Cancer Science最新文献

{"title":"A highly sensitive reporter system to monitor endogenous YAP1/TAZ activity and its application in various human cells","authors":"Hiroki Hikasa,&nbsp;Kohichi Kawahara,&nbsp;Masako Inui,&nbsp;Yukichika Yasuki,&nbsp;Keita Yamashita,&nbsp;Kohei Otsubo,&nbsp;Shojiro Kitajima,&nbsp;Miki Nishio,&nbsp;Kazunari Arima,&nbsp;Motoyoshi Endo,&nbsp;Masanori Taira,&nbsp;Akira Suzuki","doi":"10.1111/cas.16316","DOIUrl":"10.1111/cas.16316","url":null,"abstract":"<p>The activation of yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ) has been implicated in both regeneration and tumorigenesis, thus representing a double-edged sword in tissue homeostasis. However, how the activity of YAP1/TAZ is regulated or what leads to its dysregulation in these processes remains unknown. To explore the upstream stimuli modulating the cellular activity of YAP1/TAZ, we developed a highly sensitive YAP1/TAZ/TEAD-responsive DNA element (YRE) and incorporated it into a lentivirus-based reporter cell system to allow for sensitive and specific monitoring of the endogenous activity of YAP1/TAZ in terms of luciferase activity in vitro and Venus fluorescence in vivo. Furthermore, by replacing YRE with TCF- and NF-κB-binding DNA elements, we demonstrated the applicability of this reporter system to other pathways such as Wnt/β-catenin/TCF- and IL-1β/NF-κB-mediated signaling, respectively. The practicality of this system was evaluated by performing cell-based reporter screening of a chemical compound library consisting of 364 known inhibitors, using reporter-introduced cells capable of quantifying YAP1/TAZ- and β-catenin-mediated transcription activities, which led to the identification of multiple inhibitors, including previously known as well as novel modulators of these signaling pathways. We further confirmed that novel YAP1/TAZ modulators, such as potassium ionophores, Janus kinase inhibitors, platelet-derived growth factor receptor inhibitors, and genotoxic stress inducers, alter the protein level or phosphorylation of endogenous YAP1/TAZ and the expression of their target genes. Thus, this reporter system provides a powerful tool to monitor endogenous signaling activities of interest (even in living cells) and search for modulators in various cellular contexts.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"115 10","pages":"3370-3383"},"PeriodicalIF":4.5,"publicationDate":"2024-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142001114","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":"Chromatin lysine acylation: On the path to chromatin homeostasis and genome integrity","authors":"Feng Chen,&nbsp;Xingkai He,&nbsp;Wenchao Xu,&nbsp;Linmin Zhou,&nbsp;Qi Liu,&nbsp;Weicheng Chen,&nbsp;Wei-Guo Zhu,&nbsp;Jun Zhang","doi":"10.1111/cas.16321","DOIUrl":"10.1111/cas.16321","url":null,"abstract":"<p>The fundamental role of cells in safeguarding the genome's integrity against DNA double-strand breaks (DSBs) is crucial for maintaining chromatin homeostasis and the overall genomic stability. Aberrant responses to DNA damage, known as DNA damage responses (DDRs), can result in genomic instability and contribute significantly to tumorigenesis. Unraveling the intricate mechanisms underlying DDRs following severe damage holds the key to identify therapeutic targets for cancer. Chromatin lysine acylation, encompassing diverse modifications such as acetylation, lactylation, crotonylation, succinylation, malonylation, glutarylation, propionylation, and butyrylation, has been extensively studied in the context of DDRs and chromatin homeostasis. Here, we delve into the modifying enzymes and the pivotal roles of lysine acylation and their crosstalk in maintaining chromatin homeostasis and genome integrity in response to DDRs. Moreover, we offer a comprehensive perspective and overview of the latest insights, driven primarily by chromatin acylation modification and associated regulators.