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Gao Y, Zhang X, Ding M, Fu Z, Zhong L. Targeting "don't eat me" signal: breast cancer immunotherapy. Breast Cancer Res Treat 2025; 211:277-292. [PMID: 40100495 DOI: 10.1007/s10549-025-07659-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 02/17/2025] [Indexed: 03/20/2025]
Abstract
PURPOSE Breast cancer ranks as the most prevalent cancer type impacting women globally, both in terms of incidence and mortality rates, making it a major health concern for females. There's an urgent requirement to delve into new cancer treatment methods to improve patient survival rates. METHODS Immunotherapy has gained recognition as a promising area of research in the treatment of breast cancer, with targeted immune checkpoint therapies demonstrating the potential to yield sustained clinical responses and improve overall survival rates. Presently, the predominant immune checkpoints identified on breast cancer cells include CD47, CD24, PD-L1, MHC-I, and STC-1, among others. Nevertheless, the specific roles of these various immune checkpoints in breast carcinogenesis, metastasis, and immune evasion have yet to be comprehensively elucidated. We conducted a comprehensive review of the existing literature pertaining to breast cancer and immune checkpoint inhibitors, providing a summary of findings and an outlook on future research directions. RESULTS This article reviews the advancements in research concerning each immune checkpoint in breast cancer and their contributions to immune evasion, while also synthesizing immunotherapy strategies informed by these mechanisms. Furthermore, it anticipates future research priorities, thereby providing a theoretical foundation to guide immunotherapy as a potential interventional approach for breast cancer treatment. CONCLUSION Knowledge of immune checkpoints will drive the creation of novel cancer therapies, and future breast cancer research will increasingly emphasize personalized treatments tailored to patients' specific tumor characteristics.
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Affiliation(s)
- Yue Gao
- Department of Breast Surgery, Sixth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiaoyan Zhang
- Department of Breast Surgery, Sixth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Mingqiang Ding
- Department of Breast Surgery, Sixth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhenkun Fu
- Department of Immunology, School of Basic Medical Sciences, Harbin Medical University, Harbin, China.
| | - Lei Zhong
- Department of Breast Surgery, Sixth Affiliated Hospital of Harbin Medical University, Harbin, China.
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Li Y, Chen L, Xue S, Song Z, Liu H, Li H, Shen W, Zhang C, Wu H. Alternative spliceosomal protein Eftud2 mediated Kif3a exon skipping promotes SHH-subgroup medulloblastoma progression. Cell Death Differ 2025:10.1038/s41418-025-01512-9. [PMID: 40275081 DOI: 10.1038/s41418-025-01512-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 04/01/2025] [Accepted: 04/04/2025] [Indexed: 04/26/2025] Open
Abstract
Alternative splicing plays a pivotal role in various facets of organogenesis, immune response, and tumorigenesis. Medulloblastoma represents a prevalent childhood brain tumor, with approximately one-third classified as the Sonic Hedgehog (SHH) subgroup. Nevertheless, the contribution of alternative splicing to medulloblastoma oncogenesis remains elusive. This investigation delineated an upregulation of the spliceosomal protein Eftud2 in the SHH-subgroup medulloblastoma mouse model and human medulloblastoma patients. Targeted ablation of Eftud2 in granule precursor cells (GNPs) within the cerebellum prolonged the survival of SHH-subgroup medulloblastoma mice, indicating a putative association between Eftud2 expression and medulloblastoma prognosis. Functional assays unveiled that EFTUD2 depletion in human medulloblastoma cells significantly curtailed cellular proliferation by impeding the activation of the SHH signaling pathway. Through multi-omics sequencing analysis, it was discerned that Eftud2 influences exons 10-11 skipping of Kif3a, a kinesin motor critical for primary cilia formation. Notably, exons 10-11 skipping in Kif3a augmented human medulloblastoma cell proliferation by potentiating the transcriptional activity of Gli2. These findings underscore a robust correlation between Eftud2 and SHH-subgroup medulloblastoma, emphasizing its regulatory role in modulating downstream transcription factors through the alternative splicing of pivotal genes within the SHH signaling pathway, thereby propelling the aggressive proliferation of SHH-subgroup medulloblastoma.
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Affiliation(s)
- Ying Li
- Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, China
- School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Liping Chen
- Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, China
| | - Saisai Xue
- Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, China
| | - Zhihong Song
- Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, China
| | - Heli Liu
- Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, China
- Institute of Neuroscience, Hengyang Medical College, University of South China, Hengyang, Hunan, China
| | - Hao Li
- Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, China
| | - Wei Shen
- Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, China
| | - Chen Zhang
- School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China.
| | - Haitao Wu
- Department of Neurobiology, Beijing Institute of Basic Medical Sciences, Beijing, China.
- Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.
- Chinese Institute for Brain Research, Beijing, China.
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3
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Yu Y, Arrigo A, Chandra A, Zhuang C, Najjar MK, Khan MS, Zhu D, Dono A, Strowd RE, Tandon N, Zhu JJ, Hsu SH, Esquenazi Y, Chan M, Lo HW. Targeting tGLI1, a novel mediator of tumor therapeutic resistance, using Ketoconazole sensitizes glioblastoma to CDK4/6 therapy and chemoradiation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.20.639359. [PMID: 40060625 PMCID: PMC11888219 DOI: 10.1101/2025.02.20.639359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/18/2025]
Abstract
Glioblastoma (GBM) remains the most aggressive primary brain tumor in adults, with no effective treatments. While cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) show clinical promise in some cancers, they have not significantly improved survival in GBM patients. This lack of response is attributed to the treatment-resistant glioma stem cell (GSC) population. We previously identified truncated glioma-associated oncogene homolog 1 (tGLI1) as a novel transcription factor promoting GSCs; however, its role in CDK4/6i resistance has never been investigated in any cancer type. Here, we found positive correlations between tGLI1 and CDK4/6 therapeutic resistance in patient datasets and in vitro studies. Pharmacological inhibition of tGLI1 using FDA-approved ketoconazole (KCZ), a tGLI1-specific inhibitor, sensitized GBM and GSCs to CDK4/6is. KCZ+CDK4/6i combination therapy demonstrated synergistic anti-proliferative effects, significantly inhibiting GBM stemness and cell cycle progression while increasing apoptosis. The combination was more efficacious than monotherapies in two orthotopic GBM mouse models. tGLI1 promoted GBM resistance to radiation therapy and temozolomide, while KCZ potentiated effects of these treatments. Collectively, we report for the first time that tGLI1 is a novel mediator of GBM resistance to CDK4/6is, and KCZ sensitizes GBM to CDK4/6is, thereby supporting future clinical utility of novel KCZ+CDK4/6i combinatorial therapy for GBM patients.
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Affiliation(s)
- Yang Yu
- Department of Cancer Biology, Wake Forest School University of Medicine, Winston-Salem, NC
| | - Austin Arrigo
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Ankush Chandra
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Chuling Zhuang
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Mariana K Najjar
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Munazza S Khan
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Dongqin Zhu
- Department of Cancer Biology, Wake Forest School University of Medicine, Winston-Salem, NC
| | - Antonio Dono
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Roy E Strowd
- Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, NC
| | - Nitin Tandon
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Jay-Jiguang Zhu
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Sigmund H Hsu
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Yoshua Esquenazi
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Michael Chan
- Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC
| | - Hui-Wen Lo
- Department of Cancer Biology, Wake Forest School University of Medicine, Winston-Salem, NC
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
- Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
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Manore S, Zhuang C, Najjar MK, Wong GL, Bindal S, Watabe K, Lin J, Lo HW. Co-Inhibition of tGLI1 and GP130 Using FDA-Approved Ketoconazole and Bazedoxifene Is Synergistic Against the Growth and Metastasis of HER2-Enriched and Triple-Negative Breast Cancers. Cells 2024; 13:2087. [PMID: 39768178 PMCID: PMC11674475 DOI: 10.3390/cells13242087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 12/09/2024] [Accepted: 12/10/2024] [Indexed: 01/11/2025] Open
Abstract
Breast cancer stem cells (CSCs) are resistant to most cancer therapeutics and contribute to tumor recurrence and metastasis. Two breast CSC-promoting transcription factors, truncated glioma-associated oncogene homolog 1 (tGLI1) and signal transducer and activator of transcription 3 (STAT3), have been reported to be frequently co-expressed in HER2-enriched breast cancer and triple-negative breast cancer (TNBC), undergo protein-protein interactions for gene regulation and activation, and functionally cooperate to promote breast CSCs. STAT3 can be activated by activated interleukin-6 receptor/glycoprotein-130 (IL-6R/GP130). Co-targeting of tGLI1 and IL-6R/GP130 has not been investigated in breast cancer or any tumor type. Here, we report that tGLI1 and GP130 are co-overexpressed in the majority of HER2-enriched breast cancers and TNBCs at 53.8% and 44.4%, respectively. tGLI1+IL-6/IL-6R/GP130 signaling is frequently co-enriched and co-activated in HER2-enriched breast cancer and TNBC when compared to luminal subtypes. tGLI1+GP130 co-overexpression strongly promotes CSCs of HER2-enriched breast cancer and TNBC. FDA-approved tGLI1 inhibitor Ketoconazole and GP130 inhibitor Bazedoxifene synergize against breast cancer proliferation and CSC phenotypes in vitro and reduce TNBC tumor growth and metastatic burden in vivo. Our study demonstrates, for the first time, that co-targeting tGLI1 and IL-6R/GP130/STAT3 signaling pathways is synergistic against HER2-enriched breast cancer and TNBC, warranting future clinical investigations.
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Affiliation(s)
- Sara Manore
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (S.M.); (C.Z.); (M.K.N.); (G.L.W.); (S.B.)
- Wake Forest Graduate School of Biomedical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Chuling Zhuang
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (S.M.); (C.Z.); (M.K.N.); (G.L.W.); (S.B.)
- Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Mariana K. Najjar
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (S.M.); (C.Z.); (M.K.N.); (G.L.W.); (S.B.)
- Wake Forest Graduate School of Biomedical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
- Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Grace L. Wong
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (S.M.); (C.Z.); (M.K.N.); (G.L.W.); (S.B.)
- Wake Forest Graduate School of Biomedical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Shivani Bindal
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (S.M.); (C.Z.); (M.K.N.); (G.L.W.); (S.B.)
| | - Kounosuke Watabe
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA;
| | - Jiayuh Lin
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
| | - Hui-Wen Lo
- Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (S.M.); (C.Z.); (M.K.N.); (G.L.W.); (S.B.)
- Wake Forest Graduate School of Biomedical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
- Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA;
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5
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Hazra R, Chattopadhyay S, Mallick A, Gayen S, Roy S. Unravelling CD24-Siglec-10 pathway: Cancer immunotherapy from basic science to clinical studies. Immunology 2024; 173:442-469. [PMID: 39129256 DOI: 10.1111/imm.13847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 07/27/2024] [Indexed: 08/13/2024] Open
Abstract
Cancer immunotherapy has revolutionized the treatment landscape by harnessing the power of the immune system to combat malignancies. Two of the most promising players in this field are cluster of differentiation 24 (CD24) and sialic acid-binding Ig-like lectin 10 (Siglec-10), and both of them play pivotal roles in modulating immune responses. CD24, a cell surface glycoprotein, emerges as a convincing fundamental signal transducer for therapeutic intervention, given its significant implication in the processes related to tumour progression and immunogenic evasion. Additionally, the immunomodulatory functions of Siglec-10, a prominent member within the Siglec family of immune receptors, have recently become a crucial point of interest, particularly in the context of the tumour microenvironment. Hence, the intricate interplay of both CD24 and Siglec-10 assumes a critical role in fostering tumour growth, facilitating metastasis and also orchestrating immune evasion. Recent studies have found multiple evidences supporting the therapeutic potential of targeting CD24 in cancer treatment. Siglec-10, on the other hand, exhibits immunosuppressive properties that contribute to immune tolerance within the tumour microenvironment. Therefore, we delve into the complex mechanisms through which Siglec-10 modulates immune responses and facilitates immune escape in cancer. Siglec-10 also acts as a viable target for cancer immunotherapy and presents novel avenues for the development of therapeutic interventions. Furthermore, we examine the synergy between CD24 and Siglec-10 in shaping the immunosuppressive tumour microenvironment and discuss the implications for combination therapies. Therefore, understanding the roles of CD24 and Siglec-10 in cancer immunotherapy opens exciting possibilities for the development of novel therapeutics.
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Affiliation(s)
- Rudradeep Hazra
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, India
| | - Soumyadeep Chattopadhyay
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, India
| | - Arijit Mallick
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, India
| | - Sakuntala Gayen
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, India
| | - Souvik Roy
- Department of Pharmaceutical Technology, NSHM Knowledge Campus, Kolkata-Group of Institutions, Kolkata, India
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Shen D, Xia Y, Fu Y, Cao Q, Chen W, Zhu Y, Guo K, Sun L. Hedgehog pathway and cancer: A new area (Review). Oncol Rep 2024; 52:116. [PMID: 38994763 PMCID: PMC11267502 DOI: 10.3892/or.2024.8775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 06/21/2024] [Indexed: 07/13/2024] Open
Abstract
In years of research on classical pathways, the composition, information transmission mechanism, crosstalk with other pathways, and physiological and pathological effects of hedgehog (HH) pathway have been gradually clarified. HH also plays a critical role in tumor formation and development. According to the update of interpretation of tumor phenotypes, the latest relevant studies have been sorted out, to explore the specific mechanism of HH pathway in regulating different tumor phenotypes through gene mutation and signal regulation. The drugs and natural ingredients involved in regulating HH pathway were also reviewed; five approved drugs and drugs under research exert efficacy by blocking HH pathway, and at least 22 natural components have potential to treat tumors by HH pathway. Nevertheless, there is a deficiency of existing studies. The present review confirmed the great potential of HH pathway in future cancer treatment with factual basis.
