Pub Date : 2024-03-20DOI: 10.1016/j.neo.2024.100991
Lianli Ni , Xinping Zhu , Qi Zhao , Yiwei Shen , Lu Tao , Ji Zhang , Han Lin , Weishan Zhuge , Young-Chang Cho , Ri Cui , Wangyu Zhu
Dihydroartemisinin (DHA) exerts an anti-tumor effect in multiple cancers, however, the molecular mechanism of DHA and whether DHA facilitates the anti-tumor efficacy of cisplatin in non-small cell lung cancer (NSCLC) are unclear. Here, we found that DHA potentiated the anti-tumor effects of cisplatin in NSCLC cells by stimulating reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress, C-Jun-amino-terminal kinase (JNK) and p38 MAPK signaling pathways both in vitro and in vivo. Of note, we demonstrated for the first time that DHA inhibits prostaglandin G/H synthase 1 (PTGS1) expression, resulting in enhanced ROS production. Importantly, silencing PTGS1 sensitized DHA-induced cell death by increasing ROS production and activating ER-stress, JNK and p38 MAPK signaling pathways. In summary, our findings provided new experimental basis and therapeutic prospect for the combined therapy with DHA and cisplatin in some NSCLC patients.
双氢青蒿素(DHA)在多种癌症中发挥抗肿瘤作用,然而,DHA的分子机制以及DHA是否促进顺铂在非小细胞肺癌(NSCLC)中的抗肿瘤功效尚不清楚。在这里,我们发现 DHA 通过刺激活性氧(ROS)介导的内质网(ER)应激、C-Jun-氨基末端激酶(JNK)和 p38 MAPK 信号通路,在体外和体内增强了顺铂在 NSCLC 细胞中的抗肿瘤作用。值得注意的是,我们首次证明了 DHA 可抑制前列腺素 G/H 合成酶 1(PTGS1)的表达,从而导致 ROS 生成增加。重要的是,沉默 PTGS1 会增加 ROS 的产生并激活 ER-应激、JNK 和 p38 MAPK 信号通路,从而使 DHA 诱导的细胞死亡敏感化。总之,我们的研究结果为DHA与顺铂联合治疗部分NSCLC患者提供了新的实验依据和治疗前景。
{"title":"Dihydroartemisinin, a potential PTGS1 inhibitor, potentiated cisplatin-induced cell death in non-small cell lung cancer through activating ROS-mediated multiple signaling pathways","authors":"Lianli Ni , Xinping Zhu , Qi Zhao , Yiwei Shen , Lu Tao , Ji Zhang , Han Lin , Weishan Zhuge , Young-Chang Cho , Ri Cui , Wangyu Zhu","doi":"10.1016/j.neo.2024.100991","DOIUrl":"https://doi.org/10.1016/j.neo.2024.100991","url":null,"abstract":"<div><p>Dihydroartemisinin (DHA) exerts an anti-tumor effect in multiple cancers, however, the molecular mechanism of DHA and whether DHA facilitates the anti-tumor efficacy of cisplatin in non-small cell lung cancer (NSCLC) are unclear. Here, we found that DHA potentiated the anti-tumor effects of cisplatin in NSCLC cells by stimulating reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress, C-Jun-amino-terminal kinase (JNK) and p38 MAPK signaling pathways both in <em>vitro</em> and in <em>vivo</em>. Of note, we demonstrated for the first time that DHA inhibits prostaglandin G/H synthase 1 (PTGS1) expression, resulting in enhanced ROS production. Importantly, silencing PTGS1 sensitized DHA-induced cell death by increasing ROS production and activating ER-stress, JNK and p38 MAPK signaling pathways. In summary, our findings provided new experimental basis and therapeutic prospect for the combined therapy with DHA and cisplatin in some NSCLC patients.</p></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1476558624000289/pdfft?md5=9d9621fe5697150db7a70a6aa34c9a8e&pid=1-s2.0-S1476558624000289-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140163961","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}
Pub Date : 2024-03-15DOI: 10.1016/j.neo.2024.100986
Steven Kregel , Chao Wang , Xin Han , Lanbo Xiao , Ester Fernandez-Salas , Pushpinder Bawa , Brooke L. McCollum , Kari Wilder-Romans , Ingrid J. Apel , Xuhong Cao , Corey Speers , Shaomeng Wang , Arul M. Chinnaiyan
{"title":"Corrigendum to “Androgen receptor degraders overcome common resistance mechanisms developed during prostate cancer treatment” [Neoplasia, Volume 22, Issue 2 (2020) 111–119]","authors":"Steven Kregel , Chao Wang , Xin Han , Lanbo Xiao , Ester Fernandez-Salas , Pushpinder Bawa , Brooke L. McCollum , Kari Wilder-Romans , Ingrid J. Apel , Xuhong Cao , Corey Speers , Shaomeng Wang , Arul M. Chinnaiyan","doi":"10.1016/j.neo.2024.100986","DOIUrl":"https://doi.org/10.1016/j.neo.2024.100986","url":null,"abstract":"","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S147655862400023X/pdfft?md5=5ef5169bb15da24af05d45a36eb6a114&pid=1-s2.0-S147655862400023X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140134617","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}
