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1
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Sharma A, Balde A, Nazeer RA. A review on animal venom-based matrix metalloproteinase modulators and their therapeutic implications. Int Immunopharmacol 2025; 157:114703. [PMID: 40300352 DOI: 10.1016/j.intimp.2025.114703] [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: 01/18/2025] [Revised: 04/03/2025] [Accepted: 04/19/2025] [Indexed: 05/01/2025]
Abstract
Matrix Metalloproteinases (MMPs) belong to a family of proteolytic enzymes that degrade extracellular matrix components, such as collagen, elastin, laminin, and fibronectin. They also play a part in tissue remodeling by cleaving and rejoining the tissue proteins. Cancer, neurodegenerative disorders, cardiovascular diseases, arthritis, and chronic inflammatory conditions are just some of the diseases that can start or get worse when different MMPs are not working properly. Venomous Animals such as honeybees, toads, snakes, spiders, scorpions, jellyfish, and sea anemones contain venom-secreting glands, which help them defend against predators and immobilize their prey. The molecules that come from animal venom are a complicated mix of bioactive molecules, such as peptides, enzymes, proteins, and small organic compounds that do a number of biological things. Venom-derived molecules have been found to modulate MMP. These venoms and their components target specific signaling pathways, modifying MMP expression levels to either induce inflammation or exhibit anti-inflammatory effects. In this review, we study and explore different MMPs, such as MMP1, MMP2, MMP3, MMP7, MMP8, and MMP9, and their roles in the progression of certain diseases. We also look at different types of molecules derived from marine and land animal venom that are used as MMP modulators. We look at how they work by targeting specific signaling pathways to change MMPs and how they might be used as a medicine to stop diseases by decreasing MMPs.
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Affiliation(s)
- Ansumaan Sharma
- Biopharmaceuticals Lab, Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India
| | - Akshad Balde
- Biopharmaceuticals Lab, Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India
| | - Rasool Abdul Nazeer
- Biopharmaceuticals Lab, Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India.
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2
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Izhar M, Lesniak MS. Role of Extracellular Vesicles in the Pathogenesis of Brain Metastasis. JOURNAL OF EXTRACELLULAR BIOLOGY 2025; 4:e70051. [PMID: 40330713 PMCID: PMC12053894 DOI: 10.1002/jex2.70051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 04/03/2025] [Accepted: 04/04/2025] [Indexed: 05/08/2025]
Abstract
Extracellular vesicles (EVs) are small particles released by various cells, including cancer cells. They play a significant role in the development of different cancers, including brain metastasis. These EVs transport biomolecular materials such as RNA, DNA, and proteins from tumour cells to other cells, facilitating the spread of primary tumours to the brain tissue. EVs interact with the endothelial cells of the blood-brain barrier (BBB), compromising its integrity and allowing metastatic cells to pass through easily. Additionally, EVs interact with various cells in the brain's microenvironment, creating a conducive environment for incoming metastatic cells. They also influence the immune system within this premetastatic environment, promoting the growth of metastatic cells. This review paper focuses on the research regarding the role of EVs in the development of brain metastasis, including their impact on disrupting the BBB, preparing the premetastatic environment, and modulating the immune system. Furthermore, the paper discusses the potential of EVs as diagnostic and prognostic biomarkers for brain metastasis.
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Affiliation(s)
- Muhammad Izhar
- Department of NeurosurgeryMassachusetts General Hospital, Harvard Medical SchoolBostonMassachusettsUSA
- Department of NeurosurgeryStanford University School of MedicineStanfordCaliforniaUSA
| | - Maciej S. Lesniak
- Department of Neurological SurgeryLou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern UniversityChicagoIllinoisUSA
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3
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Dastagir N, Liebsch C, Kutz J, Wronski S, Pich A, Obed D, Vogt PM, Bucan V, Strauß S. Identification of antimicrobial peptides from the Ambystoma mexicanum displaying antibacterial and antitumor activity. PLoS One 2025; 20:e0316257. [PMID: 40043049 PMCID: PMC11882074 DOI: 10.1371/journal.pone.0316257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 12/09/2024] [Indexed: 05/13/2025] Open
Abstract
Antibiotic resistance is a significant healthcare concern. Therefore, identifying target molecules that can serve as antibiotic substitutes is crucial. Among the promising candidates are antimicrobial peptides (AMPs). AMPs are defense mechanisms of the innate immune system which exist in almost all living organisms. Research on the AMPs of some amphibians has shown that, in addition to their antimicrobial effectiveness, AMPs also exhibit anti-inflammatory and anti-carcinogenic properties. In this study, we identify and characterize AMPs deriving from the skin mucus of the axolotl (Ambystoma mexicanum). Upon activity spectrum evaluation of the AMPs, we synthesized and ranked 22 AMPs according to antimicrobial efficacy by means of a prediction tool. To assess the AMPs' potential as antibacterial and anticarcinogenic compounds, we performed a minimum inhibitory concentration (MIC) assay for efficacy against methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive Staphylococcus aureus (MSSA), and an apoptosis assay on T-47D mammary carcinoma cells. We identified four AMPs that showed significant inhibition of MRSA, of which three also demonstrated anticarcinogenic activity. Gene expression analysis was performed on AMP-stimulated carcinoma cells using a breast cancer-specific RT-PCR array. In cells stimulated with the AMPs, gene expression analysis showed upregulation of tumor suppressor genes and downregulation of oncogenes. Overall, our work demonstrates the antimicrobial and anticarcinogenic activity of axolotl-derived AMPs. The results of this work serve as a basis to further investigate the mode of action and potential use of axolotl AMPs as therapeutic anticancer or antibiotic agents.
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Affiliation(s)
- Nadjib Dastagir
- Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Hannover Medical School, Hannover, Germany
| | - Christina Liebsch
- Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Hannover Medical School, Hannover, Germany
| | - Jaqueline Kutz
- Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Hannover Medical School, Hannover, Germany
| | - Sabine Wronski
- Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany
| | - Andreas Pich
- Hannover Medical School, Institute for Toxicology, Hannover, Germany
| | - Doha Obed
- Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Hannover Medical School, Hannover, Germany
| | - Peter Maria Vogt
- Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Hannover Medical School, Hannover, Germany
| | - Vesna Bucan
- Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Hannover Medical School, Hannover, Germany
| | - Sarah Strauß
- Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Hannover Medical School, Hannover, Germany
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4
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Sato A, Takagi K, Yamaguchi-Tanaka M, Okushima J, Yamazaki Y, Ito A, Suzuki T. Matrix metalloproteinase-3 is a potent prognostic factor associated with cell proliferation and migration in prostate cancer. Exp Mol Pathol 2025; 141:104954. [PMID: 39933392 DOI: 10.1016/j.yexmp.2025.104954] [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: 09/10/2024] [Revised: 01/23/2025] [Accepted: 02/03/2025] [Indexed: 02/13/2025]
Abstract
Prostate cancer is a common malignancy in men around the world, and it is crucial to explore novel biomarkers to improve its treatment. Prostate cancer cells typically invade the surrounding stroma, and remodeling of the extracellular matrix (ECM) is a crucial step in the progress of prostate cancer. Matrix metalloproteinase-3 (MMP3) is an enzyme that degrades several ECM components and is implicated in human malignancies. However, the clinical and biological significance of MMP3 has not been well elucidated. We therefore immunolocalized MMP3 in prostate cancer tissues (n = 117) and demonstrated that MMP3 immunoreactivity was correlated with aggressive phenotype of prostate cancer, including higher proliferation/invasion ability, and shorter disease-free survival. In addition, subsequent in vitro analysis revealed that overexpression of MMP3 significantly increased the proliferative and migratory abilities of PC-3 and DU-145 prostate cancer cell lines, depending on conditioned media from WMPY-1 prostate stromal cells. It was concluded that MMP3 might contribute to prostate cancer progression by modifying the ECM surrounding prostate cancer cells and could serve as a potent prognostic factor in prostate cancer.
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Affiliation(s)
- Ai Sato
- Departments of Pathology and Histotechnology, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Kiyoshi Takagi
- Departments of Pathology and Histotechnology, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
| | - Mio Yamaguchi-Tanaka
- Departments of Pathology and Histotechnology, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; Departments of Personalized Medicine Center, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Jotaro Okushima
- Departments of Pathology and Histotechnology, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Yuto Yamazaki
- Department of Pathology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan
| | - Akihiro Ito
- Departments of Urology, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Takashi Suzuki
- Departments of Pathology and Histotechnology, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; Department of Pathology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan; Departments of Anatomic Pathology Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
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5
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Yue Y, Ren Y, Lu C, Jiang N, Wang S, Fu J, Kong M, Zhang G. The research progress on meningeal metastasis in solid tumors. Discov Oncol 2025; 16:254. [PMID: 40019647 PMCID: PMC11871263 DOI: 10.1007/s12672-025-01950-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 11/08/2024] [Indexed: 03/01/2025] Open
Abstract
Meningeal metastasis (MM), particularly Leptomeningeal metastases (LM), represents the advanced stage of solid tumors and poses a significant threat to patients' lives. Moreover, it imposes a substantial burden on society. LM represents the ultimate and most fatal stage of solid tumors, inflicting devastating consequences on patients and imposing a substantial burden on society. The incidence of LM continues to rise annually, emphasizing the urgent need for early recognition and treatment initiation in individuals with LM to significantly extend overall patient survival. Despite rapid advancements in current LM detection and treatment methods, the diagnosis of LM remains constrained by several limitations such as low diagnostic efficiency, the therapeutic outcomes remain suboptimal. Furthermore, there is currently no universally recognized industry standard for LM treatment, further underscoring its status as an unresolved challenge in tumor management. Additionally, progress towards elucidating the mechanisms underlying MM has stagnated. Therefore, this review aims to comprehensively summarize recent research advances pertaining to MM in solid tumors by elucidating its underlying mechanisms, exploring diagnostic and prognostic biomarkers while addressing existing research challenges.
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Affiliation(s)
- Yi Yue
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yuqing Ren
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Chunya Lu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Nan Jiang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Sihui Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Junkai Fu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Mengrui Kong
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Guojun Zhang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
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6
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Sutherland L, Lang J, Gonzalez-Juarbe N, Pickett BE. Secondary Analysis of Human Bulk RNA-Seq Dataset Suggests Potential Mechanisms for Letrozole Resistance in Estrogen-Positive (ER+) Breast Cancer. Curr Issues Mol Biol 2024; 46:7114-7133. [PMID: 39057065 PMCID: PMC11275280 DOI: 10.3390/cimb46070424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 06/26/2024] [Accepted: 07/03/2024] [Indexed: 07/28/2024] Open
Abstract
Estrogen receptor-positive (ER+) breast cancer is common among postmenopausal women and is frequently treated with Letrozole, which inhibits aromatase from synthesizing estrogen from androgens. Decreased estrogen slows the growth of tumors and can be an effective treatment. The increase in Letrozole resistance poses a unique problem for patients. To better understand the underlying molecular mechanism(s) of Letrozole resistance, we reanalyzed transcriptomic data by comparing individuals who responded to Letrozole therapy (responders) to those who were resistant to treatment (non-responders). We identified SOX11 and S100A9 as two significant differentially expressed genes (DEGs) between these patient cohorts, with "PLK1 signaling events" being the most significant signaling pathway. We also identified PRDX4 and E2F8 gene products as being the top mechanistic transcriptional markers for ER+ treatment resistance. Many of the significant DEGs that we identified play a known role in ER+ breast cancer or other types of cancer, which partially validate our results. Several of the gene products we identified are novel in the context of ER+ breast cancer. Many of the genes that we identified warrant further research to elucidate the more specific molecular mechanisms of Letrozole resistance in this patient population and could potentially be used as prognostic markers with further wet lab validation. We anticipate that these findings could contribute to improved detection and therapeutic outcomes in aromatase-resistant ER+ breast cancer patients.
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Affiliation(s)
- Lincoln Sutherland
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA; (L.S.); (J.L.)
| | - Jacob Lang
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA; (L.S.); (J.L.)
| | - Norberto Gonzalez-Juarbe
- J. Craig Venter Institute, Rockville, MD 20850, USA;
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA
| | - Brett E. Pickett
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA; (L.S.); (J.L.)