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Affiliation(s)
- Deyi Shen
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310006, P.R. China
| | - Yuwei Xia
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Yuhan Fu
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310006, P.R. China
| | - Qiaochang Cao
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310006, P.R. China
| | - Wenqian Chen
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Ying Zhu
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310006, P.R. China
| | - Kaibo Guo
- Department of Cancer Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Leitao Sun
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang 310006, P.R. China
- Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
- Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
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Sirkisoon SR, Carpenter RL, Rimkus T, Anderson A, Harrison A, Lange AM, Jin G, Watabe K, Lo HW. Correction: Interaction between STAT3 and GLI1/tGLI1 oncogenic transcription factors promotes the aggressiveness of triple-negative breast cancers and HER2-enriched breast cancer. Oncogene 2024; 43:2371. [PMID: 38867080 DOI: 10.1038/s41388-024-03084-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2024]
Affiliation(s)
| | | | - Tadas Rimkus
- Department of Cancer Biology, Winston-Salem, NC, USA
| | | | | | | | - Guangxu Jin
- Department of Radiology, Winston-Salem, NC, USA
| | - Kounosuke Watabe
- Department of Cancer Biology, Winston-Salem, NC, USA
- Wake Forest Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Hui-Wen Lo
- Department of Cancer Biology, Winston-Salem, NC, USA.
- Wake Forest Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
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Yoshida S, Tsuneoka Y, Tsukada T, Nakakura T, Kawamura A, Kai W, Yoshida K. Primary Cilia are Required for Cell-Type Determination and Angiogenesis in Pituitary Development. Endocrinology 2024; 165:bqae085. [PMID: 39001875 DOI: 10.1210/endocr/bqae085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 06/26/2024] [Accepted: 07/11/2024] [Indexed: 07/15/2024]
Abstract
The functional maturation of the pituitary gland requires adequate cell differentiation and vascular network formation. Although spatiotemporal signaling and transcription factors are known to govern pituitary development, the involvement of primary cilia, nonmoving hair-like organelles, remains unclear. In this study, we uncovered the contribution of primary cilia to cell-type determination and vascular network formation during pituitary development. Homozygous knockout mice lacking a ciliary kinase, Dyrk2-/-, exhibit abnormalities in ciliary structure and pituitary hypoplasia, accompanied by varying degrees of failure in differentiation among all types of hormone-producing cells in the anterior lobe. Aberrations in cell differentiation in Dyrk2-/- mice arise from a decrease in the expression of crucial transcription factors, Lhx4, Lhx3, and Prop1, resulting from the inactivity of Hedgehog (Hh) signaling during the early stages of development. Furthermore, the loss of Dyrk2 results in vascular system abnormalities during the middle to late stages of development. Mechanistically, transcriptome analyses revealed the downregulation of vitronectin-integrin αvβ3-VEGFR2 signaling, essential for orchestrating vascular development. Collectively, our findings demonstrate that primary cilia play a pivotal role as critical regulators of cell survival, cell determination, and angiogenesis during pituitary gland development through the activation of Hh signaling. These findings expand our understanding of the potential link between pituitary dysfunction in human disorders and ciliopathies.
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Affiliation(s)
- Saishu Yoshida
- Department of Biochemistry, The Jikei University School of Medicine, Tokyo 105-8461, Japan
- Department of Biomolecular Science, Toho University, Chiba 274-8510, Japan
| | - Yousuke Tsuneoka
- Department of Anatomy, Faculty of Medicine, Toho University, Tokyo 143-8540, Japan
| | - Takehiro Tsukada
- Department of Biomolecular Science, Toho University, Chiba 274-8510, Japan
| | - Takashi Nakakura
- Department of Anatomy, Graduate School of Medicine, Teikyo University, Tokyo 173-8605, Japan
| | - Akira Kawamura
- Department of Biochemistry, The Jikei University School of Medicine, Tokyo 105-8461, Japan
| | - Wataru Kai
- Department of Biochemistry, The Jikei University School of Medicine, Tokyo 105-8461, Japan
| | - Kiyotsugu Yoshida
- Department of Biochemistry, The Jikei University School of Medicine, Tokyo 105-8461, Japan
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9
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Li X, Tian W, Jiang Z, Song Y, Leng X, Yu J. Targeting CD24/Siglec-10 signal pathway for cancer immunotherapy: recent advances and future directions. Cancer Immunol Immunother 2024; 73:31. [PMID: 38279998 PMCID: PMC10821995 DOI: 10.1007/s00262-023-03606-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Accepted: 12/07/2023] [Indexed: 01/29/2024]
Abstract
The small, heavily glycosylated protein CD24 is primarily expressed by many immune cells and is highly expressed mostly in cancer cells. As one of the most crucial biomarkers of cancers, CD24 is frequently highly expressed in solid tumors, while tumor-associated macrophages express Siglec-10 at high levels, Siglec-10 and CD24 can interact on innate immune cells to lessen inflammatory responses to a variety of disorders. Inhibiting inflammation brought on by SHP-1 and/or SHP-2 phosphatases as well as cell phagocytosis by macrophages, the binding of CD24 to Siglec-10 can prevent toll-like receptor-mediated inflammation. Targeted immunotherapy with immune checkpoint inhibitors (ICI) has lately gained popularity as one of the best ways to treat different tumors. CD24 is a prominent innate immune checkpoint that may be a useful target for cancer immunotherapy. In recent years, numerous CD24/Siglec-10-related research studies have made tremendous progress. This study discusses the characteristics and workings of CD24/Siglec-10-targeted immunotherapy and offers a summary of current advances in CD24/Siglec-10-related immunotherapy research for cancer. We then suggested potential directions for CD24-targeted immunotherapy, basing our speculation mostly on the results of recent preclinical and clinical trials.
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Affiliation(s)
- Xingchen Li
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, 130021, Jilin, China
| | - Wenzhi Tian
- ImmuneOnco Biopharmaceuticals (Shanghai) Inc., Shanghai, 201203, China
| | - Zhongxing Jiang
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yongping Song
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Xiangyang Leng
- Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, 130021, Jilin, China.
| | - Jifeng Yu
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
- Henan International Joint Laboratory of Nuclear Protein Gene Regulation, Henan University College of Medicine, Kaifeng, 475004, Henan, China.
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10
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Jan N, Sofi S, Qayoom H, Haq BU, Shabir A, Mir MA. Targeting breast cancer stem cells through retinoids: A new hope for treatment. Crit Rev Oncol Hematol 2023; 192:104156. [PMID: 37827439 DOI: 10.1016/j.critrevonc.2023.104156] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 09/09/2023] [Accepted: 10/06/2023] [Indexed: 10/14/2023] Open
Abstract
Breast cancer is a complex and diverse disease accounting for nearly 30% of all cancers diagnosed in females. But unfortunately, patients develop resistance to the existing chemotherapeutic regimen, resulting in approximately 90% treatment failure. With over half a million deaths annually, it is imperative to explore new therapeutic approaches to combat the disease. Within a breast tumor, a small sub-population of heterogeneous cells, with a unique ability of self-renew and differentiation and responsible for tumor formation, initiation, and recurrence are referred to as breast cancer stem cells (BCSCs). These BCSCs have been identified as one of the main contributors to chemoresistance in breast cancer, making them an attractive target for developing novel therapeutic strategies. These cells exhibit surface biomarkers such as CD44+, CD24-/LOW, ALDH, CD133, and CD49f phenotypes. Higher expression of CD44+ and ALDH activity has been associated with the formation of tumors in various cancers. Moreover, the abnormal regulation of signaling pathways, including Hedgehog, Notch, β-catenin, JAK/STAT, and P13K/AKT/mTOR, leads to the formation of cancer stem cells, resulting in the development of tumors. The growing drug resistance in BC is a significant challenge, highlighting the need for new therapeutic strategies to combat this dreadful disease. Retinoids, a large group of synthetic derivatives of vitamin A, have been studied as chemopreventive agents in clinical trials and have been shown to regulate various crucial biological functions including vision, development, inflammation, and metabolism. On a cellular level, the retinoid activity has been well characterized and translated and is known to induce differentiation and apoptosis, which play important roles in the outcome of the transformation of tissues into malignant. Retinoids have been investigated extensively for their use in the treatment and prevention of cancer due to their high receptor-binding affinity to directly modulate gene expression programs. Therefore, in this study, we aim to summarize the current understanding of BCSCs, their biomarkers, and the associated signaling pathways. Retinoids, such as Adapalene, a third-generation retinoid, have shown promising anti-cancer potential and may serve as therapeutic agents to target BCSCs.
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Affiliation(s)
- Nusrat Jan
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, India
| | - Shazia Sofi
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, India
| | - Hina Qayoom
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, India
| | - Burhan Ul Haq
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, India
| | - Aisha Shabir
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, India
| | - Manzoor Ahmad Mir
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, India.
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11
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Emerging phagocytosis checkpoints in cancer immunotherapy. Signal Transduct Target Ther 2023; 8:104. [PMID: 36882399 PMCID: PMC9990587 DOI: 10.1038/s41392-023-01365-z] [Citation(s) in RCA: 134] [Impact Index Per Article: 67.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 01/31/2023] [Accepted: 02/14/2023] [Indexed: 03/09/2023] Open
Abstract
Cancer immunotherapy, mainly including immune checkpoints-targeted therapy and the adoptive transfer of engineered immune cells, has revolutionized the oncology landscape as it utilizes patients' own immune systems in combating the cancer cells. Cancer cells escape immune surveillance by hijacking the corresponding inhibitory pathways via overexpressing checkpoint genes. Phagocytosis checkpoints, such as CD47, CD24, MHC-I, PD-L1, STC-1 and GD2, have emerged as essential checkpoints for cancer immunotherapy by functioning as "don't eat me" signals or interacting with "eat me" signals to suppress immune responses. Phagocytosis checkpoints link innate immunity and adaptive immunity in cancer immunotherapy. Genetic ablation of these phagocytosis checkpoints, as well as blockade of their signaling pathways, robustly augments phagocytosis and reduces tumor size. Among all phagocytosis checkpoints, CD47 is the most thoroughly studied and has emerged as a rising star among targets for cancer treatment. CD47-targeting antibodies and inhibitors have been investigated in various preclinical and clinical trials. However, anemia and thrombocytopenia appear to be formidable challenges since CD47 is ubiquitously expressed on erythrocytes. Here, we review the reported phagocytosis checkpoints by discussing their mechanisms and functions in cancer immunotherapy, highlight clinical progress in targeting these checkpoints and discuss challenges and potential solutions to smooth the way for combination immunotherapeutic strategies that involve both innate and adaptive immune responses.
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12
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Zarzosa P, Garcia-Gilabert L, Hladun R, Guillén G, Gallo-Oller G, Pons G, Sansa-Girona J, Segura MF, Sánchez de Toledo J, Moreno L, Gallego S, Roma J. Targeting the Hedgehog Pathway in Rhabdomyosarcoma. Cancers (Basel) 2023; 15:727. [PMID: 36765685 PMCID: PMC9913695 DOI: 10.3390/cancers15030727] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 01/18/2023] [Indexed: 01/27/2023] Open
Abstract
Aberrant activation of the Hedgehog (Hh) signalling pathway is known to play an oncogenic role in a wide range of cancers; in the particular case of rhabdomyosarcoma, this pathway has been demonstrated to be an important player for both oncogenesis and cancer progression. In this review, after a brief description of the pathway and the characteristics of its molecular components, we describe, in detail, the main activation mechanisms that have been found in cancer, including ligand-dependent, ligand-independent and non-canonical activation. In this context, the most studied inhibitors, i.e., SMO inhibitors, have shown encouraging results for the treatment of basal cell carcinoma and medulloblastoma, both tumour types often associated with mutations that lead to the activation of the pathway. Conversely, SMO inhibitors have not fulfilled expectations in tumours-among them sarcomas-mostly associated with ligand-dependent Hh pathway activation. Despite the controversy existing regarding the results obtained with SMO inhibitors in these types of tumours, several compounds have been (or are currently being) evaluated in sarcoma patients. Finally, we discuss some of the reasons that could explain why, in some cases, encouraging preclinical data turned into disappointing results in the clinical setting.
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Affiliation(s)
- Patricia Zarzosa
- Childhood Cancer and Blood Disorders, Vall d’Hebron Research Institute (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Lia Garcia-Gilabert
- Childhood Cancer and Blood Disorders, Vall d’Hebron Research Institute (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Raquel Hladun
- Pediatric Oncology and Hematology Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Gabriela Guillén
- Pediatric Surgery Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Gabriel Gallo-Oller
- Childhood Cancer and Blood Disorders, Vall d’Hebron Research Institute (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Guillem Pons
- Childhood Cancer and Blood Disorders, Vall d’Hebron Research Institute (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Julia Sansa-Girona
- Childhood Cancer and Blood Disorders, Vall d’Hebron Research Institute (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Miguel F. Segura
- Childhood Cancer and Blood Disorders, Vall d’Hebron Research Institute (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Josep Sánchez de Toledo
- Childhood Cancer and Blood Disorders, Vall d’Hebron Research Institute (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Pediatric Oncology and Hematology Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Lucas Moreno
- Pediatric Oncology and Hematology Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Soledad Gallego
- Childhood Cancer and Blood Disorders, Vall d’Hebron Research Institute (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Pediatric Oncology and Hematology Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Josep Roma
- Childhood Cancer and Blood Disorders, Vall d’Hebron Research Institute (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
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13
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Wong GL, Manore SG, Doheny DL, Lo HW. STAT family of transcription factors in breast cancer: Pathogenesis and therapeutic opportunities and challenges. Semin Cancer Biol 2022; 86:84-106. [PMID: 35995341 PMCID: PMC9714692 DOI: 10.1016/j.semcancer.2022.08.003] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 08/08/2022] [Accepted: 08/10/2022] [Indexed: 02/07/2023]
Abstract
Breast cancer is the most commonly diagnosed cancer and second-leading cause of cancer deaths in women. Breast cancer stem cells (BCSCs) promote metastasis and therapeutic resistance contributing to tumor relapse. Through activating genes important for BCSCs, transcription factors contribute to breast cancer metastasis and therapeutic resistance, including the signal transducer and activator of transcription (STAT) family of transcription factors. The STAT family consists of six major isoforms, STAT1, STAT2, STAT3, STAT4, STAT5, and STAT6. Canonical STAT signaling is activated by the binding of an extracellular ligand to a cell-surface receptor followed by STAT phosphorylation, leading to STAT nuclear translocation and transactivation of target genes. It is important to note that STAT transcription factors exhibit diverse effects in breast cancer; some are either pro- or anti-tumorigenic while others maintain dual, context-dependent roles. Among the STAT transcription factors, STAT3 is the most widely studied STAT protein in breast cancer for its critical roles in promoting BCSCs, breast cancer cell proliferation, invasion, angiogenesis, metastasis, and immune evasion. Consequently, there have been substantial efforts in developing cancer therapeutics to target breast cancer with dysregulated STAT3 signaling. In this comprehensive review, we will summarize the diverse roles that each STAT family member plays in breast cancer pathobiology, as well as, the opportunities and challenges in pharmacologically targeting STAT proteins and their upstream activators in the context of breast cancer treatment.
