Cancer Science最新文献

{"title":"Landscape Analysis of CLDN18 Expression and Isoform Distribution in Solid Tumors: Insights From MONSTAR-SCREEN-2 Study.","authors":"Tadayoshi Hashimoto, Naoko Iida, Yoshiaki Nakamura, Norio Nonomura, Chigusa Morizane, Hiroji Iwata, Susumu Okano, Wataru Yamagami, Naoya Yamazaki, Shigenori Kadowaki, Makoto Ueno, Shogen Boku, Eiji Oki, Yoshito Komatsu, Satoshi Yuki, Akitaka Makiyama, Takatsugu Ogata, Naoki Takahashi, Naohiro Okano, Tomohiro Nishina, Naoya Sakamoto, Takeshi Kuwata, Riu Yamashita, Taro Shibuki, Mitsuho Imai, Takao Fujisawa, Hideaki Bando, Kohei Shitara, Takayuki Yoshino","doi":"10.1111/cas.70100","DOIUrl":"https://doi.org/10.1111/cas.70100","url":null,"abstract":"<p><p>Claudin 18.2 (CLDN18.2), a tight junction protein isoform, is an emerging therapeutic target in oncology. CLDN18 is well-characterized in gastric cancer, but its pan-cancer expression profiles and isoform distributions are poorly documented. In the present study, we analyzed CLDN18 expression in patients with solid tumors enrolled in the MONSTAR-SCREEN-2 study using immunohistochemistry (IHC, n = 349) and whole-transcriptome sequencing (WTS, n = 2191). A splice junction analysis algorithm characterized isoform distribution patterns in WTS data and evaluated temporal changes using paired pre- and postchemotherapy specimens. IHC detected CLDN18.2 (≥ 40% of tumor cells showing any staining intensity) in 16.3% of patients, with highest prevalence in gastric (54.5%), biliary tract (21.7%), pancreatic (20.7%), and small intestinal (18.2%) cancers. WTS and IHC findings were significantly correlated (p < 0.001). WTS analysis with optimized transcript thresholds (n = 2191) demonstrated the CLDN18-high population to be 13.8%, with highest proportions in gastric (64.5%), small intestinal (40.0%), pancreatic (37.8%), and biliary tract (20.0%) cancers. Isoform analysis of 364 patients revealed CLDN18.2 predominance (mean 18.2/18.1 proportion 0.945), with CLDN18.1 predominance observed in only 4.9% of patients. Longitudinal analysis of 27 paired gastric cancer samples revealed a significant reduction in CLDN18 expression and a nonsignificant decrease in the CLDN18.2 proportion following chemotherapy. This analysis validates WTS as a complementary approach to IHC for CLDN18 assessment and demonstrates significant CLDN18 expression across multiple cancer types. The predominance of CLDN18.2 supports the expansion of targeted therapeutic approaches beyond gastric cancer and indicates the potential of RNA-based screening.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210008","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}

{"title":"ACSM5 Regulates Ferroptosis in Hepatocellular Carcinoma by Up-Regulating POR and Modulating Lipid Metabolism.","authors":"Zhengqiang Wu, Xiaofeng Xiong, Mingyi Dong, Linfei Luo, Zixiang Huang, Kedong Xu, Lianwu Zhao, Fenfen Wang, Zhili Wen","doi":"10.1111/cas.70115","DOIUrl":"https://doi.org/10.1111/cas.70115","url":null,"abstract":"<p><p>The medium-chain fatty acyl-CoA synthetase-5 (ACSM5) plays a crucial role in the development of some cancers. However, its impact on liver cancer is still not clear. In this study, we found that the proliferation ability of LM3 and HepG2 cells was significantly inhibited after ACSM5 was overexpressed, and this change was blocked by the ferroptosis inhibitor deferoxamine. ACSM5 increased the levels of malondialdehyde (MDA) and lipid reactive oxygen species (ROS), reduced the level of glutathione (GSH), and thus triggered ferroptosis. Furthermore, ACSM5 promoted the upregulation of cytochrome P450 oxidoreductase (POR). Knocking down POR blocked the promoting effect of ACSM5 on ferroptosis in HCC. Moreover, ACSM5 promoted the generation of arachidonic acid and thus increased the sensitivity to ferroptosis. In summary, our findings indicate that ACSM5 induces ferroptosis in hepatocellular carcinoma (HCC) by upregulating POR. The metabolic transformation of linoleic acid to arachidonic acid was also promoted by ACSM5; therefore, sensitivity to ferroptosis was increased.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210006","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}

