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Shigeki Sekine - One of the best experts on this subject based on the ideXlab platform.
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expression of b7 h3 CD276 in surgically resected esophageal squamous cell carcinoma
Journal of Clinical Oncology, 2018Co-Authors: Yuta Maruki, Atsuo Takashima, Takahiro Miyamoto, Hidekazu Hirano, Hirokazu Shoji, Yoshitaka Honma, Satoru Iwasa, Natsuko Okita, Ken Kato, Shigeki SekineAbstract:70Background: B7-H3 (also known as CD276) belongs to a family of immune modulators that includes PD-1 and PD-L1 (also known as B7-H1 or CD274), which has been reported to be expressed in many carcinomas and associated with poor prognosis. In this study, we explored the relationship between B7-H3 expression and clinical background and prognosis of esophageal squamous cell carcinoma (ESCC) patients treated with surgery alone. Methods: The subjects of this study was the ESCC patients who received curative surgery between January 2009 and December 2014 without prior treatment, excluding T4 and M1 disease. We evaluated tumor B7-H3 expression by immunohistochemistry, which was scored to 0 (absent) if 10%). The B7-H3 expression of score 2 and 3 was regarded as positive. We compared the clinical characteristics and prognosis between B7-H3 positive and negative patients using log rank...
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Expression of B7-H3 (CD276) in surgically resected esophageal squamous cell carcinoma.
Journal of Clinical Oncology, 2018Co-Authors: Yuta Maruki, Atsuo Takashima, Takahiro Miyamoto, Hidekazu Hirano, Hirokazu Shoji, Yoshitaka Honma, Satoru Iwasa, Natsuko Okita, Ken Kato, Shigeki SekineAbstract:70 Background: B7-H3 (also known as CD276) belongs to a family of immune modulators that includes PD-1 and PD-L1 (also known as B7-H1 or CD274), which has been reported to be expressed in many carcinomas and associated with poor prognosis. In this study, we explored the relationship between B7-H3 expression and clinical background and prognosis of esophageal squamous cell carcinoma (ESCC) patients treated with surgery alone. Methods: The subjects of this study was the ESCC patients who received curative surgery between January 2009 and December 2014 without prior treatment, excluding T4 and M1 disease. We evaluated tumor B7-H3 expression by immunohistochemistry, which was scored to 0 (absent) if < 10% of cancer cells were stained, and 1 (weak), 2 (moderate), or 3 (strong) according to the intensity in stained cancer cells (> 10%). The B7-H3 expression of score 2 and 3 was regarded as positive. We compared the clinical characteristics and prognosis between B7-H3 positive and negative patients using log rank test and Cox proportional hazards regression analysis for adjusting the backgrounds. Results: 33 (45%) of 74 patients were positive for expression of B7-H3. Between H7-H3 (+) and (-) groups, there were difference in pathological T stage (pT1/pT2/pT3: 9/0/24 vs. 23/4/14, p < 0.01) and lymph vessel invasion (+/-: 7/26 vs. 17/24, p=0.08). There was no association between sex, age, N factor, and vascular invasion. B7-H3 (+) patients showed trend of poor recurrence free survival (RFS) and overall survival, not significant, (HR=1.41[95%CI:0.63-3.14] p=0.41 for RFS, HR=1.34[ 95%CI:0.52-3.48] p=0.55 for OS). However B7-H3 status was not a prognostic factor in multivariate analysis (HR=0.78[95% CI: 0.33-1.85] for RFS, HR=0.73 [ 95%CI:0.26-2.02] for OS). Conclusions: The expression ratio of B7-H3 was observed in 45% of the esophageal cancer, which was related with T stage and lymphatic vessel invasion but not with clinical outcomes such as RFS and OS.
Deborah A. Swing - One of the best experts on this subject based on the ideXlab platform.
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Eradication of Tumors through Simultaneous Ablation of CD276/B7-H3-Positive Tumor Cells and Tumor Vasculature
Cancer cell, 2017Co-Authors: Steven Seaman, Zhongyu Zhu, Saurabh Saha, Xiaoyan M. Zhang, Mi Young Yang, Mary Beth Hilton, Karen Morris, Christopher S. Szot, Holly Morris, Deborah A. SwingAbstract:Targeting the tumor vasculature with antibody-drug conjugates (ADCs) is a promising anti-cancer strategy that in order to be realized must overcome several obstacles, including identification of suitable targets and optimal warheads. Here, we demonstrate that the cell-surface protein CD276/B7-H3 is broadly overexpressed by multiple tumor types on both cancer cells and tumor-infiltrating blood vessels, making it a potentially ideal dual-compartment therapeutic target. In preclinical studies CD276 ADCs armed with a conventional MMAE warhead destroyed CD276-positive cancer cells, but were ineffective against tumor vasculature. In contrast, pyrrolobenzodiazepine-conjugated CD276 ADCs killed both cancer cells and tumor vasculature, eradicating large established tumors and metastases, and improving long-term overall survival. CD276-targeted dual-compartment ablation could aid in the development of highly selective broad-acting anti-cancer therapies.