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Affiliation(s)
- Grace L Wong
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Sara G Manore
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Daniel L Doheny
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Hui-Wen Lo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Breast Cancer Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
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14
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Budimir I, Tomasović-Lončarić Č, Kralik K, Čonkaš J, Eljuga D, Žic R, Gorjanc B, Tucaković H, Caktaš D, Jaman J, Lisek V, Vlajčić Z, Martić K, Ozretić P. Higher Expressions of SHH and AR Are Associated with a Positive Receptor Status and Have Impact on Survival in a Cohort of Croatian Breast Cancer Patients. Life (Basel) 2022; 12:1559. [PMID: 36294994 PMCID: PMC9605052 DOI: 10.3390/life12101559] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 10/04/2022] [Accepted: 10/05/2022] [Indexed: 02/05/2023] Open
Abstract
Breast cancers (BC) are usually classified into four molecular subtypes according to the expression of estrogen (ER), progesterone (PR), and human epidermal growth factor 2 (HER2) receptors and proliferation marker Ki-67. Despite available anti-hormonal therapies and due to the inherent propensity of some subtypes to develop metastasis, there is a permanent need to discover new prognostic and predictive biomarkers, as well as therapeutic targets for BC. In this study, we used immunohistochemical staining to determine the expression of androgen receptor (AR) and sonic hedgehog protein (SHH), the main ligand of the Hedgehog-GLI (HH-GLI) signaling pathway, in 185 archival primary BC tissue samples and correlated it with clinicopathological characteristics, molecular subtypes, receptors statuses, and survival in a cohort of Croatian BC patients. Results showed that higher SHH and AR expressions were associated with positive receptor status, but increased SHH expression had a negative impact on survival in receptor-negative BCs. On the contrary, higher AR expression was mostly protective. However, multivariate analysis showed that only higher AR expression could be considered as an independent prognostic biomarker for poorer overall survival in triple-negative breast cancer patients (TNBC) (HR 10.9, 95% CI 1.43-83.67; p = 0.021), what could be Croatian population-related. SHH could be a potential target for treating TNBCs and HER2-enriched BCs, in cases where HH-GLI signaling is canonical (SHH-dependent).
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Affiliation(s)
- Ivan Budimir
- Department of Plastic, Reconstructive and Aesthetic Surgery, Dubrava University Hospital, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Čedna Tomasović-Lončarić
- Clinical Department of Pathology and Cytology, Dubrava University Hospital, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Kristina Kralik
- Department of Medical Statistics and Medical Informatics, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Josipa Čonkaš
- Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Domagoj Eljuga
- Department of Plastic, Reconstructive and Aesthetic Surgery, Dubrava University Hospital, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Faculty of Health Sciences, Libertas International University, 10000 Zagreb, Croatia
| | - Rado Žic
- Department of Plastic, Reconstructive and Aesthetic Surgery, Dubrava University Hospital, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Božo Gorjanc
- Department of Plastic, Reconstructive and Aesthetic Surgery, Dubrava University Hospital, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Hrvoje Tucaković
- Department of Plastic, Reconstructive and Aesthetic Surgery, Dubrava University Hospital, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Doroteja Caktaš
- Department of Plastic, Reconstructive and Aesthetic Surgery, Dubrava University Hospital, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Josip Jaman
- Department of Plastic, Reconstructive and Aesthetic Surgery, Dubrava University Hospital, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Valentino Lisek
- Department of Abdominal Surgery, Dubrava University Hospital, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Zlatko Vlajčić
- Department of Plastic, Reconstructive and Aesthetic Surgery, Dubrava University Hospital, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Krešimir Martić
- Department of Plastic, Reconstructive and Aesthetic Surgery, Dubrava University Hospital, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Petar Ozretić
- Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
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15
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Doheny D, Manore S, Sirkisoon SR, Zhu D, Aguayo NR, Harrison A, Najjar M, Anguelov M, Cox AO, Furdui CM, Watabe K, Hollis T, Thomas A, Strowd R, Lo HW. An FDA-Approved Antifungal, Ketoconazole, and Its Novel Derivative Suppress tGLI1-Mediated Breast Cancer Brain Metastasis by Inhibiting the DNA-Binding Activity of Brain Metastasis-Promoting Transcription Factor tGLI1. Cancers (Basel) 2022; 14:4256. [PMID: 36077791 PMCID: PMC9454738 DOI: 10.3390/cancers14174256] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 08/27/2022] [Indexed: 11/16/2022] Open
Abstract
The goal of this study is to identify pharmacological inhibitors that target a recently identified novel mediator of breast cancer brain metastasis (BCBM), truncated glioma-associated oncogene homolog 1 (tGLI1). Inhibitors of tGLI1 are not yet available. To identify compounds that selectively kill tGLI1-expressing breast cancer, we screened 1527 compounds using two sets of isogenic breast cancer and brain-tropic breast cancer cell lines engineered to stably express the control, GLI1, or tGLI1 vector, and identified the FDA-approved antifungal ketoconazole (KCZ) to selectively target tGLI1-positive breast cancer cells and breast cancer stem cells, but not tGLI1-negative breast cancer and normal cells. KCZ's effects are dependent on tGLI1. Two experimental mouse metastasis studies have demonstrated that systemic KCZ administration prevented the preferential brain metastasis of tGLI1-positive breast cancer and suppressed the progression of established tGLI1-positive BCBM without liver toxicities. We further developed six KCZ derivatives, two of which (KCZ-5 and KCZ-7) retained tGLI1-selectivity in vitro. KCZ-7 exhibited higher blood-brain barrier penetration than KCZ/KCZ-5 and more effectively reduced the BCBM frequency. In contrast, itraconazole, another FDA-approved antifungal, failed to suppress BCBM. The mechanistic studies suggest that KCZ and KCZ-7 inhibit tGLI1's ability to bind to DNA, activate its target stemness genes Nanog and OCT4, and promote tumor proliferation and angiogenesis. Our study establishes the rationale for using KCZ and KCZ-7 for treating and preventing BCBM and identifies their mechanism of action.
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Affiliation(s)
- Daniel Doheny
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Sara Manore
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Sherona R. Sirkisoon
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Dongqin Zhu
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Noah R. Aguayo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Alexandria Harrison
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Mariana Najjar
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Marlyn Anguelov
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Anderson O’Brien Cox
- Proteomics and Metabolomics Shared Resource, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Cristina M. Furdui
- Proteomics and Metabolomics Shared Resource, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
- Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Kounosuke Watabe
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Thomas Hollis
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
- Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Alexandra Thomas
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
- Department of Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Roy Strowd
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
- Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
| | - Hui-Wen Lo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
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16
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Sirkisoon SR, Wong GL, Aguayo NR, Doheny DL, Zhu D, Regua AT, Arrigo A, Manore SG, Wagner C, Thomas A, Singh R, Xing F, Jin G, Watabe K, Lo HW. Breast cancer extracellular vesicles-derived miR-1290 activates astrocytes in the brain metastatic microenvironment via the FOXA2→CNTF axis to promote progression of brain metastases. Cancer Lett 2022; 540:215726. [PMID: 35589002 PMCID: PMC9387054 DOI: 10.1016/j.canlet.2022.215726] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 04/21/2022] [Accepted: 05/04/2022] [Indexed: 01/09/2023]
Abstract
Mechanisms underlying breast cancer brain metastasis (BCBM) are still unclear. In this study, we observed that extracellular vesicles (EVs) secreted from breast cancer cells with increased expression of tGLI1, a BCBM-promoting transcription factor, strongly activated astrocytes. EV-derived microRNA/miRNA microarray revealed tGLI1-positive breast cancer cells highly secreted miR-1290 and miR-1246 encapsulated in EVs. Genetic knockin/knockout studies established a direct link between tGLI1 and both miRNAs. Datamining and analysis of patient samples revealed that BCBM patients had more circulating EV-miRs-1290/1246 than those without metastasis. Ectopic expression of miR-1290 or miR-1246 strongly activated astrocytes whereas their inhibitors abrogated the effect. Conditioned media from miR-1290- or miR-1246-overexpressing astrocytes promoted mammospheres. Furthermore, miRs-1290/1246 suppressed expression of FOXA2 transcription repressor, leading to CNTF cytokine secretion and subsequent activation of astrocytes. Finally, we conducted a mouse study to demonstrate that astrocytes overexpressing miR-1290, but not miR-1246, enhanced intracranial colonization and growth of breast cancer cells. Collectively, our findings demonstrate, for the first time, that breast cancer EV-derived miR-1290 and miR-1246 activate astrocytes in the brain metastatic microenvironment and that EV-derived miR-1290 promotes progression of brain metastases through the novel EV-miR-1290→FOXA2→CNTF signaling axis.
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Affiliation(s)
- Sherona R Sirkisoon
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Grace L Wong
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Noah R Aguayo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Daniel L Doheny
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Dongqin Zhu
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Angelina T Regua
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Austin Arrigo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Sara G Manore
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Calvin Wagner
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Alexandra Thomas
- Department of Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA; Breast Cancer Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA; Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Ravi Singh
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Fei Xing
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA; Breast Cancer Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA; Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Guangxu Jin
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Kounosuke Watabe
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA; Breast Cancer Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA; Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Hui-Wen Lo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA; Breast Cancer Center of Excellence, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA; Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
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17
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Morimoto M, Toyoda H, Niwa K, Hanaki R, Okuda T, Nakato D, Amano K, Iwamoto S, Hirayama M. Nafamostat mesylate prevents metastasis and dissemination of neuroblastoma through vascular endothelial growth factor inhibition. Mol Clin Oncol 2022; 17:138. [PMID: 35949892 PMCID: PMC9353881 DOI: 10.3892/mco.2022.2571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 06/20/2022] [Indexed: 11/08/2022] Open
Abstract
Neuroblastoma is a highly malignant disease with a poor prognosis and few treatment options. Despite conventional chemotherapy for neuroblastoma, resistance, invasiveness, and metastatic mobility limit the treatment efficacy. Therefore, it is necessary to develop new strategies for treating neuroblastoma. The present study aimed to evaluate the anticancer effects of nafamostat mesylate, a previously known serine protease inhibitor, on neuroblastoma cells. Effects of nafamostat mesylate on neuroblastoma cell migration and proliferation were analyzed by wound healing assay and WST-8 assay, respectively. To elucidate the mechanisms underlying the effects of nafamostat mesylate on neuroblastoma, the expression levels of NF-κB were measured via western blotting, and the production of the cytokine vascular endothelial growth factor (VEGF) in the cell culture supernatants was determined via ELISA. In addition, a mouse model of hematogenous metastasis was used to investigate the effects of nafamostat mesylate on neuroblastoma. It was determined that nafamostat mesylate significantly inhibited migration and invasion of Neuro-2a cells, but it had no effect on cell proliferation at 24 h after treatment. Exposure of Neuro-2a cells to nafamostat mesylate resulted in decreased vascular endothelial growth factor production, which could be a pivotal mechanism underlying the inhibitory effects of neuroblastoma metastasis. The results of the present study suggest that nafamostat mesylate may be an effective treatment against neuroblastoma invasion and metastasis.
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Affiliation(s)
- Mari Morimoto
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie 514‑8507, Japan
| | - Hidemi Toyoda
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie 514‑8507, Japan
| | - Kaori Niwa
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie 514‑8507, Japan
| | - Ryo Hanaki
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie 514‑8507, Japan
| | - Taro Okuda
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie 514‑8507, Japan
| | - Daisuke Nakato
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie 514‑8507, Japan
| | - Keishiro Amano
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie 514‑8507, Japan
| | - Shotaro Iwamoto
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie 514‑8507, Japan
| | - Masahiro Hirayama
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie 514‑8507, Japan
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18
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Hou L, Pu L, Chen Y, Bai Y, Zhou Y, Chen M, Wang S, Lv Y, Ma C, Cheng P, Zhang K, Liang Q, Deng S, Wang D. Targeted Intervention of NF2-YAP Signaling Axis in CD24-Overexpressing Cells Contributes to Encouraging Therapeutic Effects in TNBC. ACS NANO 2022; 16:5807-5819. [PMID: 35420780 DOI: 10.1021/acsnano.1c10921] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Triple-negative breast cancer (TNBC) cells have not been usefully classified, and no targeted therapeutic plans are currently available, resulting in a high recurrence rate and metastasis potential. In this research, CD24high cells accounted for the vast majority of TNBC cells, and they were insensitive to Taxol but sensitive to ferroptosis agonists and effectively escaped phagocytosis by tumor-associated macrophages. Furthermore, the NF2-YAP signaling axis modulated the expression of ferroptosis suppressor protein 1 (FSP1) and CD24 in CD24high cells, with subsequent ferroptotic regulation and macrophage phagocytosis. In addition, a precision targeted therapy system was designed based on the pH level and glutathione response, and it can be effectively used to target CD24high cells to induce lysosomal escape and drug burst release through CO2 production, resulting in enhanced ferroptosis and macrophage phagocytosis through FSP1 and CD24 inhibition mediated by the NF2-YAP signaling axis. This system achieved dual antitumor effects, ultimately promoting cell death and thus inhibiting TNBC tumor growth, with some tumors even disappearing. The composite nanoprecision treatment system reported in this paper is a potential strategic tool for future use in the treatment of TNBC.
