10.1111/cas.70070","url":null,"abstract":"<p>Near-infrared photoimmunotherapy (NIR-PIT) is a recently approved cancer therapy utilizing an antibody conjugated to IR700 dye which is injected and then followed with focal NIR light. NIR-PIT is ideal for focal therapy of cancer because of its cell specificity and minimal invasiveness compared to surgical resection. Most treatment-emergent adverse events are low grade and include edema, fatigue, and pain. However, edema in specific anatomic locations could lead to significant complications, such as airway obstruction, and thus, it is desirable to reduce edema if possible. Edema and the resulting pain are likely precipitated by reactive oxygen species generated primarily from the interaction of laser light with unbound antibody–photoabsorber conjugate. These reactive species can be neutralized by reducing agents, such as vitamin C, a potent reducing agent and proton donor. Based on its photochemical mechanisms, we hypothesized that pretreating patients with L-sodium ascorbate (L-NaAA) will reduce NIR-PIT-induced edema. Here, we evaluated the effect of L-NaAA concentration on edema as well as its effect on the immune responses after NIR-PIT. L-NaAA demonstrated concentration-dependent inhibition of edema after NIR-PIT without compromising the efficacy of NIR-PIT. Furthermore, L-NaAA did not impede the anticancer immune activation elicited by NIR-PIT, nor did it affect the efficacy of Treg-targeted NIR-PIT. NIR-PIT groups, both with and without L-NaAA, significantly inhibited tumor growth and resulted in markedly prolonged survival compared to the control group, but those with L-NaAA had reduced edema. Thus, L-NaAA may serve as a useful adjunct to NIR-PIT, enhancing its safety profile without detracting from its therapeutic efficacy.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 7","pages":"1836-1846"},"PeriodicalIF":4.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70070","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144026597","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":"p53 Deficiency in Colon Cancer Cells Promotes Tumor Progression Through the Modulation of Meflin in Fibroblasts","authors":"Eiji Kimura,&nbsp;Yoshito Hayashi,&nbsp;Kentaro Nakagawa,&nbsp;Hirotsugu Saiki,&nbsp;Minoru Kato,&nbsp;Ryotaro Uema,&nbsp;Takanori Inoue,&nbsp;Takeo Yoshihara,&nbsp;Akihiko Sakatani,&nbsp;Hiromu Fukuda,&nbsp;Ayaka Tajiri,&nbsp;Yujiro Adachi,&nbsp;Kazuhiro Murai,&nbsp;Shunsuke Yoshii,&nbsp;Yoshiki Tsujii,&nbsp;Shinichiro Shinzaki,&nbsp;Hideki Iijima,&nbsp;Tetsuo Takehara","doi":"10.1111/cas.70026","DOIUrl":"10.1111/cas.70026","url":null,"abstract":"<p>Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment, play an important role in tumor progression. Colon cancer cells deficient in p53 activate fibroblasts and enhance fibroblast-mediated tumor growth. Meflin is a CAF marker capable of inhibiting tumor growth. In this study, we investigated the role of Meflin in fibroblasts using human cell lines (colon cancer HCT116 and fibroblasts CCD-18Co) and clinical specimens. TP53-suppressed HCT116 (HCT116^{<i>sh p53</i>}) cells cocultured with CCD-18Co cells showed significantly faster proliferation than HCT116^{<i>sh control</i>} cells. In xenograft experiments, the volume of tumors induced by coinoculation with HCT116^{<i>sh p53</i>} and CCD-18Co cells was significantly larger than that induced by HCT116^{<i>sh control</i>} cells co-inoculated with CCD-18Co cells. HCT116^{<i>sh p53</i>} cells increased the levels of CAF-like phenotypic markers in CCD-18Co cells. Moreover, Meflin expression was significantly reduced in CCD-18Co cells cocultured with HCT116^{<i>sh p53</i>} cells compared to that in CCD-18Co cells cocultured with HCT116^{<i>sh control</i>} cells. si-RNA-mediated inhibition of Meflin activated CCD-18Co cells into tumor-promoting CAF-like cells, which significantly promoted xenograft tumor growth. Overexpression of Meflin in CCD-18Co cells using lentivirus suppressed fibroblast-mediated growth of HCT116^{<i>sh p53</i>} tumor xenografts. The expression of Meflin in CCD-18Co cells was suppressed by TGF-β and enhanced by vitamin D. These results indicate that colon cancer cells deficient in p53 suppress Meflin expression in fibroblasts, which affects tumor growth by altering the properties of tumor growth-promoting CAFs. Our results suggest that targeting Meflin in fibroblasts may be a novel therapeutic strategy for colorectal cancer.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 7","pages":"1871-1882"},"PeriodicalIF":4.5,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70026","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144057949","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":"Steroid-Modulated Transcription Synergistically Forms DNA Double-Strand Breaks With Topoisomerase II Inhibitor","authors":"Ying Zhao,&nbsp;Tetsuro Hisayoshi,&nbsp;Doudou Zhang,&nbsp;Saaya Suzuki,&nbsp;Takashi Watanabe,&nbsp;Atsuo Kobayashi,&nbsp;Qianqian Guo,&nbsp;Yukihide Momozawa,&nbsp;Takashi Shimokawa,&nbsp;Shunsuke Kato,&nbsp;Yoshio Miki,&nbsp;Shigeaki Sunada","doi":"10.1111/cas.70081","DOIUrl":"10.1111/cas.70081","url":null,"abstract":"<p>The synergistic effects of drug combinations have emerged as a promising approach for achieving efficient cancer treatment. Through our exploration of drug combinations, we found that medroxyprogesterone acetate (MPA), a steroid, induced a synergistic antitumor effect in combination with the topoisomerase II inhibitor etoposide (ETP). In this study, we investigated the mechanisms underlying this synergistic effect for potential clinical applications. To elucidate the relevant mechanisms, we performed a cell viability assay, cell cycle analysis, DNA repair assays, detection of DNA double-strand breaks (DSBs) and the nuclear localization of topoisomerase II (Top2), and genome-wide detection of DSBs. MPA synergistically increased ETP-induced DSBs, resulting in cell cycle arrest in the G2/M phase. Interestingly, this effect was not due to the inhibition of DSB repair but to a specific increase in the Top2-DNA covalent complex formed by ETP. A genome-wide search for DSB locations revealed that DSB formation was promoted near promoter regions, suggesting the involvement of MPA transcriptional modulation in this mechanism. We also found that various steroids promoted DSB formation when combined with ETP, strongly supporting our synergistic model. Therefore, this synergistic effect is based on an innovative mechanism that differs from conventional strategies targeting the DNA damage response and is expected to contribute toward novel therapeutic options.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 7","pages":"1952-1962"},"PeriodicalIF":4.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70081","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144039968","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}