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1دورية أكاديمية
المؤلفون: Pritha Mukherjee, Xin Zhou, Susana Galli, Bruce Davidson, Lihua Zhang, Jaeil Ahn, Reem Aljuhani, Julius Benicky, Laurie Ailles, Vitor H. Pomin, Mark Olsen, Radoslav Goldman
المصدر: International Journal of Molecular Sciences, Vol 25, Iss 9, p 4998 (2024)
مصطلحات موضوعية: HNSCC, aspartate β-hydroxylase (ASPH), heparan 6-O-endosulfatase 2 (SULF2), MO-I-1151, HfFucCS, primary head and neck CAF, Biology (General), QH301-705.5, Chemistry, QD1-999
الوصف: Aspartate β-hydroxylase (ASPH) is a protein associated with malignancy in a wide range of tumors. We hypothesize that inhibition of ASPH activity could have anti-tumor properties in patients with head and neck cancer. In this study, we screened tumor tissues of 155 head and neck squamous cell carcinoma (HNSCC) patients for the expression of ASPH using immunohistochemistry. We used an ASPH inhibitor, MO-I-1151, known to inhibit the catalytic activity of ASPH in the endoplasmic reticulum, to show its inhibitory effect on the migration of SCC35 head and neck cancer cells in cell monolayers and in matrix-embedded spheroid co-cultures with primary cancer-associated fibroblast (CAF) CAF 61137 of head and neck origin. We also studied a combined effect of MO-I-1151 and HfFucCS, an inhibitor of invasion-blocking heparan 6-O-endosulfatase activity. We found ASPH was upregulated in HNSCC tumors compared to the adjacent normal tissues. ASPH was uniformly high in expression, irrespective of tumor stage. High expression of ASPH in tumors led us to consider it as a therapeutic target in cell line models. ASPH inhibitor MO-I-1151 had significant effects on reducing migration and invasion of head and neck cancer cells, both in monolayers and matrix-embedded spheroids. The combination of the two enzyme inhibitors showed an additive effect on restricting invasion in the HNSCC cell monolayers and in the CAF-containing co-culture spheroids. We identify ASPH as an abundant protein in HNSCC tumors. Targeting ASPH with inhibitor MO-I-1151 effectively reduces CAF-mediated cellular invasion in cancer cell models. We propose that the additive effect of MO-I-1151 with HfFucCS, an inhibitor of heparan 6-O-endosulfatases, on HNSCC cells could improve interventions and needs to be further explored.
وصف الملف: electronic resource
العلاقة: https://www.mdpi.com/1422-0067/25/9/4998Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test
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2دورية أكاديمية
المؤلفون: Xuewei Bai, Yanmei Zhou, Yuki Yokota, Yoshihiro Matsumoto, Bo Zhai, Nader Maarouf, Hikaru Hayashi, Rolf Carlson, Songhua Zhang, Aryanna Sousa, Bei Sun, Hossein Ghanbari, Xiaoqun Dong, Jack R. Wands
المصدر: Journal of Experimental & Clinical Cancer Research, Vol 41, Iss 1, Pp 1-18 (2022)
مصطلحات موضوعية: Aspartate β-hydroxylase (ASPH), Immune checkpoint inhibitor, Lambda phage vaccine, Triple negative breast cancer, Hepatocellular carcinoma, Metastasis, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
الوصف: Abstract Background Interactions between tumor and microenvironment determine individual response to immunotherapy. Triple negative breast cancer (TNBC) and hepatocellular carcinoma (HCC) have exhibited suboptimal responses to immune checkpoint inhibitors (ICIs). Aspartate β-hydroxylase (ASPH), an oncofetal protein and tumor associated antigen (TAA), is a potential target for immunotherapy. Methods Subcutaneous HCC and orthotopic TNBC murine models were established in immunocompetent BALB/c mice with injection of BNL-T3 and 4 T1 cells, respectively. Immunohistochemistry, immunofluorescence, H&E, flow cytometry, ELISA and in vitro cytotoxicity assays were performed. Results The ASPH-MYC signaling cascade upregulates PD-L1 expression on breast and liver tumor cells. A bio-nanoparticle based λ phage vaccine targeting ASPH was administrated to mice harboring syngeneic HCC or TNBC tumors, either alone or in combination with PD-1 blockade. In control, autocrine chemokine ligand 13 (CXCL13)-C-X-C chemokine receptor type 5 (CXCR5) axis promoted tumor development and progression in HCC and TNBC. Interactions between PD-L1+ cancer cells and PD-1+ T cells resulted in T cell exhaustion and apoptosis, causing immune evasion of cancer cells. In