{"title":"Connexin43 Promotes the Invasion and Metastasis of Lung Squamous Cell Carcinoma via GJIC-Dependent Ca²⁺/ERK Signaling Activation.","authors":"Xiaocheng Mo, Jingchuan He, Xiaoju Shen, Changsheng Li, Xiaoxiang Mo, Kai Liang, Liangjun He, Tingting Li, Xiaoqin Pan, Sisi Cao, Naiquan Mao, Shangping Xing, Zhiquan Chen, Zhuo Luo, Jie Yang","doi":"10.1111/cas.70076","DOIUrl":"https://doi.org/10.1111/cas.70076","url":null,"abstract":"<p><p>Lung squamous cell carcinoma (LUSC) is an extremely metastatic cancer with limited available treatment and poor outcomes. Connexin43 (Cx43) is frequently overactivated and positively correlated with tumorigenesis in many cancers, including breast cancer and lung adenocarcinoma, but its role in LUSC remains elusive. In this study, we demonstrated that Cx43 was highly expressed in LUSC tissues as compared to matching normal lung tissues (n = 103) and negatively related to prognosis. Through the 3D spheroid cell invasion assay, zCDX (zebrafish cell line-derived xenograft), and orthotopic lung cancer xenograft model, we further revealed that Cx43 promotes LUSC invasion and migration via forming GJIC. Knockdown of Cx43 reduced the Ca²⁺ transmission and ERK phosphorylation, whereas the addition of Ca²⁺ enhanced ERK phosphorylation and promoted LUSC invasion and migration. Furthermore, verapamil (40 μM and 80 μM), a calcium channel inhibitor, significantly inhibited ERK phosphorylation as well as the invasion and migration of LUSC cells. Mechanistically, Cx43 promoted the invasion and metastasis of LUSC via activating the Ca²⁺/ERK signaling pathway by gap junctional intracellular communication (GJIC). Our findings provide a novel mechanism insight for LUSC invasion and migration and a proof of concept for a new therapeutic strategy to tackle this disease.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192383","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}

{"title":"Diversity of U1 Small Nuclear RNAs and Diagnostic Methods for Their Mutations.","authors":"Takuma Nakashima, Tsubasa Miyauchi, Ryota Takeuchi, Yuriko Sugihara, Yusuke Funakoshi, Fumiharu Ohka, Sachi Maeda, Junko Hirato, Takako Yoshioka, Hajime Okita, Yoshitaka Narita, Yonehiro Kanemura, Yasuhiro Kojima, Yuko Watanabe, Ryuta Saito, Hiromichi Suzuki","doi":"10.1111/cas.70110","DOIUrl":"https://doi.org/10.1111/cas.70110","url":null,"abstract":"<p><p>U1 small nuclear RNA (snRNA) mutations are recurrent non-coding alterations found in various malignancies, yet their identification has proven challenging due to their repetitive nature. We characterized the complex interindividual diversity and genomic architecture of U1 snRNA loci using sequencing data and a pangenome reference. Our analysis uncovered copy number variations and the diversity of single-nucleotide variants in regions not predicted to have significant functional impact. Compared to traditional linear reference-based analyses for mutations, the pangenome graph demonstrated the best accuracy, successfully identifying previously undetectable mutations. This underscores the utility of pangenome graph references for cancer genome research, particularly in repetitive and highly diverse genomic regions. Additionally, we developed mutation detection methods employing targeted capture sequencing, rapid quantitative polymerase chain reaction, and a machine learning approach based on splicing patterns, all exhibiting high precision in identifying U1 snRNA mutations. Our findings elucidate the structural complexity of U1 snRNA loci and establish robust methodologies for precise mutation detection in these regions.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144163211","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}