Pub Date : 2024-03-14DOI: 10.1016/j.neo.2024.100987
Heidi Rausio , Alejandra Cervera , Vanina D. Heuser , Gun West , Jaana Oikkonen , Elena Pianfetti , Marta Lovino , Elisa Ficarra , Pekka Taimen , Johanna Hynninen , Rainer Lehtonen , Sampsa Hautaniemi , Olli Carpén , Kaisa Huhtinen
Gene fusions are common in high-grade serous ovarian cancer (HGSC). Such genetic lesions may promote tumorigenesis, but the pathogenic mechanisms are currently poorly understood. Here, we investigated the role of a PIK3R1-CCDC178 fusion identified from a patient with advanced HGSC. We show that the fusion induces HGSC cell migration by regulating ERK1/2 and increases resistance to platinum treatment. Platinum resistance was associated with rod and ring-like cellular structure formation. These structures contained, in addition to the fusion protein, CIN85, a key regulator of PI3K-AKT-mTOR signaling. Our data suggest that the fusion-driven structure formation induces a previously unrecognized cell survival and resistance mechanism, which depends on ERK1/2-activation.
{"title":"PIK3R1 fusion drives chemoresistance in ovarian cancer by activating ERK1/2 and inducing rod and ring-like structures","authors":"Heidi Rausio , Alejandra Cervera , Vanina D. Heuser , Gun West , Jaana Oikkonen , Elena Pianfetti , Marta Lovino , Elisa Ficarra , Pekka Taimen , Johanna Hynninen , Rainer Lehtonen , Sampsa Hautaniemi , Olli Carpén , Kaisa Huhtinen","doi":"10.1016/j.neo.2024.100987","DOIUrl":"https://doi.org/10.1016/j.neo.2024.100987","url":null,"abstract":"<div><p>Gene fusions are common in high-grade serous ovarian cancer (HGSC). Such genetic lesions may promote tumorigenesis, but the pathogenic mechanisms are currently poorly understood. Here, we investigated the role of a PIK3R1-CCDC178 fusion identified from a patient with advanced HGSC. We show that the fusion induces HGSC cell migration by regulating ERK1/2 and increases resistance to platinum treatment. Platinum resistance was associated with rod and ring-like cellular structure formation. These structures contained, in addition to the fusion protein, CIN85, a key regulator of PI3K-AKT-mTOR signaling. Our data suggest that the fusion-driven structure formation induces a previously unrecognized cell survival and resistance mechanism, which depends on ERK1/2-activation.</p></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1476558624000241/pdfft?md5=f8e2bd5c24ada23b62b40db1984af77e&pid=1-s2.0-S1476558624000241-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140134618","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}
Pub Date : 2024-03-12DOI: 10.1016/j.neo.2024.100985
Jinyi Zhao , Xuemei Ma , Peixian Gao , Xueqi Han , Pengxiang Zhao , Fei Xie , Mengyu Liu
Alterations in cellular metabolism are important hallmarks of glioblastoma(GBM). Metabolic reprogramming is a critical feature as it meets the higher nutritional demand of tumor cells, including proliferation, growth, and survival. Many genes, proteins, and metabolites associated with GBM metabolism reprogramming have been found to be aberrantly expressed, which may provide potential targets for cancer treatment. Therefore, it is becoming increasingly important to explore the role of internal and external factors in metabolic regulation in order to identify more precise therapeutic targets and diagnostic markers for GBM. In this review, we define the metabolic characteristics of GBM, investigate metabolic specificities such as targetable vulnerabilities and therapeutic resistance, as well as present current efforts to target GBM metabolism to improve the standard of care.