contrast, combination therapy (Vaccine+PD-1 inhibitor) significantly suppressed primary hepatic or mammary tumor growth (with distant pulmonary metastases in TNBC). Adaptive immune responses were attributed to expansion of activated CD4+ T helper type 1 (Th1)/CD8+ cytotoxic T cells (CTLs) that displayed enhanced effector functions, and maturation of plasma cells that secreted high titers of ASPH-specific antibody. Combination therapy significantly reduced tumor infiltration of immunosuppressive CD4+/CD25+/FOXP3+ Tregs. When the PD-1/PD-L1 signal was inhibited, CXCL13 produced by ASPH+ cancer cells recruited CXCR5+/CD8+ T lymphocytes to tertiary lymphoid structures (TLSs), comprising effector and memory CTLs, T follicular helper cells, B cell germinal center, and follicular dendritic cells. TLSs facilitate activation and maturation of DCs and actively recruit immune subsets to tumor microenvironment. These CTLs secreted CXCL13 to recruit more CXCR5+ immune cells and to lyse CXCR5+ cancer cells. Upon combination treatment, formation of TLSs predicts sensitivity to ICI blockade. Combination therapy substantially prolonged overall survival of mice with HCC or TNBC. Conclusions Synergistic antitumor efficacy attributable to a λ phage vaccine specifically targeting ASPH, an ideal TAA, combined with ICIs, inhibits tumor growth and progression of TNBC and HCC.
وصف الملف: electronic resource
العلاقة: https://doaj.org/toc/1756-9966Test
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3دورية أكاديمية
المؤلفون: Qiushi Lin, Xuesong Chen, Fanzheng Meng, Kosuke Ogawa, Min Li, Ruipeng Song, Shugeng Zhang, Ziran Zhang, Xianglu Kong, Qinggang Xu, Fuliang He, Xuewei Bai, Bei Sun, Mien-Chie Hung, Lianxin Liu, Jack Wands, Xiaoqun Dong
المصدر: Molecular Cancer, Vol 18, Iss 1, Pp 1-17 (2019)
مصطلحات موضوعية: Aspartate β-hydroxylase (ASPH), Exosome, Notch, Metastasis, Breast cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
الوصف: Abstract Background Aspartate β-hydroxylase (ASPH) is silent in normal adult tissues only to re-emerge during oncogenesis where its function is required for generation and maintenance of malignant phenotypes. Exosomes enable prooncogenic secretome delivering and trafficking for long-distance cell-to-cell communication. This study aims to explore molecular mechanisms underlying how ASPH network regulates designated exosomes to program development and progression of breast cancer. Methods Stable cell lines overexpressing or knocking-out of ASPH were established using lentivirus transfection or CRISPR-CAS9 systems. Western blot, MTT, immunofluorescence, luciferase reporter, co-immunoprecipitation, 2D/3-D invasion, tube formation, mammosphere formation, immunohistochemistry and newly developed in vitro metastasis were applied. Results Through physical interactions with Notch receptors, ligands (JAGs) and regulators (ADAM10/17), ASPH activates Notch cascade to provide raw materials (especially MMPs/ADAMs) for synthesis/release of pro-metastatic exosomes. Exosomes orchestrate EMT, 2-D/3-D invasion, stemness, angiogenesis, and premetastatic niche formation. Small molecule inhibitors (SMIs) of ASPH’s β-hydroxylase specifically/efficiently abrogated in vitro metastasis, which mimics basement membrane invasion at primary site, intravasation/extravasation (transendothelial migration), and colonization/outgrowth at distant sites. Multiple organ-metastases in orthotopic and tail vein injection murine models were substantially blocked by a specific SMI. ASPH is silenced in normal adult breast, upregulated from in situ malignancies to highly expressed in invasive/advanced ductal carcinoma. Moderate-high expression of ASPH confers more aggressive molecular subtypes (TNBC or Her2 amplified), early recurrence/progression and devastating outcome (reduced overall/disease-free survival) of breast cancer. Expression profiling of Notch signaling components positively correlates with ASPH expression in breast cancer patients, confirming that ASPH-Notch axis acts functionally in breast tumorigenesis. Conclusions ASPH-Notch axis guides particularly selective exosomes to potentiate multifaceted metastasis. ASPH’s pro-oncogenic/pro-metastatic properties are essential for breast cancer development/progression, revealing a potential target for therapy.