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"115 11","pages":"3506-3519"},"PeriodicalIF":4.5,"publicationDate":"2024-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142001115","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":"Fusobacterium nucleatum, immune responses, and metastatic organ diversity in colorectal cancer liver metastasis","authors":"Yasuyuki Shigematsu,&nbsp;Rumiko Saito,&nbsp;Gulanbar Amori,&nbsp;Hiroaki Kanda,&nbsp;Yu Takahashi,&nbsp;Kengo Takeuchi,&nbsp;Shunji Takahashi,&nbsp;Kentaro Inamura","doi":"10.1111/cas.16315","DOIUrl":"10.1111/cas.16315","url":null,"abstract":"<p>The presence of <i>Fusobacterium nucleatum</i> is associated with an immunosuppressive tumor immune microenvironment (TIM) in primary colorectal cancer (CRC), contributing to tumor progression. Its persistence in CRC liver metastasis tissues raises questions about its role in modulating local and systemic immune responses and influencing recurrence patterns. This retrospective cohort study of 218 patients with CRC liver metastasis investigated the association of <i>F. nucleatum</i> in CRC liver metastasis tissues with systemic inflammation, TIM alterations, and the number of metastatic organs involved in recurrence. Two-step polymerase chain reaction (PCR), including digital PCR, detected <i>F. nucleatum</i> in 42% (92/218) of fresh-frozen specimens of CRC liver metastases. Compared with the <i>F. nucleatum-</i>none group, the <i>F. nucleatum-</i>high group showed higher C-reactive protein levels (0.82 vs. 0.22 mg/dL; <i>P</i>_trend = 0.02), lower numbers of CD8⁺ cells (33.2 vs. 65.3 cells/mm²; <i>P</i>_trend = 0.04) and FOXP3⁺ cells (11.3 vs. 21.7 cells/mm²; <i>P</i>_trend = 0.01) in the TIM, and a greater number of metastatic organs involved in recurrence (1.6 vs. 1.1; <i>p</i> &lt; 0.001). The presence of <i>F. nucleatum</i> in CRC liver metastasis tissues was associated with increased systemic inflammation, TIM alterations, and a greater number of metastatic organs involved in recurrence. These findings suggest a potential contribution of <i>F. nucleatum</i> to the metastatic propensity of CRC cells and could inform future research to enhance understanding of the interaction between tumor, host, and microbes in the metastatic process.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"115 10","pages":"3248-3255"},"PeriodicalIF":4.5,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141976949","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":"Accurate predictors of immune checkpoint inhibitors in patients with gallbladder cancer","authors":"Naimei Li,&nbsp;Shuang Deng","doi":"10.1111/cas.16235","DOIUrl":"10.1111/cas.16235","url":null,"abstract":"<p>Immune checkpoint inhibitors (ICIs) are effective for biliary tract cancers, but data on gallbladder cancer (GBC) are limited. In a recent issue of <i>Cancer Science</i>, Cheng et al.<span>¹</span> aimed to assess the efficacy of ICIs in GBC and explore the clinicopathologic and molecular markers associated with ICI benefits. Based on logistic regression analysis, they found that alcohol intake history, a carcinoembryonic antigen (CEA) level ≥ 100 U/mL, and cutaneous immune-related adverse events (irAEs) were independent prognostic factors for these patients. High carcinoembryonic antigen (CEA) levels, cutaneous irAEs, high CD8⁺ T-cell infiltration, and an immune inflamed phenotype could be useful for predicting the efficacy of ICIs in GBC patients. However, in this letter, we raise concerns about the statistical method used in this study, while the prognostic factors or predictors for GBC patients may be different.</p><p>For a prognostic factors or predictors logistic regression analysis, the basic statistical rule demands 1 covariate per 10 outcome events.<span>^2-4</span> However, the univariable and multivariable Cox proportional hazards regression model in Table 2 of Cheng's study breaks this basic statistical rule. We could observe that there were 21 variables in Table 2 of Cheng's paper that were generated from only 43 PD patients (outcome) who developed tumor recurrence or progressed to death. In other words, analysis of these 21 variables needs at least 210 PD outcome patients, not the 43 PD patients reported in this study. Thus, these overfitted univariable and multivariable logistic models could not produce reliable results, therefore the results in Cheng's study may not be accurate predictors for these patients in the clinic.