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7
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Wei X, Liu J, Xu Z, Wang D, Zhu Q, Chen Q, Xu W. Research progress on the pharmacological mechanism, in vivo metabolism and structural modification of Erianin. Biomed Pharmacother 2024; 173:116295. [PMID: 38401517 DOI: 10.1016/j.biopha.2024.116295] [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: 11/28/2023] [Revised: 01/31/2024] [Accepted: 02/17/2024] [Indexed: 02/26/2024] Open
Abstract
Erianin is an important bibenzyl compound in dendrobium and has a wide spectrum of pharmacological properties. Since Erianin was discovered, abundant results have been achieved in the in vitro synthesis, structural modification, and pharmacological mechanism research. Researchers have developed a series of simple and efficient in vitro synthesis methods to improve the shortcomings of poor water solubility by replacing the chemical structure or coating it in nanomaterials. Erianin has a broad anti-tumor spectrum and significant anti-tumor effects. In addition, Erianin also has pharmacological actions like immune regulation, anti-inflammatory, and anti-angiogenesis. A comprehensive understanding of the synthesis, metabolism, structural modification, and pharmacological action pathways of Erianin is of great value for the utilization of Erianin. Therefore, this review conducts a relatively systematic look back at Erianin from the above four aspects, to give a reference for the evolvement and further appliance of Erianin.
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Affiliation(s)
- Xin Wei
- Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, PR China; University of Science and Technology of China, Hefei 230026, PR China
| | - Jiajia Liu
- University of Science and Technology of China, Hefei 230026, PR China; Department of Geriatrics, Gerontology Institute of Anhui Province, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, PR China
| | - Ziming Xu
- University of Science and Technology of China, Hefei 230026, PR China; Department of Ophthalmology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, PR China
| | - Dan Wang
- University of Science and Technology of China, Hefei 230026, PR China; Department of Geriatrics, Gerontology Institute of Anhui Province, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, PR China
| | - Qizhi Zhu
- Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, PR China; University of Science and Technology of China, Hefei 230026, PR China
| | - Qi Chen
- Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, PR China; University of Science and Technology of China, Hefei 230026, PR China
| | - Weiping Xu
- Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, PR China; University of Science and Technology of China, Hefei 230026, PR China; Department of Geriatrics, Gerontology Institute of Anhui Province, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, PR China; Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei 230001, PR China.
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8
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Changrong W, Zhibo Z, Jufeng G, Hongju Y, Feng Y, Jingjing X. Encapsulated Papillary Carcinoma of the Breast: A Review of Clinicopathologic Characteristics, Molecular Mechanisms, and Patient Management. Cancer Control 2024; 31:10732748241299071. [PMID: 39508178 PMCID: PMC11544663 DOI: 10.1177/10732748241299071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 10/09/2024] [Accepted: 10/23/2024] [Indexed: 11/08/2024] Open
Abstract
Encapsulated papillary carcinoma (EPC) represents a distinct entity within the spectrum of breast papillary tumors, typically manifesting as a retroareolar mass. This rare subtype can be effectively visualized using ultrasound and magnetic resonance imaging, which reveal characteristic cystic-solid nodules. Histopathologically, EPC is defined by a papillary tumor structure with a well-defined fibrous capsule, devoid of myoepithelial cells both within and around the capsule. Immunohistochemical staining for myoepithelial markers is essential to confirm the absence of these cells, thereby validating the diagnosis of EPC. At the molecular level, EPC exhibits feature similar to estrogen receptor-positive invasive ductal carcinoma (IDC), with a biological behavior that lies between ductal carcinoma in situ (DCIS) and IDC. Generally, EPC has a favorable prognosis, associated with minimal recurrence and metastatic potential. Therapeutic strategies for EPC may parallel those for DCIS, including surgical excision. Adjuvant radiotherapy is recommended following surgery for patients with concurrent DCIS or those who have undergone breast-conserving therapy. In cases with associated IDC, management prioritizes the treatment of the invasive component. High-grade EPC often requires systemic therapies due to its poorer prognosis and increased risk of lymph node involvement.
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Affiliation(s)
- Wang Changrong
- Department of Pathology, Affiliated Hangzhou First People’s Hospital, Westlake University School of Medicine, Hangzhou, China
| | - Zuo Zhibo
- Department of Pathology, Affiliated Hangzhou First People’s Hospital, Westlake University School of Medicine, Hangzhou, China
| | - Guo Jufeng
- Department of Breast Surgery, Affiliated Hangzhou First People’s Hospital, Westlake University School of Medicine, Hangzhou, China
| | - Yan Hongju
- Department of Ultrasound, Affiliated Hangzhou First People’s Hospital, Westlake University School of Medicine, Hangzhou, China
| | - You Feng
- Department of Radiology, Affiliated Hangzhou First People’s Hospital, Westlake University School of Medicine, Hangzhou, China
| | - Xiang Jingjing
- Department of Pathology, Affiliated Hangzhou First People’s Hospital, Westlake University School of Medicine, Hangzhou, China
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Cicero J, Trouvilliez S, Palma M, Ternier G, Decoster L, Happernegg E, Barois N, Van Outryve A, Dehouck L, Bourette RP, Adriaenssens E, Lagadec C, Tarhan CM, Collard D, Souguir Z, Vandenhaute E, Maubon G, Sipieter F, Borghi N, Shimizu F, Kanda T, Giacobini P, Gosselet F, Maubon N, Le Bourhis X, Van Seuningen I, Mysiorek C, Toillon RA. ProNGF promotes brain metastasis through TrkA/EphA2 induced Src activation in triple negative breast cancer cells. Exp Hematol Oncol 2023; 12:104. [PMID: 38072918 PMCID: PMC10710730 DOI: 10.1186/s40164-023-00463-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 11/29/2023] [Indexed: 10/16/2024] Open
Abstract
BACKGROUND Triple-Negative Breast Cancer is particularly aggressive, and its metastasis to the brain has a significant psychological impact on patients' quality of life, in addition to reducing survival. The development of brain metastases is particularly harmful in triple-negative breast cancer (TNBC). To date, the mechanisms that induce brain metastasis in TNBC are poorly understood. METHODS Using a human blood-brain barrier (BBB) in vitro model, an in vitro 3D organotypic extracellular matrix, an ex vivo mouse brain slices co-culture and in an in vivo xenograft experiment, key step of brain metastasis were recapitulated to study TNBC behaviors. RESULTS In this study, we demonstrated for the first time the involvement of the precursor of Nerve Growth Factor (proNGF) in the development of brain metastasis. More importantly, our results showed that proNGF acts through TrkA independent of its phosphorylation to induce brain metastasis in TNBC. In addition, we found that proNGF induces BBB transmigration through the TrkA/EphA2 signaling complex. More importantly, our results showed that combinatorial inhibition of TrkA and EphA2 decreased TBNC brain metastasis in a preclinical model. CONCLUSIONS These disruptive findings provide new insights into the mechanisms underlying brain metastasis with proNGF as a driver of brain metastasis of TNBC and identify TrkA/EphA2 complex as a potential therapeutic target.
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Affiliation(s)
- Julien Cicero
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
- Laboratoire de La Barrière Hémato-Encéphalique (LBHE), University of Artois, UR 2465, F-62300, Lens, France
- GdR2082 APPICOM- « Approche Intégrative Pour Une Compréhension Multi-Échelles de La Fonction Des Protéines Membranaires », Paris, France
| | - Sarah Trouvilliez
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
- GdR2082 APPICOM- « Approche Intégrative Pour Une Compréhension Multi-Échelles de La Fonction Des Protéines Membranaires », Paris, France
| | - Martine Palma
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
- GdR2082 APPICOM- « Approche Intégrative Pour Une Compréhension Multi-Échelles de La Fonction Des Protéines Membranaires », Paris, France
| | - Gaetan Ternier
- UMR-S1172, University of Lille, Inserm, CHU Lille, Équipe Développement et Plasticité du cerveau neuroendocrine, Lille Neuroscience et Cognition, 1 Place de Verdun, 59000, Lille Cedex, France
| | - Laurine Decoster
- UMR-S1172, University of Lille, Inserm, CHU Lille, Équipe Développement et Plasticité du cerveau neuroendocrine, Lille Neuroscience et Cognition, 1 Place de Verdun, 59000, Lille Cedex, France
| | - Eloise Happernegg
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
- Laboratoire de La Barrière Hémato-Encéphalique (LBHE), University of Artois, UR 2465, F-62300, Lens, France
- GdR2082 APPICOM- « Approche Intégrative Pour Une Compréhension Multi-Échelles de La Fonction Des Protéines Membranaires », Paris, France
| | - Nicolas Barois
- University of Lille, CNRS, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, 59000, Lille, Inserm, France
| | - Alexandre Van Outryve
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
- GdR2082 APPICOM- « Approche Intégrative Pour Une Compréhension Multi-Échelles de La Fonction Des Protéines Membranaires », Paris, France
- UMR 8520 -IEMN - Institut d'Electronique de Microélectronique et de Nanotechnologie, University of Lille, CNRS, Centrale Lille, Junia, University Polytechnique Hauts-de-France, 59000, Lille, France
| | - Lucie Dehouck
- Laboratoire de La Barrière Hémato-Encéphalique (LBHE), University of Artois, UR 2465, F-62300, Lens, France
| | - Roland P Bourette
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
| | - Eric Adriaenssens
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
| | - Chann Lagadec
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
- GdR2082 APPICOM- « Approche Intégrative Pour Une Compréhension Multi-Échelles de La Fonction Des Protéines Membranaires », Paris, France
| | - Cagatay Mehmet Tarhan
- UMR 8520 -IEMN - Institut d'Electronique de Microélectronique et de Nanotechnologie, University of Lille, CNRS, Centrale Lille, Junia, University Polytechnique Hauts-de-France, 59000, Lille, France
- LIMMS/CNRS-IIS IRL2820, The University of Tokyo, Tokyo, Japan
| | - Dominique Collard
- LIMMS/CNRS-IIS IRL2820, The University of Tokyo, Tokyo, Japan
- CNRS, IIS, University of Lille SMMiL-E Project, 59000, Lille, COL, France
| | | | | | | | - François Sipieter
- Université Paris Cité, Centre National de La Recherche Scientifique (CNRS), Institut Jacques Monod, 15 rue Hélène Brion, 75013, Paris, France
| | - Nicolas Borghi
- Université Paris Cité, Centre National de La Recherche Scientifique (CNRS), Institut Jacques Monod, 15 rue Hélène Brion, 75013, Paris, France
| | - Fumitaka Shimizu
- Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Takashi Kanda
- Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Paolo Giacobini
- UMR-S1172, University of Lille, Inserm, CHU Lille, Équipe Développement et Plasticité du cerveau neuroendocrine, Lille Neuroscience et Cognition, 1 Place de Verdun, 59000, Lille Cedex, France
| | - Fabien Gosselet
- Laboratoire de La Barrière Hémato-Encéphalique (LBHE), University of Artois, UR 2465, F-62300, Lens, France
| | | | - Xuefen Le Bourhis
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
| | - Isabelle Van Seuningen
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France
| | - Caroline Mysiorek
- Laboratoire de La Barrière Hémato-Encéphalique (LBHE), University of Artois, UR 2465, F-62300, Lens, France
| | - Robert-Alain Toillon
- UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, CNRS, Inserm, CHU Lille, Boulevard du Professeur Jules Leclercq, 59000, Lille, France.
- GdR2082 APPICOM- « Approche Intégrative Pour Une Compréhension Multi-Échelles de La Fonction Des Protéines Membranaires », Paris, France.
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10
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Othman AM, Abdel-Rahman N, Denewer M, Eissa LA. Sinapic acid and 3,3′-diindolylmethane potentiate cyclophosphamide antitumor activity through induction of apoptosis and inhibition of metastasis. Int Immunopharmacol 2023; 118:110074. [PMID: 36989898 DOI: 10.1016/j.intimp.2023.110074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 03/08/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023]
Abstract
AIM New therapeutic strategies are required to enhance the anticancer efficacy of chemotherapeutic drugs and to reduce their cytotoxicity. The purpose of this study was to assess the anti-tumor, antimetastatic and anti-apoptotic activities of sinapic acid (SA) and 3,3'-diindolylmethane (DIM) in solid Ehrlich carcinoma (SEC) induced in mice and combining SA or DIM compounds with cyclophosphamide (CYP). METHODS For induction of solid tumor, the right hind limbs of mice were inoculated subcutaneously with Ehrlich carcinoma cells. After 5 days of tumor inoculation, mice were treated with SA (56 mg/kg), DIM (40 mg/kg), CYP (10 mg/kg), and their combinations (SA/CYP) and (SA/DIM) for 21 days. The mRNA levels of Elabela, Serpina3, caspase-3, MMP-2 and MMP-9 were assessed by qPCR. Tumor and liver tissues were stained with hematoxylin and eosin for histological examination. Serum was investigated for ALT and AST activities. MAIN FINDINGS Treatment of SEC mice with SA and DIM significantly reduced solid tumor weight by 45.6% and 33.2%, respectively. They also reduced tumor size and increased life span of SEC mice. SA and DIM diminished area of metastatic nodules of tumor cells in the liver by 54.1% and 47.4%, respectively. They also reduced serum aminotransferases activities. Both SA and DIM were found to upregulate caspase 3 and downregulate MMP-2 and MMP-9. Furthermore, SA and DIM reduced gene expression of Elabela by (44.8% and 35.1%) and Serpina3 by (30.7% and 23.5%), respectively. SA and DIM were also shown to potentiate the anti-tumor activity CYP. SA and DIM showed promising antitumor effects and enhanced CYP antitumor activity mostly through upregulation of apoptotic caspase 3 and suppressing metastatic enzymes MMP-2 and MMP-9. Additionally, SA and DIM exhibited a hepatoprotective effect. Our results suggest that these natural compounds may be used to improve the efficacy and reduce the adverse effects of chemotherapeutic drugs in the treatment of solid malignancies.