وصف الملف: electronic resource
العلاقة: http://link.springer.com/article/10.1186/s12943-019-1077-0Test; https://doaj.org/toc/1476-4598Test
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المؤلفون: Lianxin Liu, Qiushi Lin, Bei Sun, Xianglu Kong, Fanzheng Meng, Min Li, Fuliang He, Jack R. Wands, Ziran Zhang, Qinggang Xu, Xuesong Chen, Xuewei Bai, Kosuke Ogawa, Mien Chie Hung, Ruipeng Song, Xiaoqun Dong, Shugeng Zhang
المصدر: Molecular Cancer, Vol 18, Iss 1, Pp 1-17 (2019)
Molecular Cancerمصطلحات موضوعية: 0301 basic medicine, Cancer Research, Proteome, Angiogenesis, Muscle Proteins, Cell Communication, medicine.disease_cause, Exosomes, Ligands, Metastasis, Mixed Function Oxygenases, Mice, 0302 clinical medicine, Breast cancer, Genes, Reporter, Neoplasm Metastasis, Tube formation, biology, Receptors, Notch, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunohistochemistry, Extracellular Matrix, Cell Transformation, Neoplastic, Phenotype, Oncology, 030220 oncology & carcinogenesis, Molecular Medicine, Heterografts, Female, Signal Transduction, Notch, Aspartate β-hydroxylase (ASPH), Notch signaling pathway, Breast Neoplasms, Exosome, Models, Biological, lcsh:RC254-282, 03 medical and health sciences, Cell Line, Tumor, medicine, Animals, Humans, Research, Calcium-Binding Proteins, Intravasation, Membrane Proteins, medicine.disease, Matrix Metalloproteinases, ASPH, Disease Models, Animal, 030104 developmental biology, Cancer research, biology.protein, Carcinogenesis, Biomarkers
الوصف: Background Aspartate β-hydroxylase (ASPH) is silent in normal adult tissues only to re-emerge during oncogenesis where its function is required for generation and maintenance of malignant phenotypes. Exosomes enable prooncogenic secretome delivering and trafficking for long-distance cell-to-cell communication. This study aims to explore molecular mechanisms underlying how ASPH network regulates designated exosomes to program development and progression of breast cancer. Methods Stable cell lines overexpressing or knocking-out of ASPH were established using lentivirus transfection or CRISPR-CAS9 systems. Western blot, MTT, immunofluorescence, luciferase reporter, co-immunoprecipitation, 2D/3-D invasion, tube formation, mammosphere formation, immunohistochemistry and newly developed in vitro metastasis were applied. Results Through physical interactions with Notch receptors, ligands (JAGs) and regulators (ADAM10/17), ASPH activates Notch cascade to provide raw materials (especially MMPs/ADAMs) for synthesis/release of pro-metastatic exosomes. Exosomes orchestrate EMT, 2-D/3-D invasion, stemness, angiogenesis, and premetastatic niche formation. Small molecule inhibitors (SMIs) of ASPH’s β-hydroxylase specifically/efficiently abrogated in vitro metastasis, which mimics basement membrane invasion at primary site, intravasation/extravasation (transendothelial migration), and colonization/outgrowth at distant sites. Multiple organ-metastases in orthotopic and tail vein injection murine models were substantially blocked by a specific SMI. ASPH is silenced in normal adult breast, upregulated from in situ malignancies to highly expressed in invasive/advanced ductal carcinoma. Moderate-high expression of ASPH confers more aggressive molecular subtypes (TNBC or Her2 amplified), early recurrence/progression and devastating outcome (reduced overall/disease-free survival) of breast cancer. Expression profiling of Notch signaling components positively correlates with ASPH expression in breast cancer patients, confirming that ASPH-Notch axis acts functionally in breast tumorigenesis. Conclusions ASPH-Notch axis guides particularly selective exosomes to potentiate multifaceted metastasis. ASPH’s pro-oncogenic/pro-metastatic properties are essential for breast cancer development/progression, revealing a potential target for therapy.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::013ddc4c7d77d79defa1f1438bca2a90Test
http://link.springer.com/article/10.1186/s12943-019-1077-0Test
النص الكامل