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eradication of tumors through simultaneous ablation of CD276 b7 h3 positive tumor cells and tumor vasculature
Cancer Cell, 2017Co-Authors: Steven Seaman, Zhongyu Zhu, Saurabh Saha, Xiaoyan M. Zhang, Mi Young Yang, Mary Beth Hilton, Karen Morris, Christopher S. Szot, Holly Morris, Deborah A. SwingAbstract:Targeting the tumor vasculature with antibody-drug conjugates (ADCs) is a promising anti-cancer strategy that in order to be realized must overcome several obstacles, including identification of suitable targets and optimal warheads. Here, we demonstrate that the cell-surface protein CD276/B7-H3 is broadly overexpressed by multiple tumor types on both cancer cells and tumor-infiltrating blood vessels, making it a potentially ideal dual-compartment therapeutic target. In preclinical studies CD276 ADCs armed with a conventional MMAE warhead destroyed CD276-positive cancer cells, but were ineffective against tumor vasculature. In contrast, pyrrolobenzodiazepine-conjugated CD276 ADCs killed both cancer cells and tumor vasculature, eradicating large established tumors and metastases, and improving long-term overall survival. CD276-targeted dual-compartment ablation could aid in the development of highly selective broad-acting anti-cancer therapies.
Yuta Maruki - One of the best experts on this subject based on the ideXlab platform.
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expression of b7 h3 CD276 in surgically resected esophageal squamous cell carcinoma
Journal of Clinical Oncology, 2018Co-Authors: Yuta Maruki, Atsuo Takashima, Takahiro Miyamoto, Hidekazu Hirano, Hirokazu Shoji, Yoshitaka Honma, Satoru Iwasa, Natsuko Okita, Ken Kato, Shigeki SekineAbstract:70Background: B7-H3 (also known as CD276) belongs to a family of immune modulators that includes PD-1 and PD-L1 (also known as B7-H1 or CD274), which has been reported to be expressed in many carcinomas and associated with poor prognosis. In this study, we explored the relationship between B7-H3 expression and clinical background and prognosis of esophageal squamous cell carcinoma (ESCC) patients treated with surgery alone. Methods: The subjects of this study was the ESCC patients who received curative surgery between January 2009 and December 2014 without prior treatment, excluding T4 and M1 disease. We evaluated tumor B7-H3 expression by immunohistochemistry, which was scored to 0 (absent) if 10%). The B7-H3 expression of score 2 and 3 was regarded as positive. We compared the clinical characteristics and prognosis between B7-H3 positive and negative patients using log rank...
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Expression of B7-H3 (CD276) in surgically resected esophageal squamous cell carcinoma.
Journal of Clinical Oncology, 2018Co-Authors: Yuta Maruki, Atsuo Takashima, Takahiro Miyamoto, Hidekazu Hirano, Hirokazu Shoji, Yoshitaka Honma, Satoru Iwasa, Natsuko Okita, Ken Kato, Shigeki SekineAbstract:70 Background: B7-H3 (also known as CD276) belongs to a family of immune modulators that includes PD-1 and PD-L1 (also known as B7-H1 or CD274), which has been reported to be expressed in many carcinomas and associated with poor prognosis. In this study, we explored the relationship between B7-H3 expression and clinical background and prognosis of esophageal squamous cell carcinoma (ESCC) patients treated with surgery alone. Methods: The subjects of this study was the ESCC patients who received curative surgery between January 2009 and December 2014 without prior treatment, excluding T4 and M1 disease. We evaluated tumor B7-H3 expression by immunohistochemistry, which was scored to 0 (absent) if < 10% of cancer cells were stained, and 1 (weak), 2 (moderate), or 3 (strong) according to the intensity in stained cancer cells (> 10%). The B7-H3 expression of score 2 and 3 was regarded as positive. We compared the clinical characteristics and prognosis between B7-H3 positive and negative patients using log rank test and Cox proportional hazards regression analysis for adjusting the backgrounds. Results: 33 (45%) of 74 patients were positive for expression of B7-H3. Between H7-H3 (+) and (-) groups, there were difference in pathological T stage (pT1/pT2/pT3: 9/0/24 vs. 23/4/14, p < 0.01) and lymph vessel invasion (+/-: 7/26 vs. 17/24, p=0.08). There was no association between sex, age, N factor, and vascular invasion. B7-H3 (+) patients showed trend of poor recurrence free survival (RFS) and overall survival, not significant, (HR=1.41[95%CI:0.63-3.14] p=0.41 for RFS, HR=1.34[ 95%CI:0.52-3.48] p=0.55 for OS). However B7-H3 status was not a prognostic factor in multivariate analysis (HR=0.78[95% CI: 0.33-1.85] for RFS, HR=0.73 [ 95%CI:0.26-2.02] for OS). Conclusions: The expression ratio of B7-H3 was observed in 45% of the esophageal cancer, which was related with T stage and lymphatic vessel invasion but not with clinical outcomes such as RFS and OS.