</p><p>To reduce the variables in the predictor logistic regression analysis, the author could compare the outcome group and the non-outcome group. Finding the significant variables between these two groups and using the reduced variables to carry out the predictor logistic regression analysis would lead to more reliable statistical results. Additionally, to finally corroborate Cheng's conclusion, other large sample size results or a validation cohort is needed to validate the predictor results reported in this study.</p><p>Last, we congratulate Cheng et al. for their outstanding work despite these comments.</p><p><b>Naimei Li:</b> Writing – original draft. <b>Shuang Deng:</b> Conceptualization; writing – original draft; writing – review and editing.</p><p>None.</p><p>The authors declare no conflict of interest.</p><p>Approval of the research protocol by an Institutional Reviewer Board: N/A.</p><p>Informed consent: N/A.</p><p>Registry and the Registration No. of the study: N/A.</p><p>Animal Studies: N/A.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"115 10","pages":"3481-3482"},"PeriodicalIF":4.5,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983667","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":"Mechanism research of non-coding RNA in immune checkpoint inhibitors therapy","authors":"Jie Bian,&nbsp;Rui Shao,&nbsp;Juan Li,&nbsp;Jing-Feng Zhu,&nbsp;Ai-Zhong Shao,&nbsp;Chao Liu,&nbsp;L. V. Lu,&nbsp;Hui-Wen Pan,&nbsp;Yi-Jun Shi,&nbsp;Na Fang","doi":"10.1111/cas.16309","DOIUrl":"10.1111/cas.16309","url":null,"abstract":"<p>Immune checkpoint inhibitor (ICI) therapies for tumors of different systems have attained significant achievements and have changed the current situation of tumor treatment due to their therapeutic characteristics of high specificity and low side effects. The immune checkpoint Programmed death 1/Programmed cell death-Ligand 1 (PD-1/PD-L1) axis exerts a vital role in the immune escape of tumor cells. As a result, it has become a key target for tumor immunotherapy. Therefore, to perfect research into potential regulatory factors for the PD-1/PD-L1 axis, in order to understand and illustrate tumor ICI therapy mechanisms, is a significant goal. Moreover, ncRNA has been verified to regulate the PD-1/PD-L1 axis in the tumor immune microenvironment to regulate tumor genesis and development. ncRNAs can improve or decrease the efficacy of ICI therapy by modulating PD-L1 expression. This review aimed to investigate the mechanisms of action of ncRNA in regulating the PD-1/PD-L1 axis in ICI therapy, to provide more efficient immunotherapy for tumors of different systems.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"115 11","pages":"3520-3531"},"PeriodicalIF":4.5,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141972162","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":"Correction to: AC016405.3, a novel long noncoding RNA, acts as a tumor suppressor through modulation of TET2 by microRNA-19a-5p sponging in glioblastoma","authors":"","doi":"10.1111/cas.16277","DOIUrl":"10.1111/cas.16277","url":null,"abstract":"<p>Siyang Ren, Yinghui Xu. AC016405.3, a novel long noncoding RNA, acts as a tumor suppressor through modulation of TET2 by microRNA-19a-5p sponging in glioblastoma. Cancer Science. 2019;110:1621–1632.</p><p>We apologize for this error.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"115 10","pages":"3496"},"PeriodicalIF":4.5,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141908098","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 multicenter study on deep learning for glioblastoma auto-segmentation with prior knowledge in multimodal imaging","authors":"Suqing Tian,&nbsp;Yinglong Liu,&nbsp;Xinhui Mao,&nbsp;Xin Xu,&nbsp;Shumeng He,&nbsp;Lecheng Jia,&nbsp;Wei Zhang,&nbsp;Peng Peng,&nbsp;Junjie Wang","doi":"10.1111/cas.16304","DOIUrl":"10.1111/cas.16304","url":null,"abstract":"<p>A precise radiotherapy plan is crucial to ensure accurate segmentation of glioblastomas (GBMs) for