{"title":"Advancing glioblastoma treatment by targeting metabolism","authors":"Jinyi Zhao , Xuemei Ma , Peixian Gao , Xueqi Han , Pengxiang Zhao , Fei Xie , Mengyu Liu","doi":"10.1016/j.neo.2024.100985","DOIUrl":"https://doi.org/10.1016/j.neo.2024.100985","url":null,"abstract":"<div><p>Alterations in cellular metabolism are important hallmarks of glioblastoma(GBM). Metabolic reprogramming is a critical feature as it meets the higher nutritional demand of tumor cells, including proliferation, growth, and survival. Many genes, proteins, and metabolites associated with GBM metabolism reprogramming have been found to be aberrantly expressed, which may provide potential targets for cancer treatment. Therefore, it is becoming increasingly important to explore the role of internal and external factors in metabolic regulation in order to identify more precise therapeutic targets and diagnostic markers for GBM. In this review, we define the metabolic characteristics of GBM, investigate metabolic specificities such as targetable vulnerabilities and therapeutic resistance, as well as present current efforts to target GBM metabolism to improve the standard of care.</p></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1476558624000228/pdfft?md5=8db8e44cf2fcb3f3b9420c8035568d7f&pid=1-s2.0-S1476558624000228-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140113167","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}
Pub Date : 2024-03-10DOI: 10.1016/j.neo.2024.100984
Mary Smithson , Sameer Al Diffalha , Regina K. Irwin , Gregory Williams , M. Chandler McLeod , Vivek Somasundaram , Susan L. Bellis , Karin M. Hardiman
Introduction
Colorectal cancer is the third most common cause of cancer death. Rectal cancer makes up a third of all colorectal cases. Treatment for locally advanced rectal cancer includes chemoradiation followed by surgery. We have previously identified ST6GAL1 as a cause of resistance to chemoradiation in vitro and hypothesized that it would be correlated with poor response in human derived models and human tissues.
Methods
Five organoid models were created from primary human rectal cancers and ST6GAL1 was knocked down via lentivirus transduction in one model. ST6GAL1 and Cleaved Caspase-3 (CC3) were assessed after chemoradiation via immunostaining. A tissue microarray (TMA) was created from twenty-six patients who underwent chemoradiation and had pre- and post-treatment specimens of rectal adenocarcinoma available at our institution. Immunohistochemistry was performed for ST6GAL1 and percent positive cancer cell staining was assessed and correlation with pathological grade of response was measured.
Results
Organoid models were treated with chemoradiation and both ST6GAL1 mRNA and protein significantly increased after treatment. The organoid model targeted with ST6GAL1 knockdown was found to have increased CC3 after treatment. In the tissue microarray, 42 percent of patient samples had an increase in percent tumor cell staining for ST6GAL1 after treatment. Post-treatment percent staining was associated with a worse grade of treatment response (p = 0.01) and increased staining post-treatment compared to pre-treatment was also associated with a worse response (p = 0.01).
Conclusion
ST6GAL1 is associated with resistance to treatment in human rectal cancer and knockdown in an organoid model abrogated resistance to apoptosis caused by chemoradiation.