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Affiliation(s)
- Lingmi Hou
- Department of Academician (expert) Workstation, Biological Targeting Laboratory of Breast Cancer, Breast and Thyroid Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, People’s Republic of China
- Department of Breast and Thyroid Surgery, Yingshan Hospital of West China Hospital, Sichuan University, Nanchong, Sichuan 673000, People’s Republic of China
| | - Lulan Pu
- Department of Academician (expert) Workstation, Biological Targeting Laboratory of Breast Cancer, Breast and Thyroid Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, People’s Republic of China
- Department of Anatomy, North Sichuan Medical College, Nanchong, Sichuan 637000, People’s Republic of China
| | - Yu Chen
- Department of Academician (expert) Workstation, Biological Targeting Laboratory of Breast Cancer, Breast and Thyroid Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, People’s Republic of China
- Department of Anatomy, North Sichuan Medical College, Nanchong, Sichuan 637000, People’s Republic of China
| | - Yuting Bai
- Department of Academician (expert) Workstation, Biological Targeting Laboratory of Breast Cancer, Breast and Thyroid Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, People’s Republic of China
- Department of Laboratory Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, People’s Republic of China
| | - Yuqing Zhou
- Department of Academician (expert) Workstation, Biological Targeting Laboratory of Breast Cancer, Breast and Thyroid Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, People’s Republic of China
- Department of Anatomy, North Sichuan Medical College, Nanchong, Sichuan 637000, People’s Republic of China
| | - Maoshan Chen
- Department of Breast and Thyroid Surgery, Affiliated Suining Central Hospital of Chongqing Medical University, Suining, Sichuan 629000, People’s Republic of China
| | - Shuqi Wang
- Department of Laboratory Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, People’s Republic of China
| | - Yipin Lv
- Department of Digestive Diseases, The General Hospital of Western Theater Command, Chengdu, Sichuan 610036, People’s Republic of China
| | - Cui Ma
- Department of Mathematics, Army Medical University, Chongqing 400038, People’s Republic of China
| | - Panke Cheng
- Department of Cardiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, People’s Republic of China
| | - Kaijiong Zhang
- Department of Clinical Laboratory, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology, Chengdu, Sichuan 610041, People’s Republic of China
| | - Qi Liang
- Department of Academician (expert) Workstation, Biological Targeting Laboratory of Breast Cancer, Breast and Thyroid Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, People’s Republic of China
- Department of Laboratory Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, People’s Republic of China
| | - Shishan Deng
- Department of Academician (expert) Workstation, Biological Targeting Laboratory of Breast Cancer, Breast and Thyroid Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, People’s Republic of China
- Department of Anatomy, North Sichuan Medical College, Nanchong, Sichuan 637000, People’s Republic of China
| | - Dongsheng Wang
- Department of Clinical Laboratory, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology, Chengdu, Sichuan 610041, People’s Republic of China
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19
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A novel promoter-associated non-coding small RNA paGLI1 recruits FUS/P65 to transactivate GLI1 gene expression and promotes infiltrating glioma progression. Cancer Lett 2022; 530:68-84. [DOI: 10.1016/j.canlet.2022.01.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/29/2021] [Accepted: 01/13/2022] [Indexed: 11/17/2022]
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20
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Harry JA, Ormiston ML. Novel Pathways for Targeting Tumor Angiogenesis in Metastatic Breast Cancer. Front Oncol 2021; 11:772305. [PMID: 34926282 PMCID: PMC8678517 DOI: 10.3389/fonc.2021.772305] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 11/12/2021] [Indexed: 12/29/2022] Open
Abstract
Breast cancer is the most common cancer affecting women and is the second leading cause of cancer related death worldwide. Angiogenesis, the process of new blood vessel development from pre-existing vasculature, has been implicated in the growth, progression, and metastasis of cancer. Tumor angiogenesis has been explored as a key therapeutic target for decades, as the blockade of this process holds the potential to reduce the oxygen and nutrient supplies that are required for tumor growth. However, many existing anti-angiogenic approaches, such as those targeting Vascular Endothelial Growth Factor, Notch, and Angiopoietin signaling, have been associated with severe side-effects, limited survival advantage, and enhanced cancer regrowth rates. To address these setbacks, alternative pathways involved in the regulation of tumor angiogenesis are being explored, including those involving Bone Morphogenetic Protein-9 signaling, the Sonic Hedgehog pathway, Cyclooxygenase-2, p38-mitogen-activated protein kinase, and Chemokine Ligand 18. This review article will introduce the concept of tumor angiogenesis in the context of breast cancer, followed by an overview of current anti-angiogenic therapies, associated resistance mechanisms and novel therapeutic targets.
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Affiliation(s)
- Jordan A Harry
- Department of Medicine, Queen's University, Kingston, ON, Canada
| | - Mark L Ormiston
- Department of Medicine, Queen's University, Kingston, ON, Canada.,Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.,Department of Surgery, Queen's University, Kingston, ON, Canada
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21
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Bryan S, Witzel I, Borgmann K, Oliveira-Ferrer L. Molecular Mechanisms Associated with Brain Metastases in HER2-Positive and Triple Negative Breast Cancers. Cancers (Basel) 2021; 13:4137. [PMID: 34439289 PMCID: PMC8392331 DOI: 10.3390/cancers13164137] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/09/2021] [Accepted: 08/12/2021] [Indexed: 12/14/2022] Open
Abstract
Breast cancer (BC) is the most frequent cause of cancer-associated death for women worldwide, with deaths commonly resulting from metastatic spread to distant organs. Approximately 30% of metastatic BC patients develop brain metastases (BM), a currently incurable diagnosis. The influence of BC molecular subtype and gene expression on breast cancer brain metastasis (BCBM) development and patient prognosis is undeniable and is, therefore, an important focus point in the attempt to combat the disease. The HER2-positive and triple-negative molecular subtypes are associated with an increased risk of developing BCBM. Several genetic and molecular mechanisms linked to HER2-positive and triple-negative BC breast cancers appear to influence BCBM formation on several levels, including increased development of circulating tumor cells (CTCs), enhanced epithelial-mesenchymal transition (EMT), and migration of primary BC cells to the brain and/or through superior local invasiveness aided by cancer stem-like cells (CSCs). These specific BC characteristics, together with the ensuing developments at a clinical level, are presented in this review article, drawing a connection between research findings and related therapeutic strategies aimed at preventing BCBM formation and/or progression. Furthermore, we briefly address the critical limitations in our current understanding of this complex topic, highlighting potential focal points for future research.
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Affiliation(s)
- Sarah Bryan
- Department of Gynaecology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (S.B.); (I.W.)
| | - Isabell Witzel
- Department of Gynaecology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (S.B.); (I.W.)
| | - Kerstin Borgmann
- Center of Oncology, Laboratory of Radiobiology & Experimental Radiooncology, Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany;
| | - Leticia Oliveira-Ferrer
- Department of Gynaecology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (S.B.); (I.W.)
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22
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Qayoom H, Wani NA, Alshehri B, Mir MA. An insight into the cancer stem cell survival pathways involved in chemoresistance in triple-negative breast cancer. Future Oncol 2021; 17:4185-4206. [PMID: 34342489 DOI: 10.2217/fon-2021-0172] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is the most complex, aggressive and fatal subtype of breast cancer. Owing to the lack of targeted therapy and heterogenic nature of TNBC, chemotherapy remains the sole treatment option for TNBC, with taxanes and anthracyclines representing the general chemotherapeutic regimen in TNBC therapy. But unfortunately, patients develop resistance to the existing chemotherapeutic regimen, resulting in approximately 90% treatment failure. Breast cancer stem cells (BCSCs) are one of the major causes for the development of chemoresistance in TNBC patients. After surviving the chemotherapy damage, the presence of BCSCs results in relapse and recurrence of TNBC. Several pathways are known to regulate BCSCs' survival, such as the Wnt/β-catenin, Hedgehog, JAK/STAT and HIPPO pathways. Therefore it is imperative to target these pathways in the context of eliminating chemoresistance. In this review we will discuss the novel strategies and various preclinical and clinical studies to give an insight into overcoming TNBC chemoresistance. We present a detailed account of recent studies carried out that open an exciting perspective in relation to the mechanisms of chemoresistance.
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Affiliation(s)
- Hina Qayoom
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, J&K, India
| | - Nissar A Wani
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir Nunar Ganderbal 191201, J&K, India
| | - Bader Alshehri
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Majmaah, KSA
| | - Manzoor A Mir
- Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar 190006, J&K, India
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23
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Carballo GB, Ribeiro JH, Lopes GPDF, Ferrer VP, Dezonne RS, Pereira CM, Spohr TCLDSE. GANT-61 Induces Autophagy and Apoptosis in Glioblastoma Cells despite their heterogeneity. Cell Mol Neurobiol 2021; 41:1227-1244. [PMID: 32504326 PMCID: PMC11448572 DOI: 10.1007/s10571-020-00891-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 05/28/2020] [Indexed: 12/24/2022]
Abstract
Glioblastoma (GBM) is the most common adult primary tumor of the CNS characterized by rapid growth and diffuse invasiveness into the brain parenchyma. The GBM resistance to chemotherapeutic drugs may be due to the presence of cancer stem cells (CSCs). The CSCs activate the same molecular pathways as healthy stem cells such as WNT, Sonic hedgehog (SHH), and Notch. Mutations or deregulations of those pathways play a key role in the proliferation and differentiation of their surrounding environment, leading to tumorigenesis. Here we investigated the effect of SHH signaling pathway inhibition in human GBM cells by using GANT-61, considering stem cell phenotype, cell proliferation, and cell death. Our results demonstrated that GANT-61 induces apoptosis and autophagy in GBM cells, by increasing the expression of LC3 II and cleaved caspase 3 and 9. Moreover, we observed that SHH signaling plays a crucial role in CSC phenotype maintenance, being also involved in the epithelial-mesenchymal transition (EMT) phenotype. We also noted that SHH pathway modulation can regulate cell proliferation as revealed through the analysis of Ki-67 and c-MYC expressions. We concluded that SHH signaling pathway inhibition may be a promising therapeutic approach to treat patients suffering from GBM refractory to traditional treatments.
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Affiliation(s)
- Gabriela Basile Carballo
- Instituto Estadual Do Cérebro Paulo Niemeyer, Rua do Rezende 156, Rio de Janeiro, RJ, 20231-092, Brazil
- Programa de Pós-Graduação em Anatomia Patológica, Hospital Universitário Clementino Fraga Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
- Orofacial Development and Regeneration, Institute of Oral Biology, Centre for Dental Medicine, University of Zurich, Zurich, Switzerland
| | - Jessica Honorato Ribeiro
- Instituto Estadual Do Cérebro Paulo Niemeyer, Rua do Rezende 156, Rio de Janeiro, RJ, 20231-092, Brazil
- Programa de Pós-Graduação em Anatomia Patológica, Hospital Universitário Clementino Fraga Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
- Radiobiology Unit, Belgian Nuclear Research Centre, SCK·CEN, Mol, Belgium
| | - Giselle Pinto de Faria Lopes
- Programa de Pós-Graduação em Anatomia Patológica, Hospital Universitário Clementino Fraga Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
- Departamento de Biotecnologia Marinha, Instituto de Estudos do Mar Almirante Paulo Moreira (IEAPM)/Coordenação de Pesquisa, Instituto Nacional de Câncer (INCA), Rio de Janeiro, RJ, Brazil
| | - Valéria Pereira Ferrer
- Programa de Pós-Graduação em Anatomia Patológica, Hospital Universitário Clementino Fraga Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
- Department of Cellular and Molecular Biology, Institute of Biology, Fluminense Federal University, Niteroi, Rio de Janeiro, Brazil
| | - Romulo Sperduto Dezonne
- Programa de Pós-Graduação em Biomedicina Translacional, Universidade Do Grande Rio, Duque de Caxias, Brazil
| | - Cláudia Maria Pereira
- Programa de Pós-Graduação em Biomedicina Translacional, Universidade Do Grande Rio, Duque de Caxias, Brazil
| | - Tania Cristina Leite de Sampaio E Spohr
- Instituto Estadual Do Cérebro Paulo Niemeyer, Rua do Rezende 156, Rio de Janeiro, RJ, 20231-092, Brazil.
- Programa de Pós-Graduação em Anatomia Patológica, Hospital Universitário Clementino Fraga Filho, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil.
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24
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Induction of the CD24 Surface Antigen in Primary Undifferentiated Human Adipose Progenitor Cells by the Hedgehog Signaling Pathway. Biologics 2021. [DOI: 10.3390/biologics1020008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
In the murine model system of adipogenesis, the CD24 cell surface protein represents a valuable marker to label undifferentiated adipose progenitor cells. Indeed, when injected into the residual fat pads of lipodystrophic mice, these CD24 positive cells reconstitute a normal white adipose tissue (WAT) depot. Unluckily, similar studies in humans are rare and incomplete. This is because it is impossible to obtain large numbers of primary CD24 positive human adipose stem cells (hASCs). This study shows that primary hASCs start to express the glycosylphosphatidylinositol (GPI)-anchored CD24 protein when cultured with a chemically defined medium supplemented with molecules that activate the Hedgehog (Hh) signaling pathway. Therefore, this in vitro system may help understand the biology and role in adipogenesis of the CD24-positive hASCs. The induced cells’ phenotype was studied by flow cytometry, Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) techniques, and their secretion profile. The results show that CD24 positive cells are early undifferentiated progenitors expressing molecules related to the angiogenic pathway.
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25
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Kotulak-Chrząszcz A, Kmieć Z, Wierzbicki PM. Sonic Hedgehog signaling pathway in gynecological and genitourinary cancer (Review). Int J Mol Med 2021; 47:106. [PMID: 33907821 PMCID: PMC8057295 DOI: 10.3892/ijmm.2021.4939] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 03/10/2021] [Indexed: 01/07/2023] Open
Abstract
Cancers of the urinary tract, as well as those of the female and male reproductive systems, account for a large percentage of malignancies worldwide. Mortality is frequently affected by late diagnosis or therapeutic difficulties. The Sonic Hedgehog (SHH) pathway is an evolutionary conserved molecular cascade, which is mainly associated with the development of the central nervous system in fetal life. The present review aimed to provide an in‑depth summary of the SHH signaling pathway, including the characterization of its major components, the mechanism of its upstream regulation and non‑canonical activation, as well as its interactions with other cellular pathways. In addition, the three possible mechanisms of the cellular SHH cascade in cancer tissue are discussed. The aim of the present review was to summarize significant findings with regards to the expression of the SHH pathway components in kidney, bladder, ovarian, cervical and prostate cancer. Reports associated with common deficits and de‑regulations of the SHH pathway were summarized, despite the differences in molecular and histological patterns among these malignancies. However, currently, neither are SHH pathway elements included in panels of prognostic/therapeutic molecular patterns in any of the discussed cancers, nor have the drugs targeting SMO or GLIs been approved for therapy. The findings of the present review may support future studies on the treatment of and/or molecular targets for gynecological and genitourinary cancers.