radiation therapy. However, the traditional manual segmentation process is labor-intensive and heavily reliant on the experience of radiation oncologists. In this retrospective study, a novel auto-segmentation method is proposed to address these problems. To assess the method's applicability across diverse scenarios, we conducted its development and evaluation using a cohort of 148 eligible patients drawn from four multicenter datasets and retrospective data collection including noncontrast CT, multisequence MRI scans, and corresponding medical records. All patients were diagnosed with histologically confirmed high-grade glioma (HGG). A deep learning-based method (PKMI-Net) for automatically segmenting gross tumor volume (GTV) and clinical target volumes (CTV1 and CTV2) of GBMs was proposed by leveraging prior knowledge from multimodal imaging. The proposed PKMI-Net demonstrated high accuracy in segmenting, respectively, GTV, CTV1, and CTV2 in an 11-patient test set, achieving Dice similarity coefficients (DSC) of 0.94, 0.95, and 0.92; 95% Hausdorff distances (HD95) of 2.07, 1.18, and 3.95 mm; average surface distances (ASD) of 0.69, 0.39, and 1.17 mm; and relative volume differences (RVD) of 5.50%, 9.68%, and 3.97%. Moreover, the vast majority of GTV, CTV1, and CTV2 produced by PKMI-Net are clinically acceptable and require no revision for clinical practice. In our multicenter evaluation, the PKMI-Net exhibited consistent and robust generalizability across the various datasets, demonstrating its effectiveness in automatically segmenting GBMs. The proposed method using prior knowledge in multimodal imaging can improve the contouring accuracy of GBMs, which holds the potential to improve the quality and efficiency of GBMs' radiotherapy.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"115 10","pages":"3415-3425"},"PeriodicalIF":4.5,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141908087","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":"CLG promotes mTOR/ULK1 pathway-mediated autophagy to inhibit OS development by inhibiting TRAF6-mediated FLT3 ubiquitination","authors":"Xiongjie Huang,&nbsp;Yanran Huang,&nbsp;Bin Peng,&nbsp;Junfang Wang,&nbsp;Huiyu Tang,&nbsp;Yanming Chen","doi":"10.1111/cas.16274","DOIUrl":"10.1111/cas.16274","url":null,"abstract":"<p>Corilagin (CLG) has antitumor activities in certain human malignant cancers. Herein, the effects and mechanisms of CLG on osteosarcoma (OS) were investigated. OS cell viability and proliferation were detected by MTT and colony formation assay. Cell cycle and apoptosis were examined using flow cytometry. The interaction between TRAF6 and FLT3 was investigated using a co-immunoprecipitation assay. Results demonstrated that CLG treatment inhibited OS cell viability and proliferation but promoted OS cell autophagy and apoptosis in a concentration-dependent manner. Mechanically, CLG inhibited TRAF6-mediated FLT3 ubiquitination degradation. TRAF6 overexpression abolished the effects of CLG on OS cell proliferation, autophagy, and apoptosis. Finally, CLG administration inhibited OS tumor growth in mice by inducing autophagy-dependent apoptosis. Taken together, CLG inhibited OS progression by facilitating mTOR/ULK1 pathway-mediated autophagy through inhibiting TRAF6-mediated FLT3 ubiquitination, which indicated that CLG was a promising candidate for the treatment of OS.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"115 10","pages":"3466-3480"},"PeriodicalIF":4.5,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141908088","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":"Overcoming immunotherapy resistance and inducing abscopal effects with boron neutron immunotherapy (B-NIT)","authors":"Takuya Fujimoto,&nbsp;Osamu Yamasaki,&nbsp;Noriyuki Kanehira,&nbsp;Hirokazu Matsushita,&nbsp;Yoshinori Sakurai,&nbsp;Naoya Kenmotsu,&nbsp;Ryo Mizuta,&nbsp;Natsuko Kondo,&nbsp;Takushi Takata,&nbsp;Mizuki Kitamatsu,&nbsp;Kazuyo Igawa,&nbsp;Atsushi Fujimura,&nbsp;Yoshihiro Otani,&nbsp;Makoto Shirakawa,&nbsp;Kunitoshi Shigeyasu,&nbsp;Fuminori Teraishi,&nbsp;Yosuke Togashi,&nbsp;Minoru Suzuki,&nbsp;Toshiyoshi Fujiwara,&nbsp;Hiroyuki