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11
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Yang L, Dong Z, Li S, Chen T. ESM1 promotes angiogenesis in colorectal cancer by activating PI3K/Akt/mTOR pathway, thus accelerating tumor progression. Aging (Albany NY) 2023; 15:2920-2936. [PMID: 37100467 DOI: 10.18632/aging.204559] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 01/23/2023] [Indexed: 04/28/2023]
Abstract
BACKGROUND This study aimed to explore the influence of endothelial cell-specific molecule 1 (ESM1) expression on colorectal cancer (CRC) cells and preliminarily analyze its possible mechanism, so as to lay a foundation for research about potential biological targets of CRC. METHODS First, CRC cells were transfected with ESM1-negative control (NC), ESM1-mimic and ESM1-inhibitor and randomly assigned to ESM1-NC group, ESM1-mimic group and ESM1-inhibitor group, respectively. Then the cells were harvested at 48 h after transfection for subsequent experiments. RESULTS The results manifested that after up-regulation of ESM1, the distance of CRC SW480 and SW620 cell lines migrating to the scratch center rose notably, and the number of migrating cells, basement membrane-penetrating cells, colonies formed and angiogenesis was increased overtly, indicating that ESM1 overexpression can promote tumor angiogenesis in CRC and accelerate tumor progression. Combined with results of bioinformatics analysis, the molecular mechanism by which ESM1 promoted tumor angiogenesis in CRC and accelerated tumor progression was explored through suppressing the protein expression of phosphatidylinositol 3-kinase (PI3K). Western blotting revealed that after intervention with PI3K inhibitor, the protein expressions of phosphorylated PI3K (p-PI3K), phosphorylated protein kinase B (p-Akt) and phosphorylated mammalian target of rapamycin (p-mTOR) were decreased evidently, and the protein expressions of matrix metalloproteinase-2 (MMP-2), MMP-3, MMP-9, Cyclin D1, Cyclin A2, VEGF, COX-2 and HIF-1α subsequently declined. CONCLUSION ESM1 may promote angiogenesis in CRC by activating the PI3K/Akt/mTOR pathway, thus accelerating tumor progression.
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Affiliation(s)
- Liqun Yang
- General Surgery, Tangshan Fengnan District Hospital, Fengnan, Tangshan 063300, China
| | - Zhigang Dong
- General Surgery, Tangshan Fengnan District Hospital, Fengnan, Tangshan 063300, China
| | - Shuyu Li
- Two Divisions of The Cardiovascular Duct, Affiliated Hospital of North China University of Science and Technology, Lubei, Tangshan 063300, China
| | - Tieliang Chen
- General Surgery, Tangshan Union Hospital, Lunan, Tangshan 063300, China
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12
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Kondapaneni RV, Shevde LA, Rao SS. A Biomimetic Hyaluronic Acid Hydrogel Models Mass Dormancy in Brain Metastatic Breast Cancer Spheroids. Adv Biol (Weinh) 2023; 7:e2200114. [PMID: 36354182 DOI: 10.1002/adbi.202200114] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 08/15/2022] [Indexed: 11/11/2022]
Abstract
Approximately 90% of breast cancer related mortalities are due to metastasis to distant organs. At the metastatic sites, cancer cells are capable of evading death by exhibiting cellular or mass dormancy. However, the mechanisms involved in attaining dormancy at the metastatic site are not well understood. This is partly due to the lack of experimental models to study metastatic site-specific interactions, particularly in the context of brain metastatic breast cancer (BMBC). Herein, an in vitro hyaluronic acid (HA) hydrogel-based model is developed to study mass dormancy in BMBC. HA hydrogels with a stiffness of ≈0.4 kPa are utilized to mimic the brain extracellular matrix. MDA-MB-231Br or BT474Br3 BMBC spheroids are prepared and cultured on top of HA hydrogels or in suspension for 7 days. HA hydrogel induced a near mass dormant state in spheroids by achieving a balance between proliferating and dead cells. In contrast, these spheroids displayed growth in suspension cultures. The ratio of %p-ERK to %p-p38 positive cells is significantly lower in HA hydrogels compared to suspension cultures. Further, it is demonstrated that hydrogel induced mass dormant state is reversible. Overall, such models provide useful tools to study dormancy in BMBC and could be employed for drug screening.
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Affiliation(s)
- Raghu Vamsi Kondapaneni
- Department of Chemical and Biological Engineering, The University of Alabama, Tuscaloosa, AL, 35487, USA
| | - Lalita A Shevde
- Department of Pathology, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Shreyas S Rao
- Department of Chemical and Biological Engineering, The University of Alabama, Tuscaloosa, AL, 35487, USA
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13
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Lang J, Guo Z, Xing S, Sun J, Qiu B, Shu Y, Wang Z, Liu G. Inhibitory role of puerarin on the A549 lung cancer cell line. Transl Cancer Res 2022; 11:4117-4125. [PMID: 36523310 PMCID: PMC9745364 DOI: 10.21037/tcr-22-2246] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 10/21/2022] [Indexed: 09/26/2023]
Abstract
BACKGROUND Although more and more drugs had been proved to be effective in controlling tumor cells, lung cancer was still the leading cause of cancer-related deaths all over the world. This study aimed to investigate the effect and mechanism of puerarin on the invasion and metastasis of A549 lung cancer cell line. METHODS A medium containing puerarin was prepared according to the gradient concentration, and 10, 20, and 40 µmol/L were selected as the experimental group (low, medium, and high concentration groups, respectively) according to the cytotoxicity experiment. Meanwhile, 0 µmol/L was used as the control group. RESULTS Following administration, metastasis-related indexes were detected by the cell scratch test, cell migration test, gene difference detection, and western blotting. 24 hours after administration, the cell scratch and Transwell showed that the migration ability of A549 cells decreased with the increasing puerarin concentration. The polymerase chain reaction (PCR) and western blotting results demonstrated that the expression of the cell invasion and metastasis-related factor, matrix metallopeptidase 9 (MMP9), was negatively correlated with drug concentration. Further investigation demonstrated that the phosphorylation of extracellular signal-regulated kinase (ERK) was also inhibited. CONCLUSIONS Puerarin can inhibit the expression of invasion and metastasis-related factors by inhibiting the phosphorylation of ERK.
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Affiliation(s)
- Jie Lang
- Department of Thoracic Surgery, Tangshan People’s Hospital, Tangshan, China
| | - Zhizhen Guo
- Department of Nephrology, Kailuan General Hospital, Tangshan, China
| | - Shushan Xing
- Department of Oncology, Tangshan Central Hospital, Tangshan, China
| | - Jian Sun
- Department of Thoracic Surgery, Tangshan People’s Hospital, Tangshan, China
| | - Bin Qiu
- Department of Thoracic Surgery, Tangshan People’s Hospital, Tangshan, China
| | - Yu Shu
- Department of Thoracic Surgery, Tangshan People’s Hospital, Tangshan, China
| | - Zhiqiang Wang
- Department of Thoracic Surgery, Tangshan People’s Hospital, Tangshan, China
| | - Guixiang Liu
- Department of Thoracic Surgery, Tangshan People’s Hospital, Tangshan, China
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14
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Moorman HR, Reategui Y, Poschel DB, Liu K. IRF8: Mechanism of Action and Health Implications. Cells 2022; 11:2630. [PMID: 36078039 PMCID: PMC9454819 DOI: 10.3390/cells11172630] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/17/2022] [Accepted: 08/21/2022] [Indexed: 11/29/2022] Open
Abstract
Interferon regulatory factor 8 (IRF8) is a transcription factor of the IRF protein family. IRF8 was originally identified as an essentialfactor for myeloid cell lineage commitment and differentiation. Deletion of Irf8 leads to massive accumulation of CD11b+Gr1+ immature myeloid cells (IMCs), particularly the CD11b+Ly6Chi/+Ly6G- polymorphonuclear myeloid-derived suppressor cell-like cells (PMN-MDSCs). Under pathological conditions such as cancer, Irf8 is silenced by its promoter DNA hypermethylation, resulting in accumulation of PMN-MDSCs and CD11b+ Ly6G+Ly6Clo monocytic MDSCs (M-MDSCs) in mice. IRF8 is often silenced in MDSCs in human cancer patients. MDSCs are heterogeneous populations of immune suppressive cells that suppress T and NK cell activity to promote tumor immune evasion and produce growth factors to exert direct tumor-promoting activity. Emerging experimental data reveals that IRF8 is also expressed in non-hematopoietic cells. Epithelial cell-expressed IRF8 regulates apoptosis and represses Osteopontin (OPN). Human tumor cells may use the IRF8 promoter DNA methylation as a mechanism to repress IRF8 expression to advance cancer through acquiring apoptosis resistance and OPN up-regulation. Elevated OPN engages CD44 to suppress T cell activation and promote tumor cell stemness to advance cancer. IRF8 thus is a transcription factor that regulates both the immune and non-immune components in human health and diseases.
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Affiliation(s)
- Hannah R. Moorman
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA
| | - Yazmin Reategui
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA
| | - Dakota B. Poschel
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA
- Georgia Cancer Center, Augusta, GA 30912, USA
- Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
| | - Kebin Liu
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA
- Georgia Cancer Center, Augusta, GA 30912, USA
- Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
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15
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Bunnell BA, Martin EC, Matossian MD, Brock CK, Nguyen K, Collins-Burow B, Burow ME. The effect of obesity on adipose-derived stromal cells and adipose tissue and their impact on cancer. Cancer Metastasis Rev 2022; 41:549-573. [PMID: 35999486 DOI: 10.1007/s10555-022-10063-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 08/16/2022] [Indexed: 11/24/2022]
Abstract
The significant increase in the incidence of obesity represents the next global health crisis. As a result, scientific research has focused on gaining deeper insights into obesity and adipose tissue biology. As a result of the excessive accumulation of adipose tissue, obesity results from hyperplasia and hypertrophy within the adipose tissue. The functional alterations in the adipose tissue are a confounding contributing factor to many diseases, including cancer. The increased incidence and aggressiveness of several cancers, including colorectal, postmenopausal breast, endometrial, prostate, esophageal, hematological, malignant melanoma, and renal carcinomas, result from obesity as a contributing factor. The increased morbidity and mortality of obesity-associated cancers are attributable to increased hormones, adipokines, and cytokines produced by the adipose tissue. The increased adipose tissue levels observed in obese patients result in more adipose stromal/stem cells (ASCs) distributed throughout the body. ASCs have been shown to impact cancer progression in vitro and in preclinical animal models. ASCs influence tumor biology via multiple mechanisms, including the increased recruitment of ASCs to the tumor site and increased production of cytokines and growth factors by ASCs and other cells within the tumor stroma. Emerging evidence indicates that obesity induces alterations in the biological properties of ASCs, subsequently leading to enhanced tumorigenesis and metastasis of cancer cells. As the focus of this review is the interaction and impact of ASCs on cancer, the presentation is limited to preclinical data generated on cancers in which there is a demonstrated role for ASCs, such as postmenopausal breast, colorectal, prostate, ovarian, multiple myeloma, osteosarcoma, cervical, bladder, and gastrointestinal cancers. Our group has investigated the interactions between obesity and breast cancer and the mechanisms that regulate ASCs and adipocytes in these different contexts through interactions between cancer cells, immune cells, and other cell types present in the tumor microenvironment (TME) are discussed. The reciprocal and circular feedback loop between obesity and ASCs and the mechanisms by which ASCs from obese patients alter the biology of cancer cells and enhance tumorigenesis will be discussed. At present, the evidence for ASCs directly influencing human tumor growth is somewhat limited, though recent clinical studies suggest there may be some link.