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Affiliation(s)
| | | | - Piotr M. Wierzbicki
- Correspondence to: Dr Piotr M. Wierzbicki, Department of Histology, Faculty of Medicine, Medical University of Gdansk, ul. Debinki 1, 80211 Gdansk, Poland, E-mail:
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26
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Avery JT, Zhang R, Boohaker RJ. GLI1: A Therapeutic Target for Cancer. Front Oncol 2021; 11:673154. [PMID: 34113570 PMCID: PMC8186314 DOI: 10.3389/fonc.2021.673154] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 04/30/2021] [Indexed: 12/11/2022] Open
Abstract
GLI1 is a transcriptional effector at the terminal end of the Hedgehog signaling (Hh) pathway and is tightly regulated during embryonic development and tissue patterning/differentiation. GLI1 has low-level expression in differentiated tissues, however, in certain cancers, aberrant activation of GLI1 has been linked to the promotion of numerous hallmarks of cancer, such as proliferation, survival, angiogenesis, metastasis, metabolic rewiring, and chemotherapeutic resistance. All of these are driven, in part, by GLI1’s role in regulating cell cycle, DNA replication and DNA damage repair processes. The consequences of GLI1 oncogenic activity, specifically the activity surrounding DNA damage repair proteins, such as NBS1, and cell cycle proteins, such as CDK1, can be linked to tumorigenesis and chemoresistance. Therefore, understanding the underlying mechanisms driving GLI1 dysregulation can provide prognostic and diagnostic biomarkers to identify a patient population that would derive therapeutic benefit from either direct inhibition of GLI1 or targeted therapy towards proteins downstream of GLI1 regulation.
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Affiliation(s)
- Justin T Avery
- Oncology Department, Drug Discovery Division, Southern Research, Birmingham, AL, United States
| | - Ruowen Zhang
- Department of Medicine, Stony Brook University, Stony Brook, NY, United States
| | - Rebecca J Boohaker
- Oncology Department, Drug Discovery Division, Southern Research, Birmingham, AL, United States
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27
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Ding J, Li HY, Zhang L, Zhou Y, Wu J. Hedgehog Signaling, a Critical Pathway Governing the Development and Progression of Hepatocellular Carcinoma. Cells 2021; 10:cells10010123. [PMID: 33440657 PMCID: PMC7826706 DOI: 10.3390/cells10010123] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 01/03/2021] [Accepted: 01/07/2021] [Indexed: 02/08/2023] Open
Abstract
Hedgehog (Hh) signaling is a classic morphogen in controlling embryonic development and tissue repairing. Aberrant activation of Hh signaling has been well documented in liver cancer, including hepatoblastoma, hepatocellular carcinoma (HCC) and cholangiocarcinoma. The present review aims to update the current understanding on how abnormal Hh signaling molecules modulate initiation, progression, drug resistance and metastasis of HCC. The latest relevant literature was reviewed with our recent findings to provide an overview regarding the molecular interplay and clinical relevance of the Hh signaling in HCC management. Hh signaling molecules are involved in the transformation of pre-carcinogenic lesions to malignant features in chronic liver injury, such as nonalcoholic steatohepatitis. Activation of GLI target genes, such as ABCC1 and TAP1, is responsible for drug resistance in hepatoma cells, with a CD133−/EpCAM− surface molecular profile, and GLI1 and truncated GLI1 account for the metastatic feature of the hepatoma cells, with upregulation of matrix metalloproteinases. A novel bioassay for the Sonic Hh ligand in tissue specimens may assist HCC diagnosis with negative α-fetoprotein and predict early microvascular invasion. In-depth exploration of the Hh signaling deepens our understanding of its molecular modulation in HCC initiation, drug sensitivity and metastasis, and guides precise management of HCC on an individual basis.
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Affiliation(s)
- Jia Ding
- Department of Gastroenterology, Shanghai Jing’an District Central Hospital, Fudan University, Shanghai 200040, China;
| | - Hui-Yan Li
- Department of Medical Microbiology and Parasitology, MOE/NHC Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; (H.-Y.L.); (L.Z.); (Y.Z.)
| | - Li Zhang
- Department of Medical Microbiology and Parasitology, MOE/NHC Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; (H.-Y.L.); (L.Z.); (Y.Z.)
| | - Yuan Zhou
- Department of Medical Microbiology and Parasitology, MOE/NHC Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; (H.-Y.L.); (L.Z.); (Y.Z.)
| | - Jian Wu
- Department of Medical Microbiology and Parasitology, MOE/NHC Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; (H.-Y.L.); (L.Z.); (Y.Z.)
- Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Correspondence: ; Tel.: +86-215-423-7705; Fax: +86-216-422-7201
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28
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Kuehn J, Espinoza-Sanchez NA, Teixeira FCOB, Pavão MSG, Kiesel L, Győrffy B, Greve B, Götte M. Prognostic significance of hedgehog signaling network-related gene expression in breast cancer patients. J Cell Biochem 2021; 122:577-597. [PMID: 33417295 DOI: 10.1002/jcb.29886] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/19/2020] [Accepted: 12/22/2020] [Indexed: 12/25/2022]
Abstract
Breast cancer continues to be a serious public health problem. The role of the hedgehog pathway in normal development of the mammary gland as well as in carcinogenesis and progression of breast cancer is the subject of intense investigation, revealing functional interactions with cell surface heparan sulfate. Nevertheless, its influence on breast cancer prognosis, and its relation to specific sulfation motifs in heparan sulfate have only been poorly studied in large patient cohorts. Using the public database KMplotter that includes gene expression and survival data of 3951 patients, we found that the higher expression of SHH, HHAT, PTCH1, GLI1, GLI2, and GLI3 positively influences breast cancer prognosis. Stratifying patients according to the expression of hormone receptors, histological grade, lymph node metastasis, and systemic therapy, we observed that GLI1, GLI2, and GLI3 expression, as well as co-expression of SHH and ELP1 were associated with worse relapse-free survival in patients with HER2-positive tumors. Moreover, GLI1 expression in progesterone receptor-negative tumors and GLI3 expression in grade 3 tumors correlated with poor prognosis. SHH, in a panel of cell lines representing different breast cancer subtypes, and HHAT, PTCH1, GLI1, GLI2, and GLI3 were mostly expressed in cell lines classified as HER2-positive and basal-like. Expression of SHH, HHAT, GLI2, and GLI3 was differentially affected by overexpression of the heparan sulfate sulfotransferases HS2ST1 and HS3ST2 in vitro. Although high HS2ST1 expression was associated with poor prognosis in KMplotter analysis, high levels of HS3ST2 were associated with a good prognosis, except for ER-positive breast cancer. We suggest the GLI transcription factors as possible markers for the diagnosis, treatment, and prognosis of breast cancer especially in HER2-positive tumors, but also in progesterone receptor-negative and grade-3 tumors. The pathway interaction and prognostic impact of specific heparan sulfate sulfotransferases provide novel perspectives regarding a therapeutical targeting of the hedgehog pathway in breast cancer.
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Affiliation(s)
- Julia Kuehn
- Department of Gynecology and Obstetrics, Münster University Hospital, Münster, Germany
| | - Nancy Adriana Espinoza-Sanchez
- Department of Gynecology and Obstetrics, Münster University Hospital, Münster, Germany.,Department of Radiotherapy-Radiooncology, Münster University Hospital, Münster, Germany
| | - Felipe C O B Teixeira
- Instituto de Bioquímica Médica Leopoldo de Meis, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Mauro S G Pavão
- Instituto de Bioquímica Médica Leopoldo de Meis, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Ludwig Kiesel
- Department of Gynecology and Obstetrics, Münster University Hospital, Münster, Germany
| | - Balázs Győrffy
- Department of Bioinformatics, Semmelweis University, and Semmelweis University 2nd Department of Pediatrics, TTK Momentum Cancer Biomarker Research Group, Budapest, Hungary
| | - Burkhard Greve
- Department of Radiotherapy-Radiooncology, Münster University Hospital, Münster, Germany
| | - Martin Götte
- Department of Gynecology and Obstetrics, Münster University Hospital, Münster, Germany
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29
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Webb MJ, Kukard C. A Review of Natural Therapies Potentially Relevant in Triple Negative Breast Cancer Aimed at Targeting Cancer Cell Vulnerabilities. Integr Cancer Ther 2020; 19:1534735420975861. [PMID: 33243021 PMCID: PMC7705812 DOI: 10.1177/1534735420975861] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
We reviewed the research into the mechanisms of growth of triple negative breast cancer (TNBC) based on laboratory pre-clinical studies that have shaped understanding of the disease over the past decade. In response to these findings, we propose an approach to potentially prevent cancer metabolic adaptation and recurrence. This paper collates pre-clinical results, first to determine the tumor’s mechanisms of growth and then to source natural substances that could potentially suppress those mechanisms. The results from in vivo and in vitro studies of TNBC were combined first to select 10 primary mechanisms (Hypoxia-inducible factor 1α, Hedgehog, MAPK, MTAP, NF-κ B, Notch, P13K, STAT3, and Wnt signaling pathways plus p53 and POL2A gene expression) that promote TNBC growth, and second to propose a treatment array of 21 natural compounds that suppress laboratory models of TNBC via these mechanisms. We included BRCA mutations in the review process, but only pathways with the most preclinical studies utilizing natural products were included. Then we outlined potential biomarkers to assess the changes in the micro-environment and monitor biochemical pathway suppression. This suppression-centric aim targets these mechanisms of growth with the goal of potentially halting tumor growth and preventing cancer cell metabolic adaptation. We chose TNBC to demonstrate this 5-step strategy of supplementary therapy, which may be replicated for other tumor types.
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Affiliation(s)
| | - Craig Kukard
- University of Newcastle, Newcastle, NSW, Australia
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Khater M, Greco F, Osborn HMI. Antiangiogenic Activity of Flavonoids: A Systematic Review and Meta-Analysis. Molecules 2020; 25:E4712. [PMID: 33066630 PMCID: PMC7594036 DOI: 10.3390/molecules25204712] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 10/08/2020] [Accepted: 10/10/2020] [Indexed: 12/16/2022] Open
Abstract
Abstract: An imbalance of angiogenesis contributes to many pathologies such as cancer, arthritis and retinopathy, hence molecules that can modulate angiogenesis are of considerable therapeutic importance. Despite many reports on the promising antiangiogenic properties of naturally occurring flavonoids, no flavonoids have progressed to the clinic for this application. This systematic review and meta-analysis therefore evaluates the antiangiogenic activities of a wide range of flavonoids and is presented in two sections. The first part of the study (Systematic overview) included 402 articles identified by searching articles published before May 2020 using ScienceDirect, PubMed and Web of Science databases. From this initial search, different classes of flavonoids with antiangiogenic activities, related pathologies and use of in vitro and/or in/ex vivo angiogenesis assays were identified. In the second part (Meta-analysis), 25 studies concerning the antiangiogenic evaluation of flavonoids using the in vivo chick chorioallantoic membrane (CAM) assay were included, following a targeted search on articles published prior to June 2020. Meta-analysis of 15 out of the 25 eligible studies showed concentration dependent antiangiogenic activity of six compared subclasses of flavonoids with isoflavones, flavonols and flavones being the most active (64 to 80% reduction of blood vessels at 100 µM). Furthermore, the key structural features required for the antiangiogenic activity of flavonoids were derived from the pooled data in a structure activity relationship (SAR) study. All in all, flavonoids are promising candidates for the development of antiangiogenic agents, however further investigations are needed to determine the key structural features responsible for their activity.
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Affiliation(s)
- Mai Khater
- School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AD, UK; (M.K.); (F.G.)
- Therapeutic Chemistry Department, Pharmaceutical & Drug Industries Research Division, National Research Centre, Cairo 12622, Egypt
| | - Francesca Greco
- School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AD, UK; (M.K.); (F.G.)
| | - Helen M. I. Osborn
- School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AD, UK; (M.K.); (F.G.)
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Doheny D, Sirkisoon S, Carpenter RL, Aguayo NR, Regua AT, Anguelov M, Manore SG, Arrigo A, Jalboush SA, Wong GL, Yu Y, Wagner CJ, Chan M, Ruiz J, Thomas A, Strowd R, Lin J, Lo HW. Combined inhibition of JAK2-STAT3 and SMO-GLI1/tGLI1 pathways suppresses breast cancer stem cells, tumor growth, and metastasis. Oncogene 2020; 39:6589-6605. [PMID: 32929154 PMCID: PMC7572897 DOI: 10.1038/s41388-020-01454-1] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 08/19/2020] [Accepted: 09/02/2020] [Indexed: 01/01/2023]
Abstract
Triple-negative breast cancer (TNBC) and HER2-positive breast cancer are particularly aggressive and associated with unfavorable prognosis. TNBC lacks effective treatments. HER2-positive tumors have treatment options but often acquire resistance to HER2-targeted therapy after initial response. To address these challenges, we determined whether novel combinations of JAK2-STAT3 and SMO-GLI1/tGLI1 inhibitors synergistically target TNBC and HER2 breast cancer since these two pathways are concurrently activated in both tumor types and enriched in metastatic tumors. Herein, we show that novel combinations of JAK2 inhibitors (ruxolitinib and pacritinib) with SMO inhibitors (vismodegib and sonidegib) synergistically inhibited in vitro growth of TNBC and HER2-positive trastuzumab-resistant BT474-TtzmR cells. Synergy was also observed against breast cancer stem cells. To determine if the combination is efficacious in inhibiting metastasis, we treated mice with intracardially inoculated TNBC cells and found the combination to inhibit lung and liver metastases, and prolong host survival without toxicity. The combination inhibited orthotopic growth, VEGF-A expression, and tumor vasculature of both TNBC and HER2-positive trastuzumab-refractory breast cancer. Lung metastasis of orthotopic BT474-TtzmR xenografts was suppressed by the combination. Together, our results indicated that dual targeting of JAK2 and SMO resulted in synergistic suppression of breast cancer growth and metastasis, thereby supporting future clinical testing.