{"title":"ST6GAL1 is associated with poor response to chemoradiation in rectal cancer","authors":"Mary Smithson , Sameer Al Diffalha , Regina K. Irwin , Gregory Williams , M. Chandler McLeod , Vivek Somasundaram , Susan L. Bellis , Karin M. Hardiman","doi":"10.1016/j.neo.2024.100984","DOIUrl":"https://doi.org/10.1016/j.neo.2024.100984","url":null,"abstract":"<div><h3>Introduction</h3><p>Colorectal cancer is the third most common cause of cancer death. Rectal cancer makes up a third of all colorectal cases. Treatment for locally advanced rectal cancer includes chemoradiation followed by surgery. We have previously identified ST6GAL1 as a cause of resistance to chemoradiation <em>in vitro</em> and hypothesized that it would be correlated with poor response in human derived models and human tissues.</p></div><div><h3>Methods</h3><p>Five organoid models were created from primary human rectal cancers and ST6GAL1 was knocked down via lentivirus transduction in one model. ST6GAL1 and Cleaved Caspase-3 (CC3) were assessed after chemoradiation via immunostaining. A tissue microarray (TMA) was created from twenty-six patients who underwent chemoradiation and had pre- and post-treatment specimens of rectal adenocarcinoma available at our institution. Immunohistochemistry was performed for ST6GAL1 and percent positive cancer cell staining was assessed and correlation with pathological grade of response was measured.</p></div><div><h3>Results</h3><p>Organoid models were treated with chemoradiation and both ST6GAL1 mRNA and protein significantly increased after treatment. The organoid model targeted with ST6GAL1 knockdown was found to have increased CC3 after treatment. In the tissue microarray, 42 percent of patient samples had an increase in percent tumor cell staining for ST6GAL1 after treatment. Post-treatment percent staining was associated with a worse grade of treatment response (p = 0.01) and increased staining post-treatment compared to pre-treatment was also associated with a worse response (p = 0.01).</p></div><div><h3>Conclusion</h3><p>ST6GAL1 is associated with resistance to treatment in human rectal cancer and knockdown in an organoid model abrogated resistance to apoptosis caused by chemoradiation.</p></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1476558624000216/pdfft?md5=e64d225a0ea5be563852b2212ff505da&pid=1-s2.0-S1476558624000216-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140095641","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}
Pub Date : 2024-02-28DOI: 10.1016/j.neo.2024.100981
Bingting Yu , Danny de Vos , Xiaopei Guo , SanFei Peng , Wenjie Xie , Maikel P. Peppelenbosch , Yang Fu , Gwenny M. Fuhler
Purpose
Helicobacter pylori (H. pylori) is a significant risk factor for development of gastric cancer (GC), one of the deadliest malignancies in the world. However, the mechanism by which H. pylori induces gastric oncogenesis remains unclear. Here, we investigated the function of IL-6 in gastric oncogenesis and macrophage-epithelial cell interactions.
Methods
We analyzed publicly available datasets to investigate the expression of IL-6 and infiltration of M2 macrophages in GC tissues, and determine the inter-cellular communication in the context of IL-6. Human gastric epithelial and macrophage cell lines (GES-1 and THP-1-derived macrophages, respectively) were used in mono- and co-culture experiments to investigate autocrine-and paracrine induction of IL-6 expression in response to H. pylori or IL-6 stimulation.
Results
We found that IL-6 is highly expressed in GC and modulates survival. M2 macrophage infiltration is predominant in GC and drives an IL-6 mediated communication with gastric epithelium cells. In vitro, IL-6 triggers its own expression in GES-1 and THP-1-derived macrophages cells. In addition, these cell lines are able to upregulate each other's IL-6 levels in an autocrine fashion, which is enhanced by H. pylori stimulation.
Conclusion
This study indicates that IL-6 in the tumor microenvironment is essential for intercellular communication. We show that H. pylori enhances an IL-6-driven autocrine and paracrine positive feedback loop between macrophages and gastric epithelial cells, which may contribute to gastric carcinogenesis.