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Affiliation(s)
- Bruce A Bunnell
- Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX, 76107, USA.
| | - Elizabeth C Martin
- Department of Biological and Agricultural Engineering, Louisiana State University, Baton Rouge, LA, USA
| | - Margarite D Matossian
- Department of Microbiology, Immunology and Genetics, University of Chicago, IL, Chicago, USA
| | - Courtney K Brock
- Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Khoa Nguyen
- Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Bridgette Collins-Burow
- Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Matthew E Burow
- Section of Hematology and Oncology, Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
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16
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Cheng T, Chen P, Chen J, Deng Y, Huang C. Landscape Analysis of Matrix Metalloproteinases Unveils Key Prognostic Markers for Patients With Breast Cancer. Front Genet 2022; 12:809600. [PMID: 35069702 PMCID: PMC8770541 DOI: 10.3389/fgene.2021.809600] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 12/16/2021] [Indexed: 12/15/2022] Open
Abstract
Breast cancer (BRCA) is the most common cancer in the world, of which incidence rate and mortality are the highest in women. Being responsible for the remodeling and degradation of extracellular matrix proteins, matrix metalloproteinases (MMPs) have been regarded as one of the most important protease family related to tumorigenesis. It has been demonstrated that MMPs play crucial roles in some tumor invasion and metastasis. However, the potential roles of MMPs in tumorigenesis and progression of BRCA and its subtype remain elusive. Herein, we conducted a systematic study on MMPs via a series of database-based retrospective analysis, including TCGA, R Studio, GEPIA, Kaplan-Meier Plotter, cBioPortal, STRING, GeneMANIA and TIMER. As a result, many MMP family members were differentially expressed in patients with BRCA, e.g., the expressions of MMP1, MMP9, MMP11 and MMP13 were up-regulated, whereas the expression levels of MMP19 and MMP28 were down-regulated. MMP9, MMP12, MMP15 and MMP27 were significantly correlated with the clinical stages of BRCA, implying their important roles in the occurrence and development of BRCA. In addition, the survival analysis indicated that different expression pattern of MMPs exhibited distinct outcomes in patient with BRCA, e.g., patients with high expression of MMP2, MMP8, MMP16, MMP17, MMP19, MMP20, MMP21, MMP24, MMP25, MMP26 and MMP27 had a prolonged survival time, while the others (MMP1, MMP7, MMP9, MMP12 and MMP15) exhibited poor prognosis. Subsequent functional and network analysis revealed MMPs were mainly correlated with parathyroid hormone synthesis and secretion pathway, collagen metabolism, and their effect on the activities of serine hydrolase, serine peptidase and aminopeptidase. Notably, our analysis showed that the expression of MMPs was significantly correlated with the infiltration of various immune cells in BRCA, including CD8+T cells, CD4+T cells, macrophages, neutrophils, B cells, and dendritic cells, suggesting the close correlations between MMPs and immune functions. In short, our study disclosed MMPs play multiple biological roles in the development of BRCA, MMP1 and MMP9 might be used as independent prognostic markers and potential therapeutic targets for diagnosis and treatment for patients with BRCA.
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Affiliation(s)
- Tianyi Cheng
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
| | - Peiying Chen
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
| | - Jingyi Chen
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
| | - Yingtong Deng
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China
| | - Chen Huang
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China.,Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China
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17
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Jusino S, Rivera-Rivera Y, Chardón-Colón C, Ruiz-Justiz AJ, Vélez-Velázquez J, Isidro A, Cruz-Robles ME, Bonilla-Claudio M, Armaiz-Pena GN, Saavedra HI. E2F3 drives the epithelial-to-mesenchymal transition, cell invasion, and metastasis in breast cancer. Exp Biol Med (Maywood) 2021; 246:2057-2071. [PMID: 34365840 PMCID: PMC8524769 DOI: 10.1177/15353702211035693] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 07/12/2021] [Indexed: 12/30/2022] Open
Abstract
E2F3 is a transcription factor that may initiate tumorigenesis if overexpressed. Previously, we demonstrated that E2F3 mRNA is overexpressed in breast cancer and that E2F3 overexpression results in centrosome amplification and unregulated mitosis, which can promote aneuploidy and chromosome instability to initiate and sustain tumors. Further, we demonstrated that E2F3 leads to overexpression of the mitotic regulator Shugoshin-1, which until recently had unknown roles in cancer. This study aims to evaluate the roles of E2F3 and Shugoshin-1 in breast cancer metastatic potential. Here we demonstrated that E2F3 and Shugoshin-1 silencing leads to reduced cell invasion and migration in two mesenchymal triple-negative breast cancer (TNBC) cell lines (MDA-MB-231 and Hs578t). Moreover, E2F3 and Shugoshin-1 modulate the expression of epithelial-to-mesenchymal transition-associated genes such as Snail, E-Cadherin, and multiple matrix metalloproteinases. Furthermore, E2F3 depletion leads to reductions in tumor growth and metastasis in NOD-scid Gamma mice. Results from this study suggest a key role for E2F3 and a novel role for Shugoshin-1 in metastatic progression. These results can further help in the improvement of TNBC targeted therapies by interfering with pathways that intersect with the E2F3 and Shugoshin-1 signaling pathways.
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Affiliation(s)
- Shirley Jusino
- Department of Basic Sciences, Division of Pharmacology and Cancer Biology, Ponce Health Sciences University-Ponce Research Institute, Ponce 00716-2348, Puerto Rico
| | - Yainyrette Rivera-Rivera
- Department of Basic Sciences, Division of Pharmacology and Cancer Biology, Ponce Health Sciences University-Ponce Research Institute, Ponce 00716-2348, Puerto Rico
| | - Camille Chardón-Colón
- Department of Basic Sciences, Division of Biochemistry, Ponce Health Sciences University-Ponce Research Institute, Ponce 00716-2348, Puerto Rico
| | | | | | - Angel Isidro
- Department of Basic Sciences, Division of Physiology, Ponce Health Sciences University-Ponce Research Institute, Ponce 00716-2348, Puerto Rico
| | - Melanie E Cruz-Robles
- Department of Basic Sciences, Division of Microbiology, Ponce Health Sciences University-Ponce Research Institute, Ponce 00716-2348, Puerto Rico
| | - Margarita Bonilla-Claudio
- Department of Basic Sciences, Division of Pharmacology and Cancer Biology, Ponce Health Sciences University-Ponce Research Institute, Ponce 00716-2348, Puerto Rico
| | - Guillermo N Armaiz-Pena
- Department of Basic Sciences, Division of Pharmacology and Cancer Biology, Ponce Health Sciences University-Ponce Research Institute, Ponce 00716-2348, Puerto Rico
| | - Harold I Saavedra
- Department of Basic Sciences, Division of Pharmacology and Cancer Biology, Ponce Health Sciences University-Ponce Research Institute, Ponce 00716-2348, Puerto Rico
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18
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Targeting matrix metalloproteinase MMP3 greatly enhances oncolytic virus mediated tumor therapy. Transl Oncol 2021; 14:101221. [PMID: 34530193 PMCID: PMC8450250 DOI: 10.1016/j.tranon.2021.101221] [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: 09/01/2021] [Accepted: 09/07/2021] [Indexed: 11/22/2022] Open
Abstract
In cancer, the extracellular matrix is extensively remodeled during chronic inflammation, thus affecting cell transcription, differentiation, migration and cell-cell interactions. Matrix metalloproteinases can degrade the extracellular matrix of tumor tissues and take important roles in disease progression. Numerous efforts to develop cancer treatments targeting matrix metalloproteinases have failed in clinical trials owing to the ineffectiveness and toxicity of the applied inhibitors. In this study, we investigated the potential of targeting matrix metalloproteinases and oncolytic virus combination in cancer therapy. We found that MMP3 expression was upregulated in various cancers and MMP3 expression in the tumor cells, but not in other tissues, was important for tumor growth and metastasis. Single treatment of colon cancer with multiple MMP3 inhibitors was not effective in mice. Nevertheless, the therapeutic effect of MMP3 was greatly improved by combination with an oncolytic virus. A potential mechanism of MMP3 in regulating tumor cell proliferation and invasion was mediated via Erk1/2 an NF-κB signaling. This study reveals that MMP3 is a promising target and the combined treatment with oncolytic virus is a potential strategy for cancer therapy.
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19
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Guan Z, Lan H, Cai X, Zhang Y, Liang A, Li J. Blood-Brain Barrier, Cell Junctions, and Tumor Microenvironment in Brain Metastases, the Biological Prospects and Dilemma in Therapies. Front Cell Dev Biol 2021; 9:722917. [PMID: 34504845 PMCID: PMC8421648 DOI: 10.3389/fcell.2021.722917] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 07/16/2021] [Indexed: 12/25/2022] Open
Abstract
Brain metastasis is the most commonly seen brain malignancy, frequently originating from lung cancer, breast cancer, and melanoma. Brain tumor has its unique cell types, anatomical structures, metabolic constraints, and immune environment, which namely the tumor microenvironment (TME). It has been discovered that the tumor microenvironment can regulate the progression, metastasis of primary tumors, and response to the treatment through the particular cellular and non-cellular components. Brain metastasis tumor cells that penetrate the brain–blood barrier and blood–cerebrospinal fluid barrier to alter the function of cell junctions would lead to different tumor microenvironments. Emerging evidence implies that these tumor microenvironment components would be involved in mechanisms of immune activation, tumor hypoxia, antiangiogenesis, etc. Researchers have applied various therapeutic strategies to inhibit brain metastasis, such as the combination of brain radiotherapy, immune checkpoint inhibitors, and monoclonal antibodies. Unfortunately, they hardly access effective treatment. Meanwhile, most clinical trials of target therapy patients with brain metastasis are always excluded. In this review, we summarized the clinical treatment of brain metastasis in recent years, as well as their influence and mechanisms underlying the differences between the composition of tumor microenvironments in the primary tumor and brain metastasis. We also look forward into the feasibility and superiority of tumor microenvironment-targeted therapies in the future, which may help to improve the strategy of brain metastasis treatment.
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Affiliation(s)
- Zhiyuan Guan
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Hongyu Lan
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xin Cai
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yichi Zhang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Annan Liang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jin Li
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Chin LT, Liu KW, Chen YH, Hsu SC, Huang L. Cell-based assays and molecular simulation reveal that the anti-cancer harmine is a specific matrix metalloproteinase-3 (MMP-3) inhibitor. Comput Biol Chem 2021; 94:107556. [PMID: 34384998 DOI: 10.1016/j.compbiolchem.2021.107556] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/20/2021] [Accepted: 07/29/2021] [Indexed: 10/20/2022]
Abstract
The biological activities of harmine have been a much clearer picture in recent years, which include anti-tumor, anti-inflammation and cytotoxic properties. Numerous in vitro and in vivo animal models have confirmed its activities, but its mode of action remains a relative unsolved issue. We therefore investigated harmine for its effects on MMP-3 and the molecular interaction was also simulated. The human glioma cancer cell line, U-87 MG cells, was subjected to different concentrations (1-10 μM) of harmine for 24 h. Methylthiazol tetrazolium (MTT) test, half maximal inhibitory concentration (IC50), western blot analysis, enzyme-linked immunosorbent assay and molecular docking through BIOVIA DiscoveryStudio™ were performed. These results showed that although harmine stimulation in vitro has very little or no effects on MMP-3 expression by U-87 MG cells, the treatment of harmine decreases MMP-3 activity in a dose dependent manner. It was further calculated that 7.9 μM is the IC50 towards MMP-3. Using a molecular dynamic simulation approach, we identified the N2, methyl of C1 and benzene ring of harmine interact with Zn2+ (2.4 Å), His205 (2.4 Å) and His211 (2.4 Å) as well as Val163 (2.7 Å) at the active site of MMP-3, respectively, and thus conferred a striking specific binding advantage. Taken altogether, the present study evidences that harmine acts as an MMP-3 inhibitor specially targeting the enzymatic active site and possibly efficiently ameliorates MMP-3-driven malignant and inflammatory diseases.
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Affiliation(s)
- Li-Te Chin
- Department of Microbiology, Immunology and Biopharmaceuticals, National Chiayi University, Chiayi City, 60004, Taiwan, ROC; Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei City, 11400, Taiwan, ROC
| | - Ke-Wei Liu
- Department of Microbiology, Immunology and Biopharmaceuticals, National Chiayi University, Chiayi City, 60004, Taiwan, ROC
| | - Yi-Han Chen
- Department of Microbiology, Immunology and Biopharmaceuticals, National Chiayi University, Chiayi City, 60004, Taiwan, ROC
| | - Shu-Ching Hsu
- Synergy Biomedical Corp., Hsinchu City, 30054, Taiwan, ROC
| | - Lin Huang
- Synergy Biomedical Corp., Hsinchu City, 30054, Taiwan, ROC.