{"title":"Ligand-Receptor Interactions Between Squamous and Endothelial Cells Induce Head and Neck Squamous Cell Carcinoma.","authors":"Takahiro Ishiyama, Daisuke Sano, Hideaki Takahashi, Nobuhiko Oridate, Yutaka Suzuki, Satoshi Fujii","doi":"10.1111/cas.70085","DOIUrl":"https://doi.org/10.1111/cas.70085","url":null,"abstract":"<p><p>Advances in narrowband imaging (NBI) have revealed that squamous epithelial lesions form alongside changes in squamous epithelial cells and intrapapillary capillary loops (IPCLs) in the head and neck. However, the molecular interactions between squamous epithelial cells and endothelial cells (ECs) that promote IPCL proliferation are unclear. This study aimed to identify the mechanisms of cooperation between parenchymal squamous cells and stromal IPCLs during the formation of head and neck squamous cell carcinoma (SCC). We investigated ligand-receptor interactions between squamous epithelial and endothelial cells of IPCLs using Visium analysis on frozen, formalin-fixed and paraffin-embedded (FFPE) tissues from hypopharyngeal squamous epithelial lesions. We examined the protein expression in hypopharyngeal superficial squamous epithelial lesions using immunohistochemistry and immunofluorescence. mRNA expression levels of these genes in SCC and non-tumor tissues were analyzed using RT-qPCR. Phenotypic changes were analyzed by inducing candidate genes into SCC cell lines via a lentivirus system. Visium analysis revealed that Fibronectin 1 (FN1) acted as a ligand in endothelial cells, Cellular communication network factor 1 (CCN1) as a ligand in SCC cells, and Integrin subunit alpha V (ITGAV) as a receptor for both FN1 and CCN1. The expression of these three candidates increased in low-grade dysplasia, an early stage of neoplastic lesions, and was significantly higher in invasive SCCs, except for CCN1. When ITGAV was introduced into SCC cell lines (FaDu and Detroit 562) and HaCaT cells treated with FN1, the cells showed increased proliferation ability. SCC develops via ligand-receptor molecular interactions between squamous epithelial and vascular endothelial cells in IPCLs.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144152581","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}

{"title":"A Novel Method for Prognostic Risk Classification After Carbon-Ion Radiotherapy for Hepatocellular Carcinoma Using Data-Mining Methods.","authors":"Kazuhiko Hayashi, Osamu Suzuki, Koji Ichise, Hirofumi Uchida, Makoto Anzai, Azusa Hasegawa, Shinichi Shimizu, Teruki Teshima, Jiro Fujimoto, Kazuhiko Ogawa","doi":"10.1111/cas.70079","DOIUrl":"https://doi.org/10.1111/cas.70079","url":null,"abstract":"<p><p>No classification methods to predict prognosis after carbon-ion radiotherapy for hepatocellular carcinoma have yet been reported. This study aimed to develop risk classification for cancer-specific survival (CSS) after carbon-ion radiotherapy for hepatocellular carcinoma using decision tree analysis as a data-mining method. In this single-center, retrospective study, we analyzed 90 consecutive patients with hepatocellular carcinoma treated with carbon-ion radiotherapy between 2018 and 2022. Liver tumors were irradiated at 60 Gy (relative biological effectiveness [RBE]) in four fractions. If the tumor was close to the gastrointestinal tract, it was irradiated at 60 Gy [RBE] in 12 fractions. Univariate and multivariate analyses of progression-free survival (PFS) and CSS were performed to assess patients' background and treatment-related factors. Decision tree analysis (DTA) was performed to assess prognostic factors for CSS that were significantly different in the multivariate analysis. The median follow-up period was 32.8 months for all patients and 35.6 months for survivors. Multivariate analysis identified dose fractionation and pretreatment alpha-fetoprotein values as significant prognostic factors for PFS and CSS. Moreover, clinical stage and pretreatment protein induced by vitamin K absence or antagonist ΙΙ values were significant prognostic factors for CSS. DTA revealed that the patients could be divided into three groups according to prognosis: low-risk, high-risk, and intermediate-risk. Consequently, the 3-year CSS rates for the low-, intermediate-, and high-risk groups were 100%, 73.3%, and 44.4%, respectively. DTA represents a new method for risk classification for CSS after carbon-ion radiotherapy for hepatocellular carcinoma based on tumor markers and clinical stage.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144144110","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}