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Affiliation(s)
- Daniel Doheny
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Sherona Sirkisoon
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Richard L Carpenter
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine-Bloomington, JH 308 1001 E. 3rd St., Bloomington, IN, 47405, USA
| | - Noah Reeve Aguayo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Angelina T Regua
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Marlyn Anguelov
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Sara G Manore
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Austin Arrigo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Sara Abu Jalboush
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Grace L Wong
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Yang Yu
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Calvin J Wagner
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Michael Chan
- Wake Forest Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA
- Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Jimmy Ruiz
- Wake Forest Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA
- Department of Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Alexandra Thomas
- Wake Forest Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA
- Department of Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Roy Strowd
- Wake Forest Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA
- Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Jiayuh Lin
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Hui-Wen Lo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
- Wake Forest Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
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The Role of Smoothened in Cancer. Int J Mol Sci 2020; 21:ijms21186863. [PMID: 32962123 PMCID: PMC7555769 DOI: 10.3390/ijms21186863] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 09/13/2020] [Accepted: 09/15/2020] [Indexed: 02/06/2023] Open
Abstract
Smoothened (SMO) belongs to the Hedgehog (HH) signaling pathway, which regulates cell growth, migration, invasion and stem cells in cancer. The HH signaling pathway includes both canonical and noncanonical pathways. The canonical HH pathway functions through major HH molecules such as HH ligands, PTCH, SMO and GLI, whereas the noncanonical HH pathway involves the activation of SMO or GLI through other pathways. The role of SMO has been discussed in different types of cancer, including breast, liver, pancreatic and colon cancers. SMO expression correlates with tumor size, invasiveness, metastasis and recurrence. In addition, SMO inhibitors can suppress cancer formation, reduce the proliferation of cancer cells, trigger apoptosis and suppress cancer stem cell activity. A better understanding of the role of SMO in cancer could contribute to the development of novel therapeutic approaches.
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Doheny D, Manore SG, Wong GL, Lo HW. Hedgehog Signaling and Truncated GLI1 in Cancer. Cells 2020; 9:cells9092114. [PMID: 32957513 PMCID: PMC7565963 DOI: 10.3390/cells9092114] [Citation(s) in RCA: 122] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 09/10/2020] [Accepted: 09/15/2020] [Indexed: 12/18/2022] Open
Abstract
The hedgehog (HH) signaling pathway regulates normal cell growth and differentiation. As a consequence of improper control, aberrant HH signaling results in tumorigenesis and supports aggressive phenotypes of human cancers, such as neoplastic transformation, tumor progression, metastasis, and drug resistance. Canonical activation of HH signaling occurs through binding of HH ligands to the transmembrane receptor Patched 1 (PTCH1), which derepresses the transmembrane G protein-coupled receptor Smoothened (SMO). Consequently, the glioma-associated oncogene homolog 1 (GLI1) zinc-finger transcription factors, the terminal effectors of the HH pathway, are released from suppressor of fused (SUFU)-mediated cytoplasmic sequestration, permitting nuclear translocation and activation of target genes. Aberrant activation of this pathway has been implicated in several cancer types, including medulloblastoma, rhabdomyosarcoma, basal cell carcinoma, glioblastoma, and cancers of lung, colon, stomach, pancreas, ovarian, and breast. Therefore, several components of the HH pathway are under investigation for targeted cancer therapy, particularly GLI1 and SMO. GLI1 transcripts are reported to undergo alternative splicing to produce truncated variants: loss-of-function GLI1ΔN and gain-of-function truncated GLI1 (tGLI1). This review covers the biochemical steps necessary for propagation of the HH activating signal and the involvement of aberrant HH signaling in human cancers, with a highlight on the tumor-specific gain-of-function tGLI1 isoform.
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Affiliation(s)
- Daniel Doheny
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (D.D.); (S.G.M.); (G.L.W.)
| | - Sara G. Manore
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (D.D.); (S.G.M.); (G.L.W.)
| | - Grace L. Wong
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (D.D.); (S.G.M.); (G.L.W.)
| | - Hui-Wen Lo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA; (D.D.); (S.G.M.); (G.L.W.)
- Wake Forest Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA
- Correspondence: ; Tel.: +1-336-716-0695
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Altevogt P, Sammar M, Hüser L, Kristiansen G. Novel insights into the function of CD24: A driving force in cancer. Int J Cancer 2020; 148:546-559. [PMID: 32790899 DOI: 10.1002/ijc.33249] [Citation(s) in RCA: 130] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 07/23/2020] [Accepted: 07/28/2020] [Indexed: 12/12/2022]
Abstract
CD24 is a highly glycosylated protein with a small protein core that is linked to the plasma membrane via a glycosyl-phosphatidylinositol anchor. CD24 is primarily expressed by immune cells but is often overexpressed in human tumors. In cancer, CD24 is a regulator of cell migration, invasion and proliferation. Its expression is associated with poor prognosis and it is used as cancer stemness marker. Recently, CD24 on tumor cells was identified as a phagocytic inhibitor ("do not eat me" signal) having a suppressive role in tumor immunity via binding to Siglec-10 on macrophages. This finding is reminiscent of the demonstration that soluble CD24-Fc can dampen the immune system in autoimmune disease. In the present review, we summarize recent progress on the role of the CD24-Siglec-10 binding axis at the interface between tumor cells and the immune system, and the role of CD24 genetic polymorphisms in cancer. We describe the specific function of cytoplasmic CD24 and discuss the presence of CD24 on tumor-released extracellular vesicles. Finally, we evaluate the potential of CD24-based immunotherapy.
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Affiliation(s)
- Peter Altevogt
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
| | - Marei Sammar
- ORT Braude College for Engineering, Karmiel, Israel
| | - Laura Hüser
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
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Concurrent Control of the Kaposi's Sarcoma-Associated Herpesvirus Life Cycle through Chromatin Modulation and Host Hedgehog Signaling: a New Prospect for the Therapeutic Potential of Lipoxin A4. J Virol 2020; 94:JVI.02177-19. [PMID: 32102879 DOI: 10.1128/jvi.02177-19] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 02/14/2020] [Indexed: 02/07/2023] Open
Abstract
Lipoxin A4 (LXA4) is an endogenous lipid mediator with compelling anti-inflammatory and proresolution properties. Studies done to assess the role of arachidonic acid pathways of the host in Kaposi's sarcoma-associated herpesvirus (KSHV) biology helped discover that KSHV infection hijacks the proinflammatory cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) pathways and concurrently reduces anti-inflammatory LXA4 secretion to maintain KSHV latency in infected cells. Treatment of KSHV-infected cells with LXA4 minimizes the activation of inflammatory and proliferative signaling pathways, including the NF-κB, AKT, and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways, but the exact mechanism of action of LXA4 remains unexplored. Here, using mass spectrometry analysis, we identified components from the minichromosome maintenance (MCM) protein and chromatin-remodeling complex SMARCB1 and SMARCC2 to be LXA4-interacting host proteins in KSHV-infected cells. We identified a higher level of nuclear aryl hydrocarbon receptor (AhR) in LXA4-treated KSHV-infected cells than in untreated KSHV-infected cells, which probably facilitates the affinity interaction of the nucleosome complex protein with LXA4. We demonstrate that SMARCB1 regulates both replication and transcription activator (RTA) activity and host hedgehog (hh) signaling in LXA4-treated KSHV-infected cells. Host hedgehog signaling was modulated in an AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR)-S6 kinase-dependent manner in LXA4-treated KSHV-infected cells. Since anti-inflammatory drugs are beneficial as adjuvants to conventional and immune-based therapies, we evaluated the potential of LXA4 treatment in regulating programmed death-ligand 1 (PD-L1) on KSHV-carrying tumor cells. Overall, our study identified LXA4-interacting host factors in KSHV-infected cells, which could help provide an understanding of the mode of action of LXA4 and its therapeutic potential against KSHV.IMPORTANCE The latent-to-lytic switch in KSHV infection is one of the critical events regulated by the major replication and transcription activator KSHV protein called RTA. Chromatin modification of the viral genome determines the phase of the viral life cycle in the host. Here, we report that LXA4 interacts with a host chromatin modulator, especially SMARCB1, which upregulates the KSHV ORF50 promoter. SMARCB1 has also been recognized to be a tumor suppressor protein which controls many tumorigenic events associated with the hedgehog (hh) signaling pathway. We also observed that LXA4 treatment reduces PD-L1 expression and that PD-L1 expression is an important immune evasion strategy used by KSHV for its survival and maintenance in the host. Our study underscores the role of LXA4 in KSHV biology and emphasizes that KSHV is strategic in downregulating LXA4 secretion in the host to establish latency. This study also uncovers the therapeutic potential of LXA4 and its targetable receptor, AhR, in KSHV's pathogenesis.
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36
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Jeng KS, Chang CF, Lin SS. Sonic Hedgehog Signaling in Organogenesis, Tumors, and Tumor Microenvironments. Int J Mol Sci 2020; 21:ijms21030758. [PMID: 31979397 PMCID: PMC7037908 DOI: 10.3390/ijms21030758] [Citation(s) in RCA: 140] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 01/20/2020] [Accepted: 01/20/2020] [Indexed: 02/07/2023] Open
Abstract
During mammalian embryonic development, primary cilia transduce and regulate several signaling pathways. Among the various pathways, Sonic hedgehog (SHH) is one of the most significant. SHH signaling remains quiescent in adult mammalian tissues. However, in multiple adult tissues, it becomes active during differentiation, proliferation, and maintenance. Moreover, aberrant activation of SHH signaling occurs in cancers of the skin, brain, liver, gallbladder, pancreas, stomach, colon, breast, lung, prostate, and hematological malignancies. Recent studies have shown that the tumor microenvironment or stroma could affect tumor development and metastasis. One hypothesis has been proposed, claiming that the pancreatic epithelia secretes SHH that is essential in establishing and regulating the pancreatic tumor microenvironment in promoting cancer progression. The SHH signaling pathway is also activated in the cancer stem cells (CSC) of several neoplasms. The self-renewal of CSC is regulated by the SHH/Smoothened receptor (SMO)/Glioma-associated oncogene homolog I (GLI) signaling pathway. Combined use of SHH signaling inhibitors and chemotherapy/radiation therapy/immunotherapy is therefore key in targeting CSCs.
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37
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Piirsoo A, Pink A, Kasak L, Kala M, Kasvandik S, Ustav M, Piirsoo M. Differential phosphorylation determines the repressor and activator potencies of GLI1 proteins and their efficiency in modulating the HPV life cycle. PLoS One 2019; 14:e0225775. [PMID: 31770404 PMCID: PMC6879148 DOI: 10.1371/journal.pone.0225775] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 11/12/2019] [Indexed: 11/19/2022] Open
Abstract
The Sonic Hedgehog (Shh) signalling pathway plays multiple roles during embryonic development and under pathological conditions. Although the core components of the Shh pathway are conserved, the regulation of signal transduction varies significantly among species and cell types. Protein kinases Ulk3 and Pka are involved in the Shh pathway as modulators of the activities of Gli transcription factors, which are the nuclear mediators of the signal. Here, we investigate the regulation and activities of two GLI1 isoforms, full-length GLI1 (GLI1FL) and GLI1ΔN. The latter protein lacks the first 128 amino acids including the conserved phosphorylation cluster and the binding motif for SUFU, the key regulator of GLI activity. Both GLI1 isoforms are co-expressed in all human cell lines analysed and possess similar DNA binding activity. ULK3 potentiates the transcriptional activity of both GLI1 proteins, whereas PKA inhibits the activity of GLI1ΔN, but not GLI1FL. In addition to its well-established role as a transcriptional activator, GLI1FL acts as a repressor by inhibiting transcription from the early promoters of human papillomavirus type 18 (HPV18). Additionally, compared to GLI1ΔN, GLI1FL is a more potent suppressor of replication of several HPV types. Altogether, our data show that the N-terminal part of GLI1FL is crucial for the realization of its full potential as a transcriptional regulator.
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Affiliation(s)
- Alla Piirsoo
- Institute of Technology, University of Tartu, Tartu, Estonia
| | - Anne Pink
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
| | - Lagle Kasak
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
| | - Martin Kala
- Institute of Technology, University of Tartu, Tartu, Estonia
| | - Sergo Kasvandik
- Institute of Technology, University of Tartu, Tartu, Estonia
| | - Mart Ustav
- Institute of Technology, University of Tartu, Tartu, Estonia
| | - Marko Piirsoo
- Institute of Technology, University of Tartu, Tartu, Estonia
- * E-mail:
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38
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Langsten KL, Kim JH, Sarver AL, Dewhirst M, Modiano JF. Comparative Approach to the Temporo-Spatial Organization of the Tumor Microenvironment. Front Oncol 2019; 9:1185. [PMID: 31788448 PMCID: PMC6854022 DOI: 10.3389/fonc.2019.01185] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 10/21/2019] [Indexed: 12/13/2022] Open
Abstract
The complex ecosystem in which tumor cells reside and interact, termed the tumor microenvironment (TME), encompasses all cells and components associated with a neoplasm that are not transformed cells. Interactions between tumor cells and the TME are complex and fluid, with each facet coercing the other, largely, into promoting tumor progression. While the TME in humans is relatively well-described, a compilation and comparison of the TME in our canine counterparts has not yet been described. As is the case in humans, dog tumors exhibit greater heterogeneity than what is appreciated in laboratory animal models, although the current level of knowledge on similarities and differences in the TME between dogs and humans, and the practical implications of that information, require further investigation. This review summarizes some of the complexities of the human and mouse TME and interjects with what is known in the dog, relaying the information in the context of the temporo-spatial organization of the TME. To the authors' knowledge, the development of the TME over space and time has not been widely discussed, and a comprehensive review of the canine TME has not been done. The specific topics covered in this review include cellular invasion and interactions within the TME, metabolic derangements in the TME and vascular invasion, and the involvement of the TME in tumor spread and metastasis.