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21
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Kanumuri R, Chelluboyina AK, Biswal J, Vignesh R, Pandian J, Venu A, Vaishnavi B, Leena DJ, Jeyaraman J, Ganesan K, Aradhyam GK, Venkatraman G, Rayala SK. Small peptide inhibitor from the sequence of RUNX3 disrupts PAK1-RUNX3 interaction and abrogates its phosphorylation-dependent oncogenic function. Oncogene 2021; 40:5327-5341. [PMID: 34253860 DOI: 10.1038/s41388-021-01927-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 06/09/2021] [Accepted: 06/24/2021] [Indexed: 02/06/2023]
Abstract
P21 Activated Kinase 1 (PAK1) is an oncogenic serine/threonine kinase known to play a significant role in the regulation of cytoskeleton and cell morphology. Runt-related transcription factor 3 (RUNX3) was initially known for its tumor suppressor function, but recent studies have reported the oncogenic role of RUNX3 in various cancers. Previous findings from our laboratory provided evidence that Threonine 209 phosphorylation of RUNX3 acts as a molecular switch in dictating the tissue-specific dualistic functions of RUNX3 for the first time. Based on these proofs and to explore the translational significance of these findings, we designed a small peptide (RMR) from the protein sequence of RUNX3 flanking the Threonine 209 phosphorylation site. The selection of this specific peptide from multiple possible peptides was based on their binding energies, hydrogen bonding, docking efficiency with the active site of PAK1 and their ability to displace PAK1-RUNX3 interaction in our prediction models. We found that this peptide is stable both in in vitro and in vivo conditions, not toxic to normal cells and inhibits the Threonine 209 phosphorylation in RUNX3 by PAK1. We also tested the efficacy of this peptide to block the RUNX3 Threonine 209 phosphorylation mediated tumorigenic functions in in vitro cell culture models, patient-derived explant (PDE) models and in in vivo tumor xenograft models. These results proved that this peptide has the potential to be developed as an efficient therapeutic molecule for targeting RUNX3 Threonine 209 phosphorylation-dependent tumor phenotypes.
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Affiliation(s)
- Rahul Kanumuri
- Department of Biotechnology, Indian Institute of technology Madras (IITM), Chennai, Tamilnadu, India
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences & Technology, Sri Ramachandra Institute of Higher Education & Research (Deemed to be University), Porur, Chennai, Tamilnadu, India
| | - Aruna Kumar Chelluboyina
- Department of Biotechnology, Indian Institute of technology Madras (IITM), Chennai, Tamilnadu, India
- Division of General Medical Sciences - Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Jayashree Biswal
- Structural Biology and Bio-Computing Lab, Department of Bioinformatics, Science Block, Alagappa University, Karaikudi, India
| | - Ravichandran Vignesh
- Department of Biotechnology, Indian Institute of technology Madras (IITM), Chennai, Tamilnadu, India
| | - Jaishree Pandian
- Unit of Excellence in Cancer Genetics, Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, India
| | - Akkanapally Venu
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences & Technology, Sri Ramachandra Institute of Higher Education & Research (Deemed to be University), Porur, Chennai, Tamilnadu, India
| | - B Vaishnavi
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences & Technology, Sri Ramachandra Institute of Higher Education & Research (Deemed to be University), Porur, Chennai, Tamilnadu, India
| | - D J Leena
- Department of Pathology, Sri Ramachandra Institute of Higher Education & Research (Deemed to be University), Porur, Chennai, Tamilnadu, India
| | - Jeyakanthan Jeyaraman
- Structural Biology and Bio-Computing Lab, Department of Bioinformatics, Science Block, Alagappa University, Karaikudi, India
| | - Kumaresan Ganesan
- Unit of Excellence in Cancer Genetics, Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, India
| | - Gopala Krishna Aradhyam
- Department of Biotechnology, Indian Institute of technology Madras (IITM), Chennai, Tamilnadu, India
| | - Ganesh Venkatraman
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences & Technology, Sri Ramachandra Institute of Higher Education & Research (Deemed to be University), Porur, Chennai, Tamilnadu, India.
| | - Suresh K Rayala
- Department of Biotechnology, Indian Institute of technology Madras (IITM), Chennai, Tamilnadu, India.
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Chen X, Zhang L, Yuan M, Kuang Z, Zou Y, Tang T, Zhang W, Hu X, Xia T, Cao T, Jia H. Sam68 Promotes the Progression of Human Breast Cancer through inducing Activation of EphA3. Curr Cancer Drug Targets 2021; 20:76-83. [PMID: 31433759 DOI: 10.2174/1568009619666190718124541] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Revised: 04/08/2019] [Accepted: 06/28/2019] [Indexed: 12/26/2022]
Abstract
BACKGROUND Src associated with mitosis of 68 kDa (Sam68), is often highly expressed in human cancers. Overexpression of Sam68 has been shown to be correlated with poor survival prognosis in some cancer patients. However, little is known whether Sam68 plays a role in promoting metastasis in breast cancer. MATERIALS AND METHODS The expression of Sam68 protein in breast cancer tissue was detected by immunohistochemistry. Trans-well assay, wound-healing, real-time PCR and Western blotting analysis were used to detect the effect of Sam68 on promoting EMT or metastasis of breast cancer. Next-generation RNA sequencing was used to analyze genes that may be regulated by Sam68. RESULTS Sam68 plays a positive role in promoting breast cancer metastasis. Sam68 was found to be overexpressed in breast cancer along with lymph node metastasis. MMP-9 was also found to be overexpressed in breast cancer tissue and was correlated to the expression of Sam68 (P<0.01). Xenograft in NOD/SCID mice and in vitro experiments confirmed that the invasion and metastatic ability of breast cancer cells were regulated by Sam68. And EPHA3 could be up-regulated by Sam68 in breast cancer. CONCLUSION High expression of Sam68 participates in breast cancer metastasis by up-regulating the EPHA3 gene.
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Affiliation(s)
- Xinxin Chen
- Department of Breast Surgery, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Lehong Zhang
- Department of Breast Surgery, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Min Yuan
- Department of Breast Surgery, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Ziqiao Kuang
- Department of Breast Surgery, Huadu District People's Hospital of Guangzhou, Guangdong, China
| | - Ying Zou
- Department of Environmental Health Sciences, University at Albany, State University of New York, Rensselaer, NY, United States
| | - Tian Tang
- Department of Pathology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Wangjian Zhang
- Department of Environmental Health Sciences, University at Albany, State University of New York, Rensselaer, NY, United States
| | - Xiaowu Hu
- Department of Breast Surgery, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Ting Xia
- Department of Breast Surgery, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Tengfei Cao
- Department of Breast Surgery, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Haixia Jia
- Department of Breast Surgery, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
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Zhang J, Zhang F, Fan J, Feng B. TGIF1 Knockdown Inhibits the Proliferation and Invasion of Gastric Cancer via AKT Signaling Pathway. Cancer Manag Res 2021; 13:2603-2612. [PMID: 33776478 PMCID: PMC7987261 DOI: 10.2147/cmar.s254348] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 12/19/2020] [Indexed: 11/26/2022] Open
Abstract
Introduction Gastric cancer is a kind of cancer with high mortality. TGIF1, as a transcription inhibitor, can inhibit the transcription of specific genes. The purpose of this study was to investigate the role of TGIF1 in gastric cancer by knocking down TGIF1. Methods The expression of TGIF1 was detected by qPCR and Western blotting; CCK8 assay, colony formation assay, transwell, and wound-healing assay were used to evaluate the proliferation, migration, and invasion of gastric cancer cells; cell apoptosis was analyzed by flow cytometry and Hoechst-PI double staining; cell cycle was detected by flow cytometry. Gelatinase experiment was performed to detect the expression level of MMP-2; apoptosis related proteins and AKT singling pathway were assessed by Western blotting. Results Knockdown of TGIF1 inhibited the proliferation, migration, and invasion of gastric cancer cells and promoted apoptosis. TGIF1 knockdown down-regulated the expression levels of MMP-2, Bcl2, CyclinD1, and p-Akt, and up-regulated the expression levels of Bax and Caspase3. These data suggested that knockdown of TGIF1 inhibited the development of gastric cancer via AKT signaling pathway. Conclusion TGIF1 knockdown inhibited the proliferation, migration, and invasion and promoted apoptosis of gastric cancer cells via the AKT signaling pathway, suggesting that TGIF1 is considered a potential inhibitor in gastric cancer.
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Affiliation(s)
- Jing Zhang
- Pharmacy Department, Hebei Chemical and Pharmaceutical College, Shijiazhuang, Hebei 050026, People's Republic of China
| | - Feiyan Zhang
- Department of Outpatient Operating Room, Heze Municipal Hospital, Heze City, Shandong Province, 274000, People's Republic of China
| | - Jiye Fan
- Department of Pharmaceutical Engineering, Hebei Chemical and Pharmaceutical College, Shijiazhuang, Hebei 050026, People's Republic of China.,College of Life Science, Hebei Normal University, Shijiazhuang, Hebei 050024, People's Republic of China
| | - Bin Feng
- Department of Gastrointestinal Surgery, Heze Municipal Hospital, Heze City, 274000 Shandong Province, People's Republic of China
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24
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Wang M, Nai MH, Huang RYJ, Leo HL, Lim CT, Chen CH. High-throughput functional profiling of single adherent cells via hydrogel drop-screen. LAB ON A CHIP 2021; 21:764-774. [PMID: 33506832 DOI: 10.1039/d0lc01294g] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
Single-adherent-cell phenotyping on an extracellular matrix (ECM) is essential to determine cellular biological functions, such as morphological adaptations and biomolecule secretions, correlated to medical treatments and metastasis, yet there is no available platform for such high-throughput screening. Here, a novel hydrogel drop-screen device was developed to rapidly measure large-scale single-cell morphologies and multiple secretions on substrates for phenotype profiling. Single cells were first anchored to microfluidically fabricated gelatin particles providing mechanical stimulations similar to those from ECM in vivo. The cellular morphologies were then examined by quantifying the amount of cytoskeleton expressed on the particles. With droplet encapsulation, adherent single-cell multiplexed secretion analysis of a disintegrin and metalloproteinases (ADAMs) and matrix metalloproteinases (MMPs) was conducted at a throughput of ∼102 cells per second, revealing distinct functional heterogeneities associated with extracellular mechanical stimulations. The level of cell heterogeneity increased with increasing substrate stuffiness. Moreover, because of the promising screening capability, a database related to both nontumorigenic and tumorigenic breast cells (MCF10A, MCF-7, and MDA-MB-231) was constructed. The respective cell distributions and heterogeneities based on the morphologies and secreted bioindicators, such as MMP-2, MMP-3, MMP-9, and ADAM-8, were measured and found to correspond to the progress of tumor metastasis.
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Affiliation(s)
- Ming Wang
- NUS Graduate School for Integrative Sciences & Engineering, National University of Singapore, 21 Lower Kent Ridge Road, 119077 Singapore and Department of Biomedical Engineering, National University of Singapore, 4 Engineering Drive 3, 117583 Singapore and Institute for Health Innovation and Technology (iHealthtech), MD6, 14 Medical Drive 14-01, 117599 Singapore
| | - Mui Hoon Nai
- Department of Biomedical Engineering, National University of Singapore, 4 Engineering Drive 3, 117583 Singapore
| | - Ruby Yun-Ju Huang
- College of Medicine, National Taiwan University, No.1 Jen-Ai Road, Taipei, 10051, Taiwan and Graduate Institute of Oncology, College of Medicine, National Taiwan University, No. 1, Sec. 4, Roosevelt road, Taipei, 10617, Taiwan and Department of Biomedical Engineering, National Taiwan University, No.1, Sec.1, Jen-Ai Road, Taipei, 10051, Taiwan
| | - Hwa Liang Leo
- NUS Graduate School for Integrative Sciences & Engineering, National University of Singapore, 21 Lower Kent Ridge Road, 119077 Singapore and Department of Biomedical Engineering, National University of Singapore, 4 Engineering Drive 3, 117583 Singapore
| | - Chwee Teck Lim
- NUS Graduate School for Integrative Sciences & Engineering, National University of Singapore, 21 Lower Kent Ridge Road, 119077 Singapore and Department of Biomedical Engineering, National University of Singapore, 4 Engineering Drive 3, 117583 Singapore and Institute for Health Innovation and Technology (iHealthtech), MD6, 14 Medical Drive 14-01, 117599 Singapore and Mechanobiology Institute, National University of Singapore, 117411 Singapore
| | - Chia-Hung Chen
- Department of Biomedical Engineering, City University of Hong Kong, Y6700, 83 Tat Chee Avenue, Hong Kong SAR, China.