{"title":"TGF-β Enhances Doxorubicin Resistance and Anchorage-Independent Growth in Cancer Cells by Inducing ALDH1A1 Expression.","authors":"Takashi Yokoyama, Masao Saitoh, Keiji Miyazawa","doi":"10.1111/cas.70109","DOIUrl":"https://doi.org/10.1111/cas.70109","url":null,"abstract":"<p><p>The transforming growth factor-β (TGF-β)/Smad signaling pathway promotes malignant transformation through various mechanisms, and its effect on enhancing drug resistance can limit the efficacy of treatment. Here, we showed that pre-stimulation of human lung cancer A549 cells with TGF-β increases resistance to doxorubicin-induced growth inhibition in a Smad3- and Smad4-dependent manner. This effect was suppressed by the aldehyde dehydrogenase (ALDH) inhibitor oxyfedrine, suggesting that ALDH family members are involved in drug resistance. TGF-β upregulated the mRNA and protein expression of ALDH1A1. The TGF-β/Smad3 transcriptional enhancer region on ALDH1A1 was identified by Smad3 ChIP-seq analysis using an open database and by reporter assays. Knockdown of ALDH1A1 in A549 cells suppressed TGF-β-induced doxorubicin resistance, and lentivirus-mediated introduction of ALDH1A1 into A549 SMAD3-KO cells restored drug resistance. We also demonstrated that ALDH1A1 is required and sufficient for TGF-β/Smad3 signaling-induced anchorage-independent growth. The results suggest that the TGF-β/Smad3/4 axis promotes resistance to doxorubicin and anchorage-independent growth by inducing the transcription of ALDH1A1.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144144113","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}

{"title":"KEYNOTE-A17: First-Line Pembrolizumab Plus Cisplatin-Pemetrexed in Japanese Participants With Advanced Pleural Mesothelioma.","authors":"Takashi Kijima, Terufumi Kato, Yasushi Goto, Kozo Kuribayashi, Koji Mikami, Yoshiki Negi, Shuji Murakami, Tatsuya Yoshida, Masae Homma, Akira Wakana, Kazuo Noguchi, Nobukazu Fujimoto","doi":"10.1111/cas.70082","DOIUrl":"https://doi.org/10.1111/cas.70082","url":null,"abstract":"<p><p>Pleural mesothelioma (PM) is an inflammatory cancer linked with asbestos exposure and has a poor prognosis. We report results of the phase 1b KEYNOTE-A17 study (NCT04153565) of first-line pembrolizumab plus chemotherapy in Japanese participants with advanced PM. Participants aged ≥ 20 years with previously untreated, histologically confirmed advanced or unresectable PM received pembrolizumab 200 mg every 3 weeks (Q3W) for ≤ 35 cycles with cisplatin 75 mg/m² and pemetrexed 500 mg/m² Q3W for 4-6 cycles. Primary endpoints were the rate of dose-limiting toxicities (DLTs), adverse events (AEs), and treatment discontinuations due to AEs. DLTs were assessed during cycle 1 in 18 participants, and having ≤ 8 participants with DLTs was considered tolerable. AEs were graded per NCI CTCAE 5.0. Tumor response was evaluated per modified RECIST for PM by the investigator. Among 19 participants enrolled, the median study follow-up was 30.8 (range, 27.8-33.3) months (data cutoff September 21, 2022). Of 18 participants evaluated for DLTs, 2 (11%) experienced 4 DLTs (hypoalbuminemia, malaise, pyrexia in 1 participant; uveitis in 1 participant). 18/19 participants (95%) experienced treatment-related AEs; 14 (74%) had grade 3-4 events (no grade 5). Treatment-related AEs led to discontinuation of any drug in 5 participants (26%). The objective response rate was 74% (partial response, n = 14), and the median (range) duration of response was 16.8 (3.0-26.3+) months. First-line pembrolizumab plus chemotherapy was tolerable based on the low incidence of DLTs and showed acceptable safety and preliminary antitumor activity in Japanese participants with advanced PM. Trial Registration: NCT04153565.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144129074","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}