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Affiliation(s)
- Kendall L Langsten
- Department of Veterinary Population Medicine, University of Minnesota, St. Paul, MN, United States
| | - Jong Hyuk Kim
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN, United States.,Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, United States.,Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
| | - Aaron L Sarver
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN, United States.,Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States.,Institute for Health Informatics, University of Minnesota, Minneapolis, MN, United States
| | - Mark Dewhirst
- Radiation Oncology Department, Duke University Medical School, Durham, NC, United States
| | - Jaime F Modiano
- Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN, United States.,Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, United States.,Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States.,Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, United States.,Center for Immunology, University of Minnesota, Minneapolis, MN, United States.,Stem Cell Institute, University of Minnesota, Minneapolis, MN, United States.,Institute for Engineering in Medicine, University of Minnesota, Minneapolis, MN, United States
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Bonfim-Silva R, Salomão KB, Pimentel TVCDA, Menezes CCBDO, Palma PVB, Fontes AM. Biological characterization of the UW402, UW473, ONS-76 and DAOY pediatric medulloblastoma cell lines. Cytotechnology 2019; 71:893-903. [PMID: 31346954 PMCID: PMC6787134 DOI: 10.1007/s10616-019-00332-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 07/19/2019] [Indexed: 12/15/2022] Open
Abstract
Medulloblastoma (MB) is the most common malignant brain tumor in children. Recent advances in molecular technologies allowed to classify MB in 4 major molecular subgroups: WNT, SHH, Group 3 and Group 4. In cancer research, cancer cell lines are important for examining and manipulating molecular and cellular process. However, it is important to know the characteristics of each cancer cell line prior to use, because there are some differences among them, even if they originate from the same cancer type. This study aimed to evaluate the similarities and differences among four human medulloblastoma cell lines, UW402, UW473, DAOY and ONS-76. The medulloblastoma cell lines were analyzed for (1) cell morphology, (2) immunophenotyping by flow cytometry for some specifics surface proteins, (3) expression level of adhesion molecules by RT-qPCR, (4) proliferative potential, (5) cell migration, and (6) in vivo tumorigenic potential. It was observed a relationship between cell growth and CDH1 (E-chaderin) adhesion molecule expression and all MB cell lines showed higher levels of CDH2 (N-chaderin) when compared to other adhesion molecule. ONS-76 showed higher gene expression of CDH5 (VE-chaderin) and higher percentage of CD144/VE-chaderin positive cells when compared to other MB cell lines. All MB cell lines showed low percentage of CD34, CD45, CD31, CD133 positive cells and high percentage of CD44, CD105, CD106 and CD29 positive cells. The DAOY cell line showed the highest migration potential, the ONS-76 cell line showed the highest proliferative potential and only DAOY and ONS-76 cell lines showed tumorigenic potential in vivo. MB cell lines showed functional and molecular differences among them, which it should be considered by the researchers in choosing the most suitable cellular model according to the study proposal.
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Affiliation(s)
- Ricardo Bonfim-Silva
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes, 3900 Monte Alegre, Ribeirão Preto, São Paulo, ZIP code: 14049-900, Brazil.
| | - Karina Bezerra Salomão
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes, 3900 Monte Alegre, Ribeirão Preto, São Paulo, ZIP code: 14049-900, Brazil
| | - Thais Valéria Costa de Andrade Pimentel
- Department of Medical Clinic, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes, 3900 Monte Alegre, Ribeirão Preto, São Paulo, ZIP code: 14049-900, Brazil
| | - Camila Cristina Branquinho de Oliveira Menezes
- Ribeirão Preto Blood Center, Clinics Hospital of the Ribeirão Preto Medical School, University of São Paulo, Av. Tenente Catão Roxo, 2501 Monte Alegre, Ribeirão Preto, São Paulo, ZIP code: 14051-140, Brazil
| | - Patrícia Vianna Bonini Palma
- Ribeirão Preto Blood Center, Clinics Hospital of the Ribeirão Preto Medical School, University of São Paulo, Av. Tenente Catão Roxo, 2501 Monte Alegre, Ribeirão Preto, São Paulo, ZIP code: 14051-140, Brazil
| | - Aparecida Maria Fontes
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes, 3900 Monte Alegre, Ribeirão Preto, São Paulo, ZIP code: 14049-900, Brazil
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40
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Sirkisoon SR, Carpenter RL, Rimkus T, Doheny D, Zhu D, Aguayo NR, Xing F, Chan M, Ruiz J, Metheny-Barlow LJ, Strowd R, Lin J, Regua AT, Arrigo A, Anguelov M, Pasche B, Debinski W, Watabe K, Lo HW. TGLI1 transcription factor mediates breast cancer brain metastasis via activating metastasis-initiating cancer stem cells and astrocytes in the tumor microenvironment. Oncogene 2019; 39:64-78. [PMID: 31462709 PMCID: PMC6938539 DOI: 10.1038/s41388-019-0959-3] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 06/24/2019] [Accepted: 07/25/2019] [Indexed: 11/24/2022]
Abstract
Mechanisms for breast cancer metastasis remain unclear. Whether truncated glioma-associated oncogene homolog 1 (TGLI1), a transcription factor known to promote angiogenesis, migration and invasion, plays any role in metastasis of any tumor type has never been investigated. In this study, results of two mouse models of breast cancer metastasis showed that ectopic expression of TGLI1, but not GLI1, promoted preferential metastasis to the brain. Conversely, selective TGLI1 knockdown using antisense oligonucleotides led to decreased breast cancer brain metastasis (BCBM) in vivo. Immunohistochemical staining showed that TGLI1, but not GLI1, was increased in lymph node metastases compared to matched primary tumors, and that TGLI1 was expressed at higher levels in BCBM specimens compared to primary tumors. TGLI1 activation is associated with a shortened time to develop BCBM and enriched in HER2-enriched and triple-negative breast cancers. Radioresistant BCBM cell lines and specimens expressed higher levels of TGLI1, but not GLI1, than radiosensitive counterparts. Since cancer stem cells (CSCs) are radioresistant and metastasis-initiating cells, we examined TGLI1 for its involvement in breast CSCs and found TGLI1 to transcriptionally activate stemness genes CD44, Nanog, Sox2, and OCT4 leading to CSC renewal, and TGLI1 outcompetes with GLI1 for binding to target promoters. We next examined whether astrocyte-priming underlies TGLI1-mediated brain tropism and found that TGLI1-positive CSCs strongly activated and interacted with astrocytes in vitro and in vivo. These findings demonstrate, for the first time, that TGLI1 mediates breast cancer metastasis to the brain, in part, through promoting metastasis-initiating CSCs and activating astrocytes in BCBM microenvironment.
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Affiliation(s)
- Sherona R Sirkisoon
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Richard L Carpenter
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.,Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Bloomington, IN, USA
| | - Tadas Rimkus
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Daniel Doheny
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Dongqin Zhu
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Noah R Aguayo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Fei Xing
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.,Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Michael Chan
- Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.,Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Jimmy Ruiz
- Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.,Department of Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Linda J Metheny-Barlow
- Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.,Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Roy Strowd
- Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.,Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Jiayuh Lin
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Angelina T Regua
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Austin Arrigo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Marlyn Anguelov
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Boris Pasche
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.,Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Waldemar Debinski
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.,Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Kounosuke Watabe
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.,Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Hui-Wen Lo
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA. .,Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
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41
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Huang Y, Fang J, Lu W, Wang Z, Wang Q, Hou Y, Jiang X, Reizes O, Lathia J, Nussinov R, Eng C, Cheng F. A Systems Pharmacology Approach Uncovers Wogonoside as an Angiogenesis Inhibitor of Triple-Negative Breast Cancer by Targeting Hedgehog Signaling. Cell Chem Biol 2019; 26:1143-1158.e6. [PMID: 31178408 PMCID: PMC6697584 DOI: 10.1016/j.chembiol.2019.05.004] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 03/29/2019] [Accepted: 05/13/2019] [Indexed: 02/07/2023]
Abstract
Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous disease that lacks clinically actionable genetic alterations that limit targeted therapies. Here we explore a systems pharmacology approach that integrates drug-target networks and large-scale genomic profiles of TNBC and identify wogonoside, one of the major active flavonoids, as a potent angiogenesis inhibitor. We validate that wogonoside attenuates cell migration, tube formation, and rat aorta microvessel outgrowth, and reduces formation of blood vessels in chicken chorioallantoic membrane and TNBC cell-induced Matrigel plugs. In addition, wogonoside inhibits growth and angiogenesis in TNBC cell xenograft models. This network-based approach predicts, and we empirically validate, wogonoside's antiangiogenic effects resulting from vascular endothelial growth factor secretion. Mechanistically, wogonoside inhibits Gli1 nuclear translocation and transcriptional activities associated with Hedgehog signaling, by promoting Smoothened degradation in a proteasome-dependent mechanism. This study offers a powerful, integrated, systems pharmacology-based strategy for oncological drug discovery and identifies wogonoside as a potential TNBC angiogenesis inhibitor.
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MESH Headings
- Angiogenesis Inhibitors/chemistry
- Angiogenesis Inhibitors/isolation & purification
- Angiogenesis Inhibitors/pharmacology
- Animals
- Antineoplastic Agents, Phytogenic/chemistry
- Antineoplastic Agents, Phytogenic/isolation & purification
- Antineoplastic Agents, Phytogenic/pharmacology
- Biological Products/chemistry
- Biological Products/isolation & purification
- Biological Products/pharmacology
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Drug Screening Assays, Antitumor
- Female
- Flavanones/chemistry
- Flavanones/isolation & purification
- Flavanones/pharmacology
- Glucosides/chemistry
- Glucosides/isolation & purification
- Glucosides/pharmacology
- Hedgehog Proteins/antagonists & inhibitors
- Hedgehog Proteins/metabolism
- Humans
- Mammary Neoplasms, Experimental/drug therapy
- Mammary Neoplasms, Experimental/metabolism
- Mammary Neoplasms, Experimental/pathology
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- Scutellaria baicalensis/chemistry
- Signal Transduction/drug effects
- Triple Negative Breast Neoplasms/drug therapy
- Triple Negative Breast Neoplasms/metabolism
- Triple Negative Breast Neoplasms/pathology
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Affiliation(s)
- Yujie Huang
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Jiansong Fang
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
| | - Weiqiang Lu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
| | - Zihao Wang
- Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
| | - Qi Wang
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
| | - Yuan Hou
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Xingwu Jiang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Ofer Reizes
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA
| | - Justin Lathia
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44915, USA
| | - Ruth Nussinov
- Computational Structural Biology Section, Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Charis Eng
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Feixiong Cheng
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
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42
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Bhateja P, Cherian M, Majumder S, Ramaswamy B. The Hedgehog Signaling Pathway: A Viable Target in Breast Cancer? Cancers (Basel) 2019; 11:cancers11081126. [PMID: 31394751 PMCID: PMC6721501 DOI: 10.3390/cancers11081126] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 07/23/2019] [Accepted: 07/30/2019] [Indexed: 12/24/2022] Open
Abstract
The hedgehog (Hh) pathway plays a key role in embryonic development and stem cell programs. Deregulation of the Hh pathway is a key driver of basal cell carcinoma, and therapeutic targeting led to approval of Hh inhibitor, vismodegib, in the management of this cancer. The Hh pathway is implicated in other malignancies including hormone receptor (HR+) positive and triple negative breast cancer (TNBC). Hh signaling, which is activated in human mammary stem cells, results in activation of glioma-associated oncogene (GLI) transcription factors. High GLI1 expression correlates with worse outcomes in breast cancer. Non-canonical GLI1 activation is one mechanism by which estrogen exposure promotes breast cancer stem cell proliferation and epithelial–mesenchymal transition. Tamoxifen resistant cell lines show aberrant activation of Hh signaling, and knockdown of Hh pathway inhibited growth of tamoxifen resistant cells. As in other cancers Hh signaling is activated by the PI3K/AKT pathway in these endocrine resistant cell lines. Hh pathway activation has also been reported to mediate chemotherapy resistance in TNBC via various mechanisms including paracrine signaling to tumor micro-environment and selective proliferation of cancer stem cells. Co-activation of Hh and Wnt signaling pathways is a poor prognostic marker in TNBC. Early phase clinical trials are evaluating the combination of smoothened (SMO) inhibitors and chemotherapy in TNBC. In addition to SMO inhibitors like vismodegib and sonidegib, which are in clinical use for basal cell carcinoma, GLI1 inhibitors like GANT58 and GANT61 are in preclinical drug development and might be an effective mechanism to overcome drug resistance in breast cancer. Gene signatures predictive of Hh pathway activation could enrich for patients likely to respond to these agents.
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Affiliation(s)
- Priyanka Bhateja
- Division of Medical Oncology, Department of Internal medicine, James Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA
| | - Mathew Cherian
- Division of Medical Oncology, Department of Internal medicine, James Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA
| | - Sarmila Majumder
- Division of Medical Oncology, Department of Internal medicine, James Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA
| | - Bhuvaneswari Ramaswamy
- Division of Medical Oncology, Department of Internal medicine, James Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.
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43
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Zhang G, Qu Y, Niu Y, Zhang H, Sun Q, Liu X, Li Y, Zhang H, Liu M. Difference in pathogenicity of 2 strains of avian leukosis virus subgroup J in broiler chicken. Poult Sci 2019; 98:2772-2780. [PMID: 30768138 DOI: 10.3382/ps/pez065] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Accepted: 01/30/2019] [Indexed: 11/20/2022] Open
Abstract
Avian leukosis virus subgroup J has been found to infect many types of chickens with various genetic backgrounds. The ALV-J strain NX0101, which was isolated from broiler breeders in 2001, mainly induces the formation of myeloid cell tumors. However, strain HN10PY01, which was recently isolated from laying hens, mainly induces the formation of myeloid cell tumors and hemangioma. In order to determine the difference in pathogenicity of the 2 strains in broiler chickens, 2 groups of chicken embryos were infected with NA0101 and HN10PY01 separately. A comparison was made of the mortality, oncogenicity, body weights, indexes for immune organs, levels of ALV group-specific antigen p27, and mRNA expression levels of the tumor-related gene, p53, in ALV-J-infected birds and immune organs of theses chickens in response to Newcastle Disease Virus (NDV) and avian influenza virus subtype H9 (AIV-H9) vaccination. The results indicated that strain NX0101 was highly pathogenic in broiler chickens and led to a 30% mortality rate and 45% oncogenicity, compared with the HN10PY01-infected birds. Weight of chickens was also significantly lower after 15 wk (P < 0.05). In addition, the mRNA expression levels of tumor-related p53 in medulla, liver, and lung in broilers infected with strain NX0101 were significantly higher than those infected with strain HN10PY01 (P < 0.05). These results indicated that strain NX0101 had a higher replication ability in broiler chickens. The findings of this study will contribute to further elucidating the mechanisms underlying host susceptibility and tumor classification in ALV-J-infected chickens.