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25
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Kuriyama H, Fukushima S, Kimura T, Kanemaru H, Miyashita A, Okada E, Kubo Y, Nakahara S, Tokuzumi A, Nishimura Y, Kajihara I, Makino K, Aoi J, Masuguchi S, Tsukamoto H, Inozume T, Zhang R, Nakatsura T, Uemura Y, Senju S, Ihn H. Immunotherapy with 4-1BBL-Expressing iPS Cell-Derived Myeloid Lines Amplifies Antigen-Specific T Cell Infiltration in Advanced Melanoma. Int J Mol Sci 2021; 22:1958. [PMID: 33669419 PMCID: PMC7920470 DOI: 10.3390/ijms22041958] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 02/11/2021] [Accepted: 02/15/2021] [Indexed: 11/16/2022] Open
Abstract
We have established an immune cell therapy with immortalized induced pluripotent stem-cell-derived myeloid lines (iPS-ML). The benefits of using iPS-ML are the infinite proliferative capacity and ease of genetic modification. In this study, we introduced 4-1BBL gene to iPS-ML (iPS-ML-41BBL). The analysis of the cell-surface molecules showed that the expression of CD86 was upregulated in iPS-ML-41BBL more than that in control iPS-ML. Cytokine array analysis was performed using supernatants of the spleen cells that were cocultured with iPS-ML or iPS-ML-41BBL. Multiple cytokines that are beneficial to cancer immunotherapy were upregulated. Peritoneal injections of iPS-ML-41BBL inhibited tumor growth of peritoneally disseminated mouse melanoma and prolonged survival of mice compared to that of iPS-ML. Furthermore, the numbers of antigen-specific CD8+ T cells were significantly increased in the spleen and tumor tissues treated with epitope peptide-pulsed iPS-ML-41BBL compared to those treated with control iPS-ML. The number of CXCR6-positive T cells were increased in the tumor tissues after treatment with iPS-ML-41BBL compared to that with control iPS-ML. These results suggest that iPS-ML-41BBL could activate antigen-specific T cells and promote their infiltration into the tumor tissues. Thus, iPS-ML-41BBL may be a candidate for future immune cell therapy aiming to change immunological "cold tumor" to "hot tumor".
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Affiliation(s)
- Haruka Kuriyama
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (H.K.); (T.K.); (H.K.); (A.M.); (E.O.); (Y.K.); (S.N.); (A.T.); (Y.N.); (I.K.); (K.M.); (J.A.); (S.M.); (H.I.)
| | - Satoshi Fukushima
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (H.K.); (T.K.); (H.K.); (A.M.); (E.O.); (Y.K.); (S.N.); (A.T.); (Y.N.); (I.K.); (K.M.); (J.A.); (S.M.); (H.I.)
| | - Toshihiro Kimura
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (H.K.); (T.K.); (H.K.); (A.M.); (E.O.); (Y.K.); (S.N.); (A.T.); (Y.N.); (I.K.); (K.M.); (J.A.); (S.M.); (H.I.)
| | - Hisashi Kanemaru
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (H.K.); (T.K.); (H.K.); (A.M.); (E.O.); (Y.K.); (S.N.); (A.T.); (Y.N.); (I.K.); (K.M.); (J.A.); (S.M.); (H.I.)
| | - Azusa Miyashita
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (H.K.); (T.K.); (H.K.); (A.M.); (E.O.); (Y.K.); (S.N.); (A.T.); (Y.N.); (I.K.); (K.M.); (J.A.); (S.M.); (H.I.)
| | - Etsuko Okada
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (H.K.); (T.K.); (H.K.); (A.M.); (E.O.); (Y.K.); (S.N.); (A.T.); (Y.N.); (I.K.); (K.M.); (J.A.); (S.M.); (H.I.)
| | - Yosuke Kubo
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (H.K.); (T.K.); (H.K.); (A.M.); (E.O.); (Y.K.); (S.N.); (A.T.); (Y.N.); (I.K.); (K.M.); (J.A.); (S.M.); (H.I.)
| | - Satoshi Nakahara
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (H.K.); (T.K.); (H.K.); (A.M.); (E.O.); (Y.K.); (S.N.); (A.T.); (Y.N.); (I.K.); (K.M.); (J.A.); (S.M.); (H.I.)
| | - Aki Tokuzumi
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (H.K.); (T.K.); (H.K.); (A.M.); (E.O.); (Y.K.); (S.N.); (A.T.); (Y.N.); (I.K.); (K.M.); (J.A.); (S.M.); (H.I.)
| | - Yuki Nishimura
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (H.K.); (T.K.); (H.K.); (A.M.); (E.O.); (Y.K.); (S.N.); (A.T.); (Y.N.); (I.K.); (K.M.); (J.A.); (S.M.); (H.I.)
| | - Ikko Kajihara
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (H.K.); (T.K.); (H.K.); (A.M.); (E.O.); (Y.K.); (S.N.); (A.T.); (Y.N.); (I.K.); (K.M.); (J.A.); (S.M.); (H.I.)
| | - Katsunari Makino
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (H.K.); (T.K.); (H.K.); (A.M.); (E.O.); (Y.K.); (S.N.); (A.T.); (Y.N.); (I.K.); (K.M.); (J.A.); (S.M.); (H.I.)
| | - Jun Aoi
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (H.K.); (T.K.); (H.K.); (A.M.); (E.O.); (Y.K.); (S.N.); (A.T.); (Y.N.); (I.K.); (K.M.); (J.A.); (S.M.); (H.I.)
| | - Shinichi Masuguchi
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (H.K.); (T.K.); (H.K.); (A.M.); (E.O.); (Y.K.); (S.N.); (A.T.); (Y.N.); (I.K.); (K.M.); (J.A.); (S.M.); (H.I.)
| | - Hirotake Tsukamoto
- Department of Immunology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan;
| | - Takashi Inozume
- Department of Dermatology, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan;
| | - Rong Zhang
- Division of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center (NCC), Kashiwa 277-8577, Japan; (R.Z.); (T.N.); (Y.U.)
| | - Tetsuya Nakatsura
- Division of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center (NCC), Kashiwa 277-8577, Japan; (R.Z.); (T.N.); (Y.U.)
| | - Yasushi Uemura
- Division of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center (NCC), Kashiwa 277-8577, Japan; (R.Z.); (T.N.); (Y.U.)
| | - Satoru Senju
- Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan;
| | - Hironobu Ihn
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (H.K.); (T.K.); (H.K.); (A.M.); (E.O.); (Y.K.); (S.N.); (A.T.); (Y.N.); (I.K.); (K.M.); (J.A.); (S.M.); (H.I.)
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Perifocal edema volume is not associated with immunohistochemical features reflecting proliferation potential, microvessel density, neoangiogenesis and invasiveness in brain metastasis. Clin Neurol Neurosurg 2021; 202:106537. [PMID: 33571782 DOI: 10.1016/j.clineuro.2021.106537] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 01/25/2021] [Accepted: 01/28/2021] [Indexed: 11/23/2022]
Abstract
OBJECTIVE Perifocal edema of brain tumors is associated with survival and neurological symptoms. Our aim was to analyze associations between perifocal edema and immunohistochemical features including proliferation potential, microvessel density, neoangiogenesis and invasiveness in brain metastasis (BM). METHODS 35 patients with BM were included into the retrospective study. The tumors were localized supratentorial in 25 lesions (71.4%) and infratentorial in 10 lesions (28.6%). The following immunohistochemical features were calculated on histopathological specimens: microvessel density, proliferation index Ki 67, matrix-metallopeptidase 9 (MMP9) extracellular matrix metalloproteinase inducer (EMMPRIN) and vascular endothelial growth factor (VEGF) expression. Tumor and edema volumes were estimated semiautomatically on magnetic resonance images. RESULTS There were no correlations between tumor volume and edema volume. Moreover, no correlation was identified between the investigated immunohistochemical features and tumor/edema volume. In the non-small cell lung cancer subgroup, a positive correlation between tumor volume and VEGF expression was observed (r = 0.52, P = 0.02) and edema volume correlated inversely with MMP9 expression (r = -0.53, P = 0.02). CONCLUSION In BM, no linear associations exist between tumor volumes, edema volumes and immunohistochemical features reflecting proliferation potential, neoangiogenesis, microvessel density and MMP9 expression. However, in the subgroup of non-small cell lung cancer, there might be associations between MMP9 expression and edema volume as well as between tumor volume and angiogenesis.
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27
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Phadke M, Ozgun A, Eroglu Z, Smalley KSM. Melanoma brain metastases: Biological basis and novel therapeutic strategies. Exp Dermatol 2021; 31:31-42. [PMID: 33455008 DOI: 10.1111/exd.14286] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 12/21/2020] [Accepted: 01/13/2021] [Indexed: 01/09/2023]
Abstract
The development of brain metastases is the deadliest complication of advanced melanoma and has long been associated with a dismal prognosis. The recent years have seen incredible progress in the development of therapies for melanoma brain metastases (MBM), with both targeted therapies (the BRAF-MEK inhibitor combination) and immune checkpoint inhibitors (the anti-CTLA-4, anti-PD-1 combination) showing impressive levels of activity. Despite this, durations of response for these therapies remain lower at intracranial sites of metastasis compared to extracranial metastases and it has been suggested that there are unique features of the brain microenvironment that contribute to therapeutic escape. In this review, we outline the latest research into the biology and pathophysiology of melanoma brain metastasis development and progression. We then discuss the current status of clinical trial that are open to patients with MBM and end by describing the ongoing challenges for the field.
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Affiliation(s)
- Manali Phadke
- The Department of Tumor Biology, The Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Alpaslan Ozgun
- The Department of Cutaneous Oncology, The Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Zeynep Eroglu
- The Department of Cutaneous Oncology, The Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Keiran S M Smalley
- The Department of Tumor Biology, The Moffitt Cancer Center & Research Institute, Tampa, FL, USA.,The Department of Cutaneous Oncology, The Moffitt Cancer Center & Research Institute, Tampa, FL, USA
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Maiti A, Hait NC. Autophagy-mediated tumor cell survival and progression of breast cancer metastasis to the brain. J Cancer 2021; 12:954-964. [PMID: 33442395 PMCID: PMC7797661 DOI: 10.7150/jca.50137] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 10/07/2020] [Indexed: 02/07/2023] Open
Abstract
Brain metastases represent a substantial amount of morbidity and mortality in breast cancer (BC). Metastatic breast tumor cells committed to brain metastases are unique because they escape immune surveillance, can penetrate the blood-brain barrier, and also adapt to the brain tissue microenvironment (TME) for colonization and outgrowth. In addition, dynamic intracellular interactions between metastatic cancer cells and neighboring astrocytes in the brain are thought to play essential roles in brain tumor progression. A better understanding of the above mechanisms will lead to developing more effective therapies for brain metastases. Growing literature suggests autophagy, a conserved lysosomal degradation pathway involved in cellular homeostasis under stressful conditions, plays essential roles in breast tumor metastatic transformation and brain metastases. Cancer cells must adapt under various microenvironmental stresses, such as hypoxia, and nutrient (glucose) deprivation, in order to survive and progress. Clinical studies reveal that tumoral expression of autophagy-related proteins is higher in brain metastasis compared to primary breast tumors. In this review, we outline the molecular mechanisms underlying autophagy-mediated BC cell survival and metastasis to the brain.