Steven Seaman - One of the best experts on this subject based on the ideXlab platform.
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High-resolution structural genomics reveals new therapeutic vulnerabilities in glioblastoma
2018Co-Authors: Michael J. Johnston, Steven Seaman, Ana Nikolic, Nicoletta Ninkovic, Paul Guilhamon, Florence M.g. Cavalli, Franz J. Zemp, John J.y. Lee, Aly Abdelkareem, Katrina EllestadAbstract:SUMMARYWe investigated the role of 3D genome architecture in instructing functional properties of glioblastoma stem cells (GSCs) by generating the highest-resolution 3D genome maps to-date for this cancer. Integration of DNA contact maps with chromatin and transcriptional profiles identified specific mechanisms of gene regulation, including individual physical interactions between regulatory regions and their target genes. Residing in structurally conserved regions in GSCs was CD276, a gene known to play a role in immuno-modulation. We show that, unexpectedly, CD276 is part of a stemness network in GSCs and can be targeted with an antibody-drug conjugate to curb self-renewal, a key stemness property. Our results demonstrate that integrated structural genomics datasets can be employed to rationally identify therapeutic vulnerabilities in self-renewing cells.SIGNIFICANCEIn adult GBM, GSCs act as therapy-resistant reservoirs to nucleate tumor recurrence. New therapeutic approaches that target these cell populations hold the potential of significantly improving patient care and overall prognosis for this always-lethal cancer. Our work describes new links between 3D genome architecture and stemness properties in GSCs. In particular, through integration of multiple genomics and structural genomics datasets, we found an unexpected connection between immune-related genes and self-renewal programs in GBM. Among these, we show that targeting CD276 with knockdown strategies or specific antibody-drug conjugates achieve suppression of self-renewal. Strategies to target CD276+ cells are currently in clinical trials for solid tumors. Our results indicate that CD276-targeting agents could be deployed in GBM to specifically target GSC populations.HIGHLIGHTSWe generated high (sub-5 kb) resolution Hi-C maps for stem-like cells from GBM patients.Integration of Hi-C and genomics datasets dissects mechanisms of gene regulation.3D genomes poise immune-related genes, including CD276, for expression.Targeting CD276 curbs self-renewal properties of GBM cells.
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Eradication of Tumors through Simultaneous Ablation of CD276/B7-H3-Positive Tumor Cells and Tumor Vasculature
Cancer cell, 2017Co-Authors: Steven Seaman, Zhongyu Zhu, Saurabh Saha, Xiaoyan M. Zhang, Mi Young Yang, Mary Beth Hilton, Karen Morris, Christopher S. Szot, Holly Morris, Deborah A. SwingAbstract:Targeting the tumor vasculature with antibody-drug conjugates (ADCs) is a promising anti-cancer strategy that in order to be realized must overcome several obstacles, including identification of suitable targets and optimal warheads. Here, we demonstrate that the cell-surface protein CD276/B7-H3 is broadly overexpressed by multiple tumor types on both cancer cells and tumor-infiltrating blood vessels, making it a potentially ideal dual-compartment therapeutic target. In preclinical studies CD276 ADCs armed with a conventional MMAE warhead destroyed CD276-positive cancer cells, but were ineffective against tumor vasculature. In contrast, pyrrolobenzodiazepine-conjugated CD276 ADCs killed both cancer cells and tumor vasculature, eradicating large established tumors and metastases, and improving long-term overall survival. CD276-targeted dual-compartment ablation could aid in the development of highly selective broad-acting anti-cancer therapies.