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Affiliation(s)
- Guihua Zhang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Taian City, Shandong Province 271018, China.,Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Taian City, Shandong Province 271018, China
| | - Yajin Qu
- NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical Collage (PUMC), Beijing 100021, China
| | - Yujuan Niu
- The Biomedical Sciences Institute (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao 266003, China
| | - Huixia Zhang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Taian City, Shandong Province 271018, China.,Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Taian City, Shandong Province 271018, China
| | - Qinqin Sun
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Taian City, Shandong Province 271018, China.,Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Taian City, Shandong Province 271018, China
| | - Xingpo Liu
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Taian City, Shandong Province 271018, China.,Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Taian City, Shandong Province 271018, China
| | - Yue Li
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Taian City, Shandong Province 271018, China.,Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Taian City, Shandong Province 271018, China
| | - Hui Zhang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Taian City, Shandong Province 271018, China.,Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Taian City, Shandong Province 271018, China
| | - Mengda Liu
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Taian City, Shandong Province 271018, China.,Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Taian City, Shandong Province 271018, China
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44
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Role of Hedgehog Signaling in Vasculature Development, Differentiation, and Maintenance. Int J Mol Sci 2019; 20:ijms20123076. [PMID: 31238510 PMCID: PMC6627637 DOI: 10.3390/ijms20123076] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 06/17/2019] [Accepted: 06/20/2019] [Indexed: 12/16/2022] Open
Abstract
The role of Hedgehog (Hh) signaling in vascular biology has first been highlighted in embryos by Pepicelli et al. in 1998 and Rowitch et al. in 1999. Since then, the proangiogenic role of the Hh ligands has been confirmed in adults, especially under pathologic conditions. More recently, the Hh signaling has been proposed to improve vascular integrity especially at the blood–brain barrier (BBB). However, molecular and cellular mechanisms underlying the role of the Hh signaling in vascular biology remain poorly understood and conflicting results have been reported. As a matter of fact, in several settings, it is currently not clear whether Hh ligands promote vessel integrity and quiescence or destabilize vessels to promote angiogenesis. The present review relates the current knowledge regarding the role of the Hh signaling in vasculature development, maturation and maintenance, discusses the underlying proposed mechanisms and highlights controversial data which may serve as a guideline for future research. Most importantly, fully understanding such mechanisms is critical for the development of safe and efficient therapies to target the Hh signaling in both cancer and cardiovascular/cerebrovascular diseases.
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45
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Pietrobono S, Gagliardi S, Stecca B. Non-canonical Hedgehog Signaling Pathway in Cancer: Activation of GLI Transcription Factors Beyond Smoothened. Front Genet 2019; 10:556. [PMID: 31244888 PMCID: PMC6581679 DOI: 10.3389/fgene.2019.00556] [Citation(s) in RCA: 216] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 05/24/2019] [Indexed: 12/16/2022] Open
Abstract
The Hedgehog-GLI (HH-GLI) pathway is a highly conserved signaling that plays a critical role in controlling cell specification, cell–cell interaction and tissue patterning during embryonic development. Canonical activation of HH-GLI signaling occurs through binding of HH ligands to the twelve-pass transmembrane receptor Patched 1 (PTCH1), which derepresses the seven-pass transmembrane G protein-coupled receptor Smoothened (SMO). Thus, active SMO initiates a complex intracellular cascade that leads to the activation of the three GLI transcription factors, the final effectors of the HH-GLI pathway. Aberrant activation of this signaling has been implicated in a wide variety of tumors, such as those of the brain, skin, breast, gastrointestinal, lung, pancreas, prostate and ovary. In several of these cases, activation of HH-GLI signaling is mediated by overproduction of HH ligands (e.g., prostate cancer), loss-of-function mutations in PTCH1 or gain-of-function mutations in SMO, which occur in the majority of basal cell carcinoma (BCC), SHH-subtype medulloblastoma and rhabdomyosarcoma. Besides the classical canonical ligand-PTCH1-SMO route, mounting evidence points toward additional, non-canonical ways of GLI activation in cancer. By non-canonical we refer to all those mechanisms of activation of the GLI transcription factors occurring independently of SMO. Often, in a given cancer type canonical and non-canonical activation of HH-GLI signaling co-exist, and in some cancer types, more than one mechanism of non-canonical activation may occur. Tumors harboring non-canonical HH-GLI signaling are less sensitive to SMO inhibition, posing a threat for therapeutic efficacy of these antagonists. Here we will review the most recent findings on the involvement of alternative signaling pathways in inducing GLI activity in cancer and stem cells. We will also discuss the rationale of targeting these oncogenic pathways in combination with HH-GLI inhibitors as a promising anti-cancer therapies.
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Affiliation(s)
- Silvia Pietrobono
- Tumor Cell Biology Unit - Core Research Laboratory, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy
| | - Sinforosa Gagliardi
- Tumor Cell Biology Unit - Core Research Laboratory, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy
| | - Barbara Stecca
- Tumor Cell Biology Unit - Core Research Laboratory, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy
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46
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He J, Zuo Q, Hu B, Jin H, Wang C, Cheng Z, Deng X, Yang C, Ruan H, Yu C, Zhao F, Yao M, Fang J, Gu J, Zhou J, Fan J, Qin W, Yang XR, Wang H. A novel, liver-specific long noncoding RNA LINC01093 suppresses HCC progression by interaction with IGF2BP1 to facilitate decay of GLI1 mRNA. Cancer Lett 2019; 450:98-109. [PMID: 30790682 DOI: 10.1016/j.canlet.2019.02.033] [Citation(s) in RCA: 92] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 01/25/2019] [Accepted: 02/14/2019] [Indexed: 12/30/2022]
Abstract
Long noncoding RNAs (lncRNAs) are implicated as novel drivers in hepatocellular carcinoma (HCC), but the underlying mechanisms of this relationship with hepatocarcinogenesis are unknown. We report a novel, liver-specific lncRNA LINC01093 that shows significant downregulation in HCC tissues. LINC01093 expression is inversely correlated with cancer embolus and HCC TNM stage and as a prognostic predictor for HCC patients. LINC01093 overexpression significantly suppresses HCC cell proliferation and metastasis in vitro and in vivo. Conversely, its knockdown promotes HCC progression. Mechanistic analyses indicate that LINC01093 directly binds insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), interfering with interaction between IGF2BP1 and glioma-associated oncogene homolog 1 (GLI1) mRNA. The result is degradation of GLI1 mRNA, further affecting expression of GLI1 downstream molecules involved in HCC progression. The liver-enriched lncRNA LINC01093 is a promising prognostic indicator for HCC patients, and the newly identified LINC01093-IGF2BP1-GLI1 axis shows potential for therapeutic targets in HCC.
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Affiliation(s)
- Jia He
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Qiaozhu Zuo
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Bo Hu
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Haojie Jin
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Cun Wang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Zhuoan Cheng
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China
| | - Xuan Deng
- Shanghai Medical College of Fudan University, Shanghai, 200032, China
| | - Chen Yang
- Shanghai Medical College of Fudan University, Shanghai, 200032, China
| | - Haoyu Ruan
- Shanghai Medical College of Fudan University, Shanghai, 200032, China
| | - Chengtao Yu
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China
| | - Fangyu Zhao
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Ming Yao
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Jingyuan Fang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Jianren Gu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Jian Zhou
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Jia Fan
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Wenxin Qin
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China
| | - Xin-Rong Yang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, 200032, China.
| | - Hui Wang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, China.
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47
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Riaz SK, Ke Y, Wang F, Kayani MA, Malik MFA. Influence of SHH/GLI1 axis on EMT mediated migration and invasion of breast cancer cells. Sci Rep 2019; 9:6620. [PMID: 31036836 PMCID: PMC6488587 DOI: 10.1038/s41598-019-43093-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 04/16/2019] [Indexed: 12/14/2022] Open
Abstract
Sonic Hedgehog signaling is critical for breast morphogenesis and cancer. The present study was conducted to explore the influence of SHH/GLI1 axis on epithelial mesenchymal transition and invasion in breast cancer cells. SHH/GLI1 positive samples demonstrated high expression of Snail and Vimentin with relatively low expression of E-cadherin. Overexpression of Vimentin and Snail in SHH/GLI1 positive patients was also associated with poor overall survival. Interestingly, GANT61 (GLI1 inhibitor) exposure significantly reduced cell viability and induced apoptosis at 10 µM. Suppression of Hedgehog pathway either by CRISPR mediated SHH knock out or GANT61 altered regulation of EMT markers in breast cancer cells. Moreover, in-activation of SHH/GLI1 axis also significantly restricted cell migration and invasiveness. These findings suggest that targeting SHH/GLI1 axis alters expression of EMT markers and abrogates neoplastic invasion in breast cancer cells.
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Affiliation(s)
- Syeda Kiran Riaz
- Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
- Centre for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Centre, Houston, Texas, USA
| | - Yuepeng Ke
- Centre for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Centre, Houston, Texas, USA
| | - Fen Wang
- Centre for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Centre, Houston, Texas, USA
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Role of Hedgehog Signaling in Breast Cancer: Pathogenesis and Therapeutics. Cells 2019; 8:cells8040375. [PMID: 31027259 PMCID: PMC6523618 DOI: 10.3390/cells8040375] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 04/22/2019] [Accepted: 04/23/2019] [Indexed: 02/06/2023] Open
Abstract
Breast cancer (BC) is the leading cause of cancer-related mortality in women, only followed by lung cancer. Given the importance of BC in public health, it is essential to identify biomarkers to predict prognosis, predetermine drug resistance and provide treatment guidelines that include personalized targeted therapies. The Hedgehog (Hh) signaling pathway plays an essential role in embryonic development, tissue regeneration, and stem cell renewal. Several lines of evidence endorse the important role of canonical and non-canonical Hh signaling in BC. In this comprehensive review we discuss the role of Hh signaling in breast development and homeostasis and its contribution to tumorigenesis and progression of different subtypes of BC. We also examine the efficacy of agents targeting different components of the Hh pathway both in preclinical models and in clinical trials. The contribution of the Hh pathway in BC tumorigenesis and progression, its prognostic role, and its value as a therapeutic target vary according to the molecular, clinical, and histopathological characteristics of the BC patients. The evidence presented here highlights the relevance of the Hh signaling in BC, and suggest that this pathway is key for BC progression and metastasis.
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Gli Proteins: Regulation in Development and Cancer. Cells 2019; 8:cells8020147. [PMID: 30754706 PMCID: PMC6406693 DOI: 10.3390/cells8020147] [Citation(s) in RCA: 120] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 01/29/2019] [Accepted: 02/02/2019] [Indexed: 12/18/2022] Open
Abstract
Gli proteins are transcriptional effectors of the Hedgehog signaling pathway. They play key roles in the development of many organs and tissues, and are deregulated in birth defects and cancer. We review the molecular mechanisms of Gli protein regulation in mammals, with special emphasis on posttranslational modifications and intracellular transport. We also discuss how Gli proteins interact with co-activators and co-repressors to fine-tune the expression of Hedgehog target genes. Finally, we provide an overview of the regulation of developmental processes and tissue regeneration by Gli proteins and discuss how these proteins are involved in cancer progression, both through canonical regulation via the Hedgehog pathway and through cross-talk with other signaling pathways.
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Cai K, Na W, Guo M, Xu R, Wang X, Qin Y, Wu Y, Jiang J, Huang H. Targeting the cross-talk between the hedgehog and NF-κB signaling pathways in multiple myeloma. Leuk Lymphoma 2019; 60:772-781. [PMID: 30644322 DOI: 10.1080/10428194.2018.1493727] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Multiple myeloma (MM) is an incurable plasma cell malignancy. Aberrant activation of the Hedgehog (Hh) and NF-κB signaling pathways is observed in MM and plays a pivotal role in the development of MM by promoting myeloma cell growth, survival, and drug resistance. In this study, we found that the Sonic Hh (SHh) ligand in the bone marrow microenvironment is responsible for the enhancement of NF-κB activity in MM cell lines NCI-H929 and U266. Notably, we discovered that Hh signaling regulates NF-κB through its classical pathway (SHh/PTCH1/SMO/GLI1) in MM cells. Meanwhile, non-classical pathway by SMO recruitment of TRAF6 to ubiquitination is also involved in it. Moreover, the SMO inhibitor cyclopamine enhances the cytotoxic effects of bortezomib in MM cell lines. Our study reveals the cross-talk between Hh members and the NF-κB pathway in the myeloma cells and provides a theoretical basis for combined utilization of Hh members and proteasome inhibition in MM.
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Affiliation(s)
- Ke Cai
- a Department of Hematology , The Affiliated Hospital of Nantong University , Nantong , Jiangsu , 226001 , P.R. China
| | - Wenxiu Na
- a Department of Hematology , The Affiliated Hospital of Nantong University , Nantong , Jiangsu , 226001 , P.R. China
| | - Mengjie Guo
- b School of Medicine and Life Sciences , Nanjing University of Chinese Medicine , Nanjing , 210023 , P.R. China
| | - Ruirong Xu
- a Department of Hematology , The Affiliated Hospital of Nantong University , Nantong , Jiangsu , 226001 , P.R. China
| | - Xinfeng Wang
- a Department of Hematology , The Affiliated Hospital of Nantong University , Nantong , Jiangsu , 226001 , P.R. China
| | - Yi Qin
- a Department of Hematology , The Affiliated Hospital of Nantong University , Nantong , Jiangsu , 226001 , P.R. China
| | - Yan Wu
- a Department of Hematology , The Affiliated Hospital of Nantong University , Nantong , Jiangsu , 226001 , P.R. China
| | - Jie Jiang
- a Department of Hematology , The Affiliated Hospital of Nantong University , Nantong , Jiangsu , 226001 , P.R. China
| | - Hongming Huang
- a Department of Hematology , The Affiliated Hospital of Nantong University , Nantong , Jiangsu , 226001 , P.R. China
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