{"title":"IL-6 facilitates cross-talk between epithelial cells and tumor- associated macrophages in Helicobacter pylori-linked gastric carcinogenesis","authors":"Bingting Yu , Danny de Vos , Xiaopei Guo , SanFei Peng , Wenjie Xie , Maikel P. Peppelenbosch , Yang Fu , Gwenny M. Fuhler","doi":"10.1016/j.neo.2024.100981","DOIUrl":"https://doi.org/10.1016/j.neo.2024.100981","url":null,"abstract":"<div><h3>Purpose</h3><p><em>Helicobacter pylori (H. pylori)</em> is a significant risk factor for development of gastric cancer (GC), one of the deadliest malignancies in the world. However, the mechanism by which <em>H. pylori</em> induces gastric oncogenesis remains unclear. Here, we investigated the function of IL-6 in gastric oncogenesis and macrophage-epithelial cell interactions.</p></div><div><h3>Methods</h3><p>We analyzed publicly available datasets to investigate the expression of <em>IL-6</em> and infiltration of M2 macrophages in GC tissues, and determine the inter-cellular communication in the context of IL-6. Human gastric epithelial and macrophage cell lines (GES-1 and THP-1-derived macrophages, respectively) were used in mono- and co-culture experiments to investigate autocrine-and paracrine induction of IL-6 expression in response to <em>H. pylori</em> or IL-6 stimulation.</p></div><div><h3>Results</h3><p>We found that IL-6 is highly expressed in GC and modulates survival. M2 macrophage infiltration is predominant in GC and drives an IL-6 mediated communication with gastric epithelium cells. <em>In vitro</em>, IL-6 triggers its own expression in GES-1 and THP-1-derived macrophages cells. In addition, these cell lines are able to upregulate each other's IL-6 levels in an autocrine fashion, which is enhanced by <em>H. pylori</em> stimulation.</p></div><div><h3>Conclusion</h3><p>This study indicates that IL-6 in the tumor microenvironment is essential for intercellular communication. We show that <em>H. pylori</em> enhances an IL-6-driven autocrine and paracrine positive feedback loop between macrophages and gastric epithelial cells, which may contribute to gastric carcinogenesis.</p></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1476558624000186/pdfft?md5=66f78ac2b09e0475ccaa1d5ae71a143c&pid=1-s2.0-S1476558624000186-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139992903","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}
Glioblastoma is the deadliest form of brain tumor. The presence of the blood–brain barrier (BBB) significantly hinders chemotherapy, necessitating the development of innovative treatment options for this tumor. This report presents the in vitro and in vivo efficacy of an antibody–drug conjugate (ADC) that targets glypican-1 (GPC1) in glioblastoma. The GPC1-ADC was created by conjugating a humanized anti-GPC1 antibody (clone T2) with monomethyl auristatin E (MMAE) via maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl linkers. Immunohistochemical staining analysis of a glioblastoma tissue microarray revealed that GPC1 expression was elevated in more than half of the cases. GPC1-ADC, when bound to GPC1, was efficiently and rapidly internalized in glioblastoma cell lines. It inhibited the growth of GPC1-positive glioma cell lines by inducing cell cycle arrest in the G2/M phase and triggering apoptosis in vitro. We established a heterotopic xenograft model by subcutaneously implanting KALS-1 and administered GPC1-ADC intravenously. GPC1-ADC significantly inhibited tumor growth and increased the number of mitotic cells. We also established an orthotopic xenograft model by intracranially implanting luciferase-transfected KS-1-Luc#19. After injecting Evans blue and resecting brain tissues, dye leakage was observed in the implantation area, confirming BBB disruption. We administered GPC1-ADC intravenously and measured the luciferase activity using an in vivo imaging system. GPC1-ADC significantly inhibited tumor growth and extended survival. In conclusion, GPC1-ADC demonstrated potent intracranial activity against GPC1-positive glioblastoma in an orthotopic xenograft model. These results indicate that GPC1-ADC could represent a groundbreaking new therapy for treating glioblastoma beyond the BBB.
{"title":"Glypican-1-targeted antibody–drug conjugate inhibits the growth of glypican-1-positive glioblastoma","authors":"Shun Uchida , Satoshi Serada , Yuji Suzuki , Eiji Funajima , Kei Kitakami , Kazumasa Dobashi , Satomi Tamatani , Yuichi Sato , Takaaki Beppu , Kuniaki Ogasawara , Testuji Naka","doi":"10.1016/j.neo.2024.100982","DOIUrl":"https://doi.org/10.1016/j.neo.2024.100982","url":null,"abstract":"<div><p>Glioblastoma is the deadliest form of brain tumor. The presence of the blood–brain barrier (BBB) significantly hinders chemotherapy, necessitating the development of innovative treatment options for this tumor. This report presents the <em>in vitro</em> and <em>in vivo</em> efficacy of an antibody–drug conjugate (ADC) that targets glypican-1 (GPC1) in glioblastoma. The GPC1-ADC was created by conjugating a humanized anti-GPC1 antibody (clone T2) with monomethyl auristatin E (MMAE) <em>via</em> maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl linkers. Immunohistochemical staining analysis of a glioblastoma tissue microarray revealed that GPC1 expression was elevated in more than half of the cases. GPC1-ADC, when bound to GPC1, was efficiently and rapidly internalized in glioblastoma cell lines. It inhibited the growth of GPC1-positive glioma cell lines by inducing cell cycle arrest in the G2/M phase and triggering apoptosis <em>in vitro</em>. We