{"title":"The Pro-Apoptotic Effect of Glucose Restriction in NSCLC via AMPK-Regulated Circadian Clock Gene Bmal1.","authors":"Tao Wei, Ying Cheng, Jierong Ge, Manting Zhu, Hong Chen, Qing Feng","doi":"10.1111/cas.70098","DOIUrl":"https://doi.org/10.1111/cas.70098","url":null,"abstract":"<p><p>The circadian clock is a crucial regulator of mammalian physiology, controlling daily oscillations in key biological processes, such as cell proliferation, apoptosis, and DNA damage repair. Disruption of circadian rhythms has been identified as a significant risk factor for cancer development and progression, yet the specific molecular mechanisms linking circadian dysfunction to cancer remain poorly understood. Recent studies have increasingly focused on the role of diet in modulating circadian rhythms, highlighting the potential for dietary interventions in cancer management. However, how dietary factors like glucose restriction interact with circadian rhythms to influence cancer cell behavior remains an open question. Here, we investigate the mechanisms underlying glucose restriction-induced apoptosis in non-small cell lung cancer (NSCLC) cells, with a focus on the role of circadian clock genes. Analysis of the GEPIA database revealed that the circadian gene Bmal1 is highly expressed in normal tissues and associated with better prognosis in lung adenocarcinoma patients. In NSCLC cells, Bmal1 expression correlated with proapoptotic gene activity. In a tumor xenograft model using severe combined immunodeficiency (SCID) mice, a glucose-restricted (ketogenic) diet significantly delayed tumor growth and increased the expression of Bmal1 and proapoptotic genes. These findings suggest that glucose restriction promotes apoptosis in NSCLC cells through a Bmal1-mediated pathway, providing novel insights into the intersection between circadian regulation and cancer biology. Targeting core circadian clock genes like Bmal1 may represent a promising therapeutic strategy for managing lung cancer, broadening our understanding of how circadian rhythms can be harnessed for cancer prevention and treatment.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144112045","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}

{"title":"Antitumor Activities by a Humanized Cancer-Specific Anti-Podoplanin Monoclonal Antibody humPMab-117 Against Human Tumors.","authors":"Tomohiro Tanaka, Hiroyuki Suzuki, Tomokazu Ohishi, Manabu Kawada, Mika K Kaneko, Yukinari Kato","doi":"10.1111/cas.70103","DOIUrl":"https://doi.org/10.1111/cas.70103","url":null,"abstract":"<p><p>Podoplanin (PDPN), also referred to as T1α/Aggrus, is a type I transmembrane sialoglycoprotein that plays a crucial role in invasiveness, stemness, and epithelial-to-mesenchymal transition, all of which contribute to the malignant progression of tumors. Therefore, a monoclonal antibody (mAb) against PDPN has been evaluated in preclinical models as a promising tumor therapy strategy. However, PDPN plays an essential role in normal development, such as in the development of the lungs. On-target toxicity by anti-PDPN mAbs to normal cells should be avoided to minimize adverse effects. A cancer-specific mAb against PDPN, PMab-117 (rat IgM, kappa), was previously established. This study engineered the humanized IgG₁ version (humPMab-117) to investigate antitumor activity. Flow cytometry analysis confirmed that humPMab-117 recognized PDPN-overexpressed glioma LN229 (LN229/PDPN) cells as well as PDPN-positive PC-10 (human lung squamous cell carcinoma) and LN319 (human glioblastoma) cells. In contrast, humPMab-117 did not react with normal epithelial cells from the lung bronchus, gingiva, mammary gland, corneal, and normal kidney podocytes, suggesting that humPMab-117 retains cancer-specific reactivity. Furthermore, humPMab-117 effectively induced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against LN229/PDPN, PC-10, and LN319 cells. In the xenograft tumor models, humPMab-117 demonstrated strong antitumor efficacy. These results suggest the potential of humPMab-117 as a therapeutic antibody for treating PDPN-positive malignant tumors.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111746","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}