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Affiliation(s)
- Aparna Maiti
- Division of Breast Surgery and Department of Surgical Oncology, Department of Molecular & Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, 14263, USA
| | - Nitai C. Hait
- Division of Breast Surgery and Department of Surgical Oncology, Department of Molecular & Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, 14263, USA
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Stephens DC, Powell TW, Taraska JW, Harris DA. Imaging the rapid yet transient accumulation of regulatory lipids, lipid kinases, and protein kinases during membrane fusion, at sites of exocytosis of MMP-9 in MCF-7 cells. Lipids Health Dis 2020; 19:195. [PMID: 32829709 PMCID: PMC7444259 DOI: 10.1186/s12944-020-01374-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 08/17/2020] [Indexed: 11/10/2022] Open
Abstract
Background The regulation of exocytosis is physiologically vital in cells and requires a variety of distinct proteins and lipids that facilitate efficient, fast, and timely release of secretory vesicle cargo. Growing evidence suggests that regulatory lipids act as important lipid signals and regulate various biological processes including exocytosis. Though functional roles of many of these regulatory lipids has been linked to exocytosis, the dynamic behavior of these lipids during membrane fusion at sites of exocytosis in cell culture remains unknown. Methods Total internal reflection fluorescence microscopy (TIRF) was used to observe the spatial organization and temporal dynamics (i.e. spatial positioning and timing patterns) of several lipids, and accessory proteins, like lipid kinases and protein kinases, in the form of protein kinase C (PRKC) associated with sites of exocytosis of matrix metalloproteinase-9 (MMP-9) in living MCF-7 cancer cells. Results Following stimulation with phorbol myristate acetate (PMA) to promote exocytosis, a transient accumulation of several distinct regulatory lipids, lipid kinases, and protein kinases at exocytic sites was observed. This transient accumulation centered at the time of membrane fusion is followed by a rapid diffusion away from the fusion sites. Additionally, the synthesis of these regulatory lipids, degradation of these lipids, and the downstream effectors activated by these lipids, are also achieved by the recruitment and accumulation of key enzymes at exocytic sites (during the moment of cargo release). This includes key enzymes like lipid kinases, protein kinases, and phospholipases that facilitate membrane fusion and exocytosis of MMP-9. Conclusions This work suggests that these regulatory lipids and associated effector proteins are locally synthesized and/or recruited to sites of exocytosis, during membrane fusion and cargo release. More importantly, their enrichment at fusion sites serves as an important spatial and temporal organizing “element” defining individual exocytic sites.
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Affiliation(s)
- Dominique C Stephens
- Department of Chemistry, Howard University, 525 College Street NW, Washington, D.C, 20059, USA
| | - Tyrel W Powell
- Department of Chemistry, Howard University, 525 College Street NW, Washington, D.C, 20059, USA
| | - Justin W Taraska
- Laboratory of Molecular Biophysics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Dinari A Harris
- Department of Chemistry, Howard University, 525 College Street NW, Washington, D.C, 20059, USA.
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Huang X, Li J, Li M, Huang J, Jiang X, Fu H, Wu J, Bao M, Wang S, Zhang M, Gao G. Polyphenol-Enriched Extracts from Trapa acornis Husks Inhibit Her2-Positive SK-BR-3 Breast Cancer Cell Proliferation and In Vivo Tumor Angiogenesis. Nutr Cancer 2020; 73:1145-1156. [PMID: 32672134 DOI: 10.1080/01635581.2020.1792951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
The study aimed to investigate the antitumor effects of Trapa acornis husks (TAH) extract on SK-BR-3 cells of Her2-positive breast cancer. The bioactive compounds of TAH extracts were analyzed qualitatively and quantitatively by Ultra-Performance Liquid Chromatography/Mass Spectrometry (UPLC-MS)/high-performance liquid chromatographic system (HPLC). The effects of TAH extracts on cell proliferation, cell cycle, and apoptosis of SK-BR-3 cells were determined by CCK-8 and flow cytometry. Besides, the In Vivo antitumor effect of TAH extracts was detected. UPLC-MS/HPLC showed that the main bioactive compounds of TAH were gallic acid and galloylglucose derivatives. TAH extracts significantly inhibited the proliferation of SK-BR-3 cells in a dose- and time-dependent manner (P < 0.01). With the increase of TAH extracts concentration, cells in G2/M stage were increased and cell apoptosis was significantly increased. Immunohistochemical analysis showed that TAH extracts can significantly reduce the positive expression rate of Ki67 and Factor VIII index in tumor tissues. The mRNA expression levels of VEGF, MMP2, MMP9, and uPA were reduced after TAH extracts intervention (P < 0.01). TAH extracts also decreased the protein expression of p-Her2, p-ERK1/2, VEGF, MMP2, MMP9, and uPA (P < 0.01). In conclusion, polyphenol-enriched extracts from TAH might inhibit breast cancer cell proliferation and In Vivo tumor angiogenesis.
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Affiliation(s)
- Xuan Huang
- Key Laboratory of Natural Medicine and Health Food R & D Technology, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, PR China
| | - Jun Li
- Jiaxing Vocational Technical College, Jiaxing, Zhejiang, PR China
| | - Mingjuan Li
- Key Laboratory of Natural Medicine and Health Food R & D Technology, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, PR China
| | - Jia Huang
- Key Laboratory of Natural Medicine and Health Food R & D Technology, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, PR China
| | - Xiaohong Jiang
- Key Laboratory of Natural Medicine and Health Food R & D Technology, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, PR China
| | - Hongfei Fu
- College of Food Science and Engineering, Northwest A&F University, Yangling, Shanxi, PR China
| | - Jiming Wu
- Key Laboratory of Natural Medicine and Health Food R & D Technology, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, PR China
| | - Mingyang Bao
- College of Medicine, Jiaxing University, Jiaxing, Zhejiang, PR China
| | - Shuzhen Wang
- College of Medicine, Jiaxing University, Jiaxing, Zhejiang, PR China
| | - Muyuan Zhang
- College of Medicine, Jiaxing University, Jiaxing, Zhejiang, PR China
| | - Guangchun Gao
- Key Laboratory of Natural Medicine and Health Food R & D Technology, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, PR China
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Vimentin plays an important role in the promotion of breast cancer cell migration and invasion by leucine aminopeptidase 3. Cytotechnology 2020; 72:639-647. [PMID: 32572729 DOI: 10.1007/s10616-020-00402-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Accepted: 05/20/2020] [Indexed: 02/07/2023] Open
Abstract
Breast cancer is a common type of cancer in females. Our previous studies indicated that leucine aminopeptidase 3 (LAP3) promotes migration and invasion of breast cancer cells. Vimentin is a mesenchymal marker, and its upregulation represents the promotion of epithelial-mesenchymal transition. In this study, we found that LAP3 and vimentin were highly expressed in breast cancer tissues, and the overexpression of LAP3 in breast cancer cells promoted the expression of vimentin. Western blot analysis indicated that the overexpression of LAP3 upregulated the phosphorylation of Erk1/2. MEK inhibitor PD98059 downregulated the expression of vimentin, matrix metalloproteinase-2/9 (MMP-2/9), and fascin through the inhibition of Erk1/2 activity. We hypothesized that LAP3 promoted tumor migration and invasion by upregulating vimentin. The knockdown of vimentin resulted in the inhibited migration and invasion of MDA-MB-231 and MDA-MB-468 cells. The expression of MMP-2/9 and fascin could also be downregulated. In conclusion, vimentin might play an important role in the promotion of breast cancer metastasis by LAP3.
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Ponzetti M, Rucci N. Switching Homes: How Cancer Moves to Bone. Int J Mol Sci 2020; 21:E4124. [PMID: 32527062 PMCID: PMC7313057 DOI: 10.3390/ijms21114124] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/04/2020] [Accepted: 06/05/2020] [Indexed: 02/06/2023] Open
Abstract
Bone metastases (BM) are a very common complication of the most prevalent human cancers. BM are extremely painful and may be life-threatening when associated with hypercalcaemia. BM can lead to kidney failure and cardiac arrhythmias and arrest, but why and how do cancer cells decide to "switch homes" and move to bone? In this review, we will present what answers science has provided so far, with focus on the molecular mechanisms and cellular aspects of well-established findings, such as the concept of "vicious cycle" and "osteolytic" vs. "osteosclerotic" bone metastases; as well as on novel concepts, such as cellular dormancy and extracellular vesicles. At the molecular level, we will focus on hypoxia-associated factors and angiogenesis, the Wnt pathway, parathyroid hormone-related peptide (PTHrP) and chemokines. At the supramolecular/cellular level, we will discuss tumour dormancy, id est the mechanisms through which a small contingent of tumour cells coming from the primary site may be kept dormant in the endosteal niche for many years. Finally, we will present a potential role for the multimolecular mediators known as extracellular vesicles in determining bone-tropism and establishing a premetastatic niche by influencing the bone microenvironment.
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Affiliation(s)
| | - Nadia Rucci
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy;
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Morad G, Daisy CC, Otu HH, Libermann TA, Dillon ST, Moses MA. Cdc42-Dependent Transfer of mir301 from Breast Cancer-Derived Extracellular Vesicles Regulates the Matrix Modulating Ability of Astrocytes at the Blood-Brain Barrier. Int J Mol Sci 2020; 21:E3851. [PMID: 32481745 PMCID: PMC7311991 DOI: 10.3390/ijms21113851] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 05/19/2020] [Accepted: 05/25/2020] [Indexed: 12/21/2022] Open
Abstract
Breast cancer brain metastasis is a major clinical challenge and is associated with a dismal prognosis. Understanding the mechanisms underlying the early stages of brain metastasis can provide opportunities to develop efficient diagnostics and therapeutics for this significant clinical challenge. We have previously reported that breast cancer-derived extracellular vesicles (EVs) breach the blood-brain barrier (BBB) via transcytosis and can promote brain metastasis. Here, we elucidate the functional consequences of EV transport across the BBB. We demonstrate that brain metastasis-promoting EVs can be internalized by astrocytes and modulate the behavior of these cells to promote extracellular matrix remodeling in vivo. We have identified protein and miRNA signatures in these EVs that can lead to the interaction of EVs with astrocytes and, as such, have the potential to serve as targets for development of diagnostics and therapeutics for early detection and therapeutic intervention in breast cancer brain metastasis.
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Affiliation(s)
- Golnaz Morad
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA 02115, USA; (G.M.); (C.C.D.)
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
- Graduate School of Arts and Sciences, Harvard University, Cambridge, MA 02138, USA
| | - Cassandra C. Daisy
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA 02115, USA; (G.M.); (C.C.D.)
| | - Hasan H. Otu
- Department of Electrical and Computer Engineering, University of Nebraska-Lincoln, Lincoln, NE 68588, USA;
| | - Towia A. Libermann
- BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA; (T.A.L.); (S.T.D.)
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Simon T. Dillon
- BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA; (T.A.L.); (S.T.D.)
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Marsha A. Moses
- Vascular Biology Program, Boston Children’s Hospital, Boston, MA 02115, USA; (G.M.); (C.C.D.)
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
- Department of Surgery, Boston Children’s Hospital, Boston, MA 02115, USA
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Lee JI, Kil JH, Yu GH, Karadeniz F, Oh JH, Seo Y, Kong CS. 3,5-Dicaffeoyl-epi-quinic acid inhibits the PMA-stimulated activation and expression of MMP-9 but not MMP-2 via downregulation of MAPK pathway. ACTA ACUST UNITED AC 2020; 75:113-120. [DOI: 10.1515/znc-2019-0163] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 02/10/2020] [Indexed: 12/15/2022]
Abstract
Abstract
Matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9, are very important gelatinases that are overexpressed during tumor metastasis. Up to date, several MMP inhibitors have been developed from natural sources as well as organic synthesis. In the present study, the MMP-2 and MMP-9 inhibitory effects of 3,5-dicaffeoyl-epi-quinic acid (DCEQA), a caffeoylquinic acid derivative isolated from Atriplex gmelinii, were investigated in phorbol 12-myristate 13-acetate (PMA)-treated human HT1080 fibrosarcoma cells. Gelatin zymography and immunoblotting showed that DCEQA significantly inhibited the PMA-induced activation and expression of MMP-9 but was not able to show any effect against MMP-2. DCEQA treatment was also shown to upregulate the protein expression of tissue inhibitor of MMP-1 along with decreased MMP-9 protein levels. Moreover, the effect of DCEQA on phosphorylation of mitogen activated protein kinases (MAPKs), analyzed by immunoblotting, indicated the DCEQA inhibited the MMP-9 by downregulation of MAPK pathway. Collectively, current results suggested that DCEQA is a potent MMP-9 inhibitor and can be utilized as lead compound for treatment of pathological complications involving enhanced MMP activity such as cancer metastasis.