established a heterotopic xenograft model by subcutaneously implanting KALS-1 and administered GPC1-ADC intravenously. GPC1-ADC significantly inhibited tumor growth and increased the number of mitotic cells. We also established an orthotopic xenograft model by intracranially implanting luciferase-transfected KS-1-Luc#19. After injecting Evans blue and resecting brain tissues, dye leakage was observed in the implantation area, confirming BBB disruption. We administered GPC1-ADC intravenously and measured the luciferase activity using an <em>in vivo</em> imaging system. GPC1-ADC significantly inhibited tumor growth and extended survival. In conclusion, GPC1-ADC demonstrated potent intracranial activity against GPC1-positive glioblastoma in an orthotopic xenograft model. These results indicate that GPC1-ADC could represent a groundbreaking new therapy for treating glioblastoma beyond the BBB.</p></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1476558624000198/pdfft?md5=30ea273849b18d645bc33f865a23dfba&pid=1-s2.0-S1476558624000198-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139986841","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}
Pub Date : 2024-02-27DOI: 10.1016/j.neo.2024.100983
Jing Hu , Xinyi Chen , Feifei Sun , Lili Liu , Long Liu , Zimeng Yang , Hanwen Zhang , Zeyuan Yu , Ru Zhao , Yueyao Wang , Hui Liu , Xiaorong Yang , Fusheng Sun , Bo Han
While BRAF alterations have been established as a driver in various solid malignancies, the characterization of BRAF alterations in prostate cancer (PCa) has not been thoroughly interrogated. By bioinformatics analysis, we first found that BRAF alterations were associated with advanced PCa and exhibited mutually exclusive pattern with ERG alteration across multiple cohorts. Of the most interest, recurrent non-V600 BRAF mutations were found in 3 of 21 (14.3 %) PCa patients demonstrating IDC-P morphology. Furthermore, experimental overexpression of BRAFK601E and BRAFL597R exhibited emergence of oncogenic phenotypes with intensified MAPK signaling in vitro, which could be targeted by MEK inhibitors. Comparison of the incidence of BRAF alterations in IDC-P between western and Chinese ancestry revealed an increased prevalence in the Chinese population. The BRAF mutation may represent important genetic alteration in a subset of IDC-P, highlighting the role of MAPK signaling pathway in this subtype of PCa. To the best of knowledge, this is the first description of non-V600 BRAF mutation in setting of IDC-P, which may in part explain the aggressive phenotype seen in IDC-P and could also bring more treatment options for PCa patients with IDC-P harboring such mutations.
{"title":"Identification of recurrent BRAF non-V600 mutations in intraductal carcinoma of the prostate in Chinese populations","authors":"Jing Hu , Xinyi Chen , Feifei Sun , Lili Liu , Long Liu , Zimeng Yang , Hanwen Zhang , Zeyuan Yu , Ru Zhao , Yueyao Wang , Hui Liu , Xiaorong Yang , Fusheng Sun , Bo Han","doi":"10.1016/j.neo.2024.100983","DOIUrl":"https://doi.org/10.1016/j.neo.2024.100983","url":null,"abstract":"<div><p>While <em>BRAF</em> alterations have been established as a driver in various solid malignancies, the characterization of <em>BRAF</em> alterations in prostate cancer (PCa) has not been thoroughly interrogated. By bioinformatics analysis, we first found that <em>BRAF</em> alterations were associated with advanced PCa and exhibited mutually exclusive pattern with ERG alteration across multiple cohorts. Of the most interest, recurrent non-V600 <em>BRAF</em> mutations were found in 3 of 21 (14.3 %) PCa patients demonstrating IDC-P morphology. Furthermore, experimental overexpression of <em>BRAF<sup>K601E</sup></em> and <em>BRAF<sup>L597R</sup></em> exhibited emergence of oncogenic phenotypes with intensified MAPK signaling <em>in vitro</em>, which could be targeted by MEK inhibitors<em>.</em> Comparison of the incidence of <em>BRAF</em> alterations in IDC-P between western and Chinese ancestry revealed an increased prevalence in the Chinese population. The <em>BRAF</em> mutation may represent important genetic alteration in a subset of IDC-P, highlighting the role of MAPK signaling pathway in this subtype of PCa. To the best of knowledge, this is the first description of non-V600 <em>BRAF</em> mutation in setting of IDC-P, which may in part explain the aggressive phenotype seen in IDC-P and could also bring more treatment options for PCa patients with IDC-P harboring such mutations.</p></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1476558624000204/pdfft?md5=ffc2fe277ab8b3fe511b61dba80b747a&pid=1-s2.0-S1476558624000204-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139975672","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}
Pub Date : 2024-02-26DOI: 10.1016/j.neo.2024.100976
Lin Fan , Jiahe Liu , Baoyang Ju , Doudou Lou , Yushen Tian
Background
Breast cancer in different molecular subtypes, which is determined by the overexpression rates of human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), progesterone receptor (PR), and Ki67, exhibit distinct symptom characteristics and sensitivity to different treatment. The immunohistochemical method, one of the most common detecting tools for tumour markers, is heavily relied on artificial judgment and in clinical practice, with an inherent limitation in interpreting stability and operating efficiency. Here, a holistic intelligent breast tumour diagnosis system has been developed for tumour-markeromic analysis, combining the automatic interpretation and clinical suggestion.