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eradication of tumors through simultaneous ablation of CD276 b7 h3 positive tumor cells and tumor vasculature
Cancer Cell, 2017Co-Authors: Steven Seaman, Zhongyu Zhu, Saurabh Saha, Xiaoyan M. Zhang, Mi Young Yang, Mary Beth Hilton, Karen Morris, Christopher S. Szot, Holly Morris, Deborah A. SwingAbstract:Targeting the tumor vasculature with antibody-drug conjugates (ADCs) is a promising anti-cancer strategy that in order to be realized must overcome several obstacles, including identification of suitable targets and optimal warheads. Here, we demonstrate that the cell-surface protein CD276/B7-H3 is broadly overexpressed by multiple tumor types on both cancer cells and tumor-infiltrating blood vessels, making it a potentially ideal dual-compartment therapeutic target. In preclinical studies CD276 ADCs armed with a conventional MMAE warhead destroyed CD276-positive cancer cells, but were ineffective against tumor vasculature. In contrast, pyrrolobenzodiazepine-conjugated CD276 ADCs killed both cancer cells and tumor vasculature, eradicating large established tumors and metastases, and improving long-term overall survival. CD276-targeted dual-compartment ablation could aid in the development of highly selective broad-acting anti-cancer therapies.
Yanling Chen - One of the best experts on this subject based on the ideXlab platform.
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CD276 Promotes Vasculogenic Mimicry Formation in Hepatocellular Carcinoma via the PI3K/AKT/MMPs Pathway.
OncoTargets and therapy, 2020Co-Authors: Rui Cheng, Bi Wang, Xin-ran Cai, Zhi-shan Chen, Liang-yi Zhou, Yanling ChenAbstract:Purpose CD276 protein expression and vasculogenic mimicry (VM) formation are associated with the poor prognosis of hepatocellular carcinoma (HCC) patients. Although both the effects of CD276 and VM formation involve the activation of matrix metalloproteinases, and their relationship has not yet been explored. The following study investigated the effect of CD276 expression on VM formation and the potential mechanisms. Materials and Methods CD276 expression and VM were examined in commercial tissue microarrays by immunohistochemistry and CD31/PAS double staining. Tumor cell proliferation, invasion, migration and, tube formation were detected in vitro after transfecting HCC cell lines with an shRNA lentiviral vector against CD276. The expression of MMP14, MMP2, VE-cadherin, E-cadherin, and vimentin and MMPs activation was detected by Western blot, immunofluorescence and gelatin zymography assay. In addition, an orthotopic xenograft model of HCC cells was established in vivo, after which VM was detected, along with its marker molecules. Results CD276 expression was associated with VM and poor prognosis in HCC patients. RNA interference of CD276 reduced tumor cell proliferation, invasion, migration, and VM formation in vitro and in vivo. Furthermore, CD276 knockdown up-regulated the expression of E-cadherin but inhibited the phosphorylation of AKT, the expression of MMP14, MMP2, VE-cadherin, vimentin and the activation of MMP2 and MMP9 in HCC cell lines. Conclusion CD276 may promote VM formation by activating the PI3K/AKT/MMPs pathway and inducing the EMT process in HCC. CD276 may serve as a promising candidate for the anti-VM treatment of HCC.
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CD276 promotes vasculogenic mimicry formation in hepatocellular carcinoma via the pi3k akt mmps pathway
OncoTargets and Therapy, 2020Co-Authors: Rui Cheng, Bi Wang, Xin-ran Cai, Zhi-shan Chen, Liang-yi Zhou, Yanling ChenAbstract:Purpose CD276 protein expression and vasculogenic mimicry (VM) formation are associated with the poor prognosis of hepatocellular carcinoma (HCC) patients. Although both the effects of CD276 and VM formation involve the activation of matrix metalloproteinases, and their relationship has not yet been explored. The following study investigated the effect of CD276 expression on VM formation and the potential mechanisms. Materials and Methods CD276 expression and VM were examined in commercial tissue microarrays by immunohistochemistry and CD31/PAS double staining. Tumor cell proliferation, invasion, migration and, tube formation were detected in vitro after transfecting HCC cell lines with an shRNA lentiviral vector against CD276. The expression of MMP14, MMP2, VE-cadherin, E-cadherin, and vimentin and MMPs activation was detected by Western blot, immunofluorescence and gelatin zymography assay. In addition, an orthotopic xenograft model of HCC cells was established in vivo, after which VM was detected, along with its marker molecules. Results CD276 expression was associated with VM and poor prognosis in HCC patients. RNA interference of CD276 reduced tumor cell proliferation, invasion, migration, and VM formation in vitro and in vivo. Furthermore, CD276 knockdown up-regulated the expression of E-cadherin but inhibited the phosphorylation of AKT, the expression of MMP14, MMP2, VE-cadherin, vimentin and the activation of MMP2 and MMP9 in HCC cell lines. Conclusion CD276 may promote VM formation by activating the PI3K/AKT/MMPs pathway and inducing the EMT process in HCC. CD276 may serve as a promising candidate for the anti-VM treatment of HCC.