Michiue","doi":"10.1111/cas.16298","DOIUrl":"10.1111/cas.16298","url":null,"abstract":"<p>Immune checkpoint inhibitors (ICIs) are effective against many advanced malignancies. However, many patients are nonresponders to immunotherapy, and overcoming this resistance to treatment is important. Boron neutron capture therapy (BNCT) is a local chemoradiation therapy with the combination of boron drugs that accumulate selectively in cancer and the neutron irradiation of the cancer site. Here, we report the first boron neutron immunotherapy (B-NIT), combining BNCT and ICI immunotherapy, which was performed on a radioresistant and immunotherapy-resistant advanced-stage B16F10 melanoma mouse model. The BNCT group showed localized tumor suppression, but the anti-PD-1 antibody immunotherapy group did not show tumor suppression. Only the B-NIT group showed strong tumor growth inhibition at both BNCT-treated and shielded distant sites. Intratumoral CD8+ T-cell infiltration and serum high mobility group box 1 (HMGB1) levels were higher in the B-NIT group. Analysis of CD8⁺ T cells in tumor-infiltrating lymphocytes (TILs) showed that CD62L- CD44⁺ effector memory T cells and CD69⁺ early-activated T cells were predominantly increased in the B-NIT group. Administration of CD8-depleting mAb to the B-NIT group completely suppressed the augmented therapeutic effects. This indicated that B-NIT has a potent immune-induced abscopal effect, directly destroying tumors with BNCT, inducing antigen-spreading effects, and protecting normal tissue. B-NIT, immunotherapy combined with BNCT, is the first treatment to overcome immunotherapy resistance in malignant melanoma. In the future, as its therapeutic efficacy is demonstrated not only in melanoma but also in other immunotherapy-resistant malignancies, B-NIT can become a new treatment candidate for advanced-stage cancers.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"115 10","pages":"3231-3247"},"PeriodicalIF":4.5,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141908100","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":"Newly developed humanized anti-CKAP4 antibody suppresses pancreatic cancer growth by inhibiting DKK1-CKAP4 signaling","authors":"Ryota Sada,&nbsp;Hideki Yamamoto,&nbsp;Shinji Matsumoto,&nbsp;Akikazu Harada,&nbsp;Akira Kikuchi","doi":"10.1111/cas.16278","DOIUrl":"10.1111/cas.16278","url":null,"abstract":"<p>Cytoskeleton-associated protein 4 (CKAP4) is a cell surface receptor for Dickkopf 1 (DKK1), a secreted protein. The DKK1–CKAP4 pathway is activated in various malignant tumors, including pancreatic, lung, esophageal, and liver cancers, to promote tumor growth. Thus, CKAP4 has been expected to represent a novel molecular target of cancer therapy. Recombinant mouse anti-CKAP4 antibodies were generated based on an original mouse antibody (3F11-2B10) and inhibited DKK1–CKAP4 signaling and xenograft tumor formation induced by pancreatic cancer cells, which was comparable with 3F11-2B10. From the 3F11-2B10 nucleotide sequence, humanized anti-CKAP4 antibody (Hv1Lt1) was subsequently developed. The binding affinity of Hv1Lt1 for CKAP4 was superior to that of 3F11-2B10. Hv1Lt1 inhibited DKK1 binding to CKAP4, AKT activity, and sphere formation of pancreatic cancer cells, which was comparable with 3F11-2B10. Hv1Lt1 also suppressed xenograft tumor formation induced by human pancreatic cancer cells and tumor growth in murine cancer models, in which murine pancreatic cancer organoids were orthotopically transplanted into the pancreas. In resected tumor samples from mice treated with Hv1Lt1, anti-tumor immune reactions were modulated and cytotoxic T cells were highly infiltrated in the tumor microenvironment. Additionally, combination of Hv1Lt1 and other chemotherapy drugs exhibited stronger effects compared with monotherapy. These results suggest that Hv1Lt1 represents a promising anti-cancer therapy.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"115 10","pages":"3358-3369"},"PeriodicalIF":4.5,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141908099","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}