Methods
The holistic intelligent breast tumour diagnosis system included two main modules. The interpreting modules were constructed based on convolutional neural network, for comprehensively extracting and analyzing the multi-features of immunostaining. Referring to the clinical classification criteria, the interpreting results were encoded in a low-dimensional feature representation in the subtyping module, to efficiently output a holistic detecting result of the critical tumour-markeromic with diagnosis suggestions on molecular subtypes.
Results
The overexpression rates of HER2, ER, PR, and Ki67, as well as an effective determination of molecular subtypes were successfully obtained by this diagnosis system, with an average sensitivity of 97.6 % and an average specificity of 96.1 %, among those, the sensitivity and specificity for interpreting HER2 were up to 99.8 % and 96.9 %.
Conclusion
The holistic intelligent breast tumour diagnosis system shows improved performance in the interpretation of immunohistochemical images over pathologist-level, which can be expected to overcome the limitations of conventional manual interpretation in efficiency, precision, and repeatability.
{"title":"A deep learning based holistic diagnosis system for immunohistochemistry interpretation and molecular subtyping","authors":"Lin Fan , Jiahe Liu , Baoyang Ju , Doudou Lou , Yushen Tian","doi":"10.1016/j.neo.2024.100976","DOIUrl":"https://doi.org/10.1016/j.neo.2024.100976","url":null,"abstract":"<div><h3>Background</h3><p>Breast cancer in different molecular subtypes, which is determined by the overexpression rates of human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), progesterone receptor (PR), and Ki67, exhibit distinct symptom characteristics and sensitivity to different treatment. The immunohistochemical method, one of the most common detecting tools for tumour markers, is heavily relied on artificial judgment and in clinical practice, with an inherent limitation in interpreting stability and operating efficiency. Here, a holistic intelligent breast tumour diagnosis system has been developed for tumour-markeromic analysis, combining the automatic interpretation and clinical suggestion.</p></div><div><h3>Methods</h3><p>The holistic intelligent breast tumour diagnosis system included two main modules. The interpreting modules were constructed based on convolutional neural network, for comprehensively extracting and analyzing the multi-features of immunostaining. Referring to the clinical classification criteria, the interpreting results were encoded in a low-dimensional feature representation in the subtyping module, to efficiently output a holistic detecting result of the critical tumour-markeromic with diagnosis suggestions on molecular subtypes.</p></div><div><h3>Results</h3><p>The overexpression rates of HER2, ER, PR, and Ki67, as well as an effective determination of molecular subtypes were successfully obtained by this diagnosis system, with an average sensitivity of 97.6 % and an average specificity of 96.1 %, among those, the sensitivity and specificity for interpreting HER2 were up to 99.8 % and 96.9 %.</p></div><div><h3>Conclusion</h3><p>The holistic intelligent breast tumour diagnosis system shows improved performance in the interpretation of immunohistochemical images over pathologist-level, which can be expected to overcome the limitations of conventional manual interpretation in efficiency, precision, and repeatability.</p></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1476558624000137/pdfft?md5=a0bfe62e5827eebf3b9ba7233d057374&pid=1-s2.0-S1476558624000137-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139975671","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}