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Affiliation(s)
- Jung Im Lee
- Marine Biotechnology Center for Pharmaceuticals and Foods , Silla University , Baegyang-daero 700 beon-gil 140 , Sasang-gu, Busan 46958 , Korea
| | - Jung-Ha Kil
- Marine Biotechnology Center for Pharmaceuticals and Foods , Silla University , Baegyang-daero 700 beon-gil 140 , Sasang-gu, Busan 46958 , Korea
| | - Ga Hyun Yu
- Department of Food and Nutrition, College of Medical and Life Sciences , Silla University , Baegyang-daero 700 beon-gil 140 , Sasang-gu, Busan 46958 , Korea
| | - Fatih Karadeniz
- Marine Biotechnology Center for Pharmaceuticals and Foods , Silla University , Baegyang-daero 700 beon-gil 140 , Sasang-gu, Busan 46958 , Korea
| | - Jung Hwan Oh
- Marine Biotechnology Center for Pharmaceuticals and Foods , Silla University , Baegyang-daero 700 beon-gil 140 , Sasang-gu, Busan 46958 , Korea
| | - Youngwan Seo
- Division of Marine Bioscience , College of Ocean Science and Technology, Korea Maritime and Ocean University , Busan 49112 , Korea
| | - Chang-Suk Kong
- Marine Biotechnology Center for Pharmaceuticals and Foods , Silla University , Baegyang-daero 700 beon-gil 140 , Sasang-gu, Busan 46958 , Korea
- Department of Food and Nutrition, College of Medical and Life Sciences , Silla University , Baegyang-daero 700 beon-gil 140, Sasang-gu , Busan 46958 , Korea , Phone: +82-51-999-5429
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Wyatt GL, Crump LS, Young CM, Wessells VM, McQueen CM, Wall SW, Gustafson TL, Fan YY, Chapkin RS, Porter WW, Lyons TR. Cross-talk between SIM2s and NFκB regulates cyclooxygenase 2 expression in breast cancer. Breast Cancer Res 2019; 21:131. [PMID: 31783895 PMCID: PMC6884910 DOI: 10.1186/s13058-019-1224-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 11/07/2019] [Indexed: 02/10/2023] Open
Abstract
Background Breast cancer is a leading cause of cancer-related death for women in the USA. Thus, there is an increasing need to investigate novel prognostic markers and therapeutic methods. Inflammation raises challenges in treating and preventing the spread of breast cancer. Specifically, the nuclear factor kappa b (NFκB) pathway contributes to cancer progression by stimulating proliferation and preventing apoptosis. One target gene of this pathway is PTGS2, which encodes for cyclooxygenase 2 (COX-2) and is upregulated in 40% of human breast carcinomas. COX-2 is an enzyme involved in the production of prostaglandins, which mediate inflammation. Here, we investigate the effect of Singleminded-2s (SIM2s), a transcriptional tumor suppressor that is implicated in inhibition of tumor growth and metastasis, in regulating NFκB signaling and COX-2. Methods For in vitro experiments, reporter luciferase assays were utilized in MCF7 cells to investigate promoter activity of NFκB and SIM2. Real-time PCR, immunoblotting, immunohistochemistry, and chromatin immunoprecipitation assays were performed in SUM159 and MCF7 cells. For in vivo experiments, MCF10DCIS.COM cells stably expressing SIM2s-FLAG or shPTGS2 were injected into SCID mice and subsequent tumors harvested for immunostaining and analysis. Results Our results reveal that SIM2 attenuates the activation of NFκB as measured using NFκB-luciferase reporter assay. Furthermore, immunostaining of lysates from breast cancer cells overexpressing SIM2s showed reduction in various NFκB signaling proteins, as well as pAkt, whereas knockdown of SIM2 revealed increases in NFκB signaling proteins and pAkt. Additionally, we show that NFκB signaling can act in a reciprocal manner to decrease expression of SIM2s. Likewise, suppressing NFκB translocation in DCIS.COM cells increased SIM2s expression. We also found that NFκB/p65 represses SIM2 in a dose-dependent manner, and when NFκB is suppressed, the effect on the SIM2 is negated. Additionally, our ChIP analysis confirms that NFκB/p65 binds directly to SIM2 promoter site and that the NFκB sites in the SIM2 promoter are required for NFκB-mediated suppression of SIM2s. Finally, overexpression of SIM2s decreases PTGS2 in vitro, and COX-2 staining in vivo while decreasing PTGS2 and/or COX-2 activity results in re-expression of SIM2. Conclusion Our findings identify a novel role for SIM2s in NFκB signaling and COX-2 expression.
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Affiliation(s)
- Garhett L Wyatt
- Department of Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, TX, USA
| | - Lyndsey S Crump
- Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, USA.,The University of Colorado Cancer Center Young Women's Breast Cancer Translational Program, Aurora, CO, USA
| | - Chloe M Young
- Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, USA.,The University of Colorado Cancer Center Young Women's Breast Cancer Translational Program, Aurora, CO, USA
| | - Veronica M Wessells
- Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, USA.,The University of Colorado Cancer Center Young Women's Breast Cancer Translational Program, Aurora, CO, USA
| | - Cole M McQueen
- Department of Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, TX, USA
| | - Steven W Wall
- Department of Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, TX, USA
| | - Tanya L Gustafson
- Department of Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, TX, USA
| | - Yang-Yi Fan
- Department of Nutrition, Texas A&M University, College Station, TX, USA
| | - Robert S Chapkin
- Department of Nutrition, Texas A&M University, College Station, TX, USA
| | - Weston W Porter
- Department of Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, TX, USA.
| | - Traci R Lyons
- Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, USA. .,The University of Colorado Cancer Center Young Women's Breast Cancer Translational Program, Aurora, CO, USA.
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Carvalho R, Paredes J, Ribeiro AS. Impact of breast cancer cells´ secretome on the brain metastatic niche remodeling. Semin Cancer Biol 2019; 60:294-301. [PMID: 31711993 DOI: 10.1016/j.semcancer.2019.10.011] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 10/11/2019] [Accepted: 10/16/2019] [Indexed: 02/07/2023]
Abstract
Brain metastases occur in approximately 10-20% of patients with metastatic breast cancer showing a very poor overall survival. Curiously, different molecular subtypes (that show specific gene expression signatures and differential prognostic significance) are associated with different risks for brain metastases development, suggesting that cancer cells harbor specific molecular programs that award them intrinsic advantages to survive in this specific foreign tissue. Emerging data has been revealing that biophysical and/or mechanical properties of the brain extracellular matrix (ECM), along with those of the brain resident cells, play a crucial role in creating the best conditions for survival, colonization and outgrowth of breast cancer cells in this distinct microenvironment. Although several reports show that cancer cells modulate metastatic niches way before they reach the target organ, few data exist for the brain metastatic niche. Indeed, little is known concerning how factors secreted by cancer cells activate brain resident cells and/or modify brain ECM biomechanical properties and how these modifications impact cells´ ability to metastasize the brain. The brain is a particular organ, protected by the blood brain barrier (BBB), and containing exclusive functional units and very special cell types. Additionally, it is the organ with the most singular ECM and biomechanical properties. Thus, this cancer cell-brain metastatic niche interaction must present distinct properties. Consequently, the search for putative molecular markers that modulate the brain pre-metastatic niche, thus promoting the successful metastatic homing of cancer cells, is urgently needed. In this review, we will discuss key aspects regarding breast cancer cells and the brain pre-metastatic niche paracrine communication that is crucial to initiate the metastatic cascade. We will focus on cancer cell`s secretome influence into the brain microenvironment, specifically on its impact on tissue mechanics and on brain resident cells as regulators of the pre-metastatic niche formation, ultimately promoting metastatic colonization.
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Affiliation(s)
| | - J Paredes
- i3S/IPATIMUP, 4200-135, Porto, Portugal
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Stephens DC, Osunsanmi N, Sochacki KA, Powell TW, Taraska JW, Harris DA. Spatiotemporal organization and protein dynamics involved in regulated exocytosis of MMP-9 in breast cancer cells. J Gen Physiol 2019; 151:1386-1403. [PMID: 31676484 PMCID: PMC6888755 DOI: 10.1085/jgp.201812299] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Accepted: 09/30/2019] [Indexed: 12/22/2022] Open
Abstract
This paper describes the dynamics of proteins and lipids during exocytosis of MMP-9 from cancer cells in real time using fluorescence microscopy. Stephens et al. find that core exocytic proteins, accessory proteins, and lipids are involved at sites of secretory vesicle fusion. Altered regulation of exocytosis is an important mechanism controlling many diseases, including cancer. Defects in exocytosis have been implicated in many cancer cell types and are generally attributed to mutations in cellular transport, trafficking, and assembly of machinery necessary for exocytosis of secretory vesicle cargo. In these cancers, up-regulation of trafficking and secretion of matrix metalloproteinase-9 (MMP-9), a proteolytic enzyme, is responsible for degrading the extracellular matrix, a necessary step in tumor progression. Using TIRF microscopy, we identified proteins associated with secretory vesicles containing MMP-9 and imaged the local dynamics of these proteins at fusion sites during regulated exocytosis of MMP-9 from MCF-7 breast cancer cells. We found that many regulators of exocytosis, including several Rab GTPases, Rab effector proteins, and SNARE/SNARE modulator proteins, are stably assembled on docked secretory vesicles before exocytosis. At the moment of fusion, many of these components are quickly lost from the vesicle, while several endocytic proteins and lipids are simultaneously recruited to exocytic sites at precisely that moment. Our findings provide insight into the dynamic behavior of key core exocytic proteins, accessory proteins, lipids, and some endocytic proteins at single sites of secretory vesicle fusion in breast cancer cells.
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Affiliation(s)
| | | | - Kem A Sochacki
- Laboratory of Molecular Biophysics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
| | - Tyrel W Powell
- Department of Chemistry, Howard University, Washington, DC
| | - Justin W Taraska
- Laboratory of Molecular Biophysics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
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Pedrosa RMSM, Mustafa DA, Soffietti R, Kros JM. Breast cancer brain metastasis: molecular mechanisms and directions for treatment. Neuro Oncol 2019; 20:1439-1449. [PMID: 29566179 DOI: 10.1093/neuonc/noy044] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The development of brain metastasis (BM) of breast cancer is usually a late event with deleterious effect on the prognosis. Treatment options for intracerebral seeding of breast cancer are limited and, so far, nonspecific. Molecular detailing of subsequent events of penetration, seeding, and outgrowth in brain is highly relevant for developing therapeutic strategies to treat, or prevent, BM.We scrutinize recent literature for molecules and pathways that are operative in the formation of breast cancer BM. We also summarize current data on therapeutic efforts to specifically address BM of breast cancer. Data on molecular pathways underlying the formation of BM of breast cancer are sketchy and to some extent inconsistent. The molecular makeup of BM differs from that of the primary tumors, as well as from metastases at other sites. Current efforts to treat breast cancer BM are limited, and drugs used have proven effects on the primary tumors but lack specificity for the intracerebral tumors.More basic research is necessary to better characterize BM of breast cancer. Apart from the identification of drug targets defined by the intracerebral tumors, also targets in the molecular pathways involved in passing the blood-brain barrier and intracerebral tumor cell growth should be revealed.
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Affiliation(s)
- Rute M S M Pedrosa
- Department of Pathology, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Dana A Mustafa
- Department of Pathology, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Riccardo Soffietti
- Department of Neuro-Oncology, University of Turin and City of Health and Science Hospital, Turin, Italy
| | - Johan M Kros
- Department of Pathology, Erasmus Medical Center, Rotterdam, the Netherlands
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Yuan Q, Cheng Y, Lou X, Xia F. Rational Fabrication and Biomedical Application of Biomolecule‐Conjugated AIEgens through Click Reaction. CHINESE J CHEM 2019. [DOI: 10.1002/cjoc.201900211] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Qiming Yuan
- Engineering Research Center of Nano‐Geomaterials of Ministry of Education, Faculty of Materials Science and ChemistryChina University of Geosciences Wuhan Hubei 430074 China
| | - Yong Cheng
- Engineering Research Center of Nano‐Geomaterials of Ministry of Education, Faculty of Materials Science and ChemistryChina University of Geosciences Wuhan Hubei 430074 China
- State Key Laboratory of Material Processing and Die & Mould Technology, School of Materials Science and EngineeringHuazhong University of Science and Technology Wuhan Hubei 430074 China
| | - Xiaoding Lou
- Engineering Research Center of Nano‐Geomaterials of Ministry of Education, Faculty of Materials Science and ChemistryChina University of Geosciences Wuhan Hubei 430074 China
- Zhejiang Institute, China University of Geosciences Hangzhou Zhejiang 311305 China
| | - Fan Xia
- Engineering Research Center of Nano‐Geomaterials of Ministry of Education, Faculty of Materials Science and ChemistryChina University of Geosciences Wuhan Hubei 430074 China
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Fan H, Lu S, Wang S, Zhang S. Identification of critical genes associated with human osteosarcoma metastasis based on integrated gene expression profiling. Mol Med Rep 2019; 20:915-930. [PMID: 31173206 PMCID: PMC6625205 DOI: 10.3892/mmr.2019.10323] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Accepted: 02/13/2019] [Indexed: 12/12/2022] Open
Abstract
Osteosarcoma is the most common type of malignant bone cancer, which often affects teenagers and young adults. The present study aimed to screen for critical genes and microRNAs (miRNAs/miRs) involved in osteosarcoma. A total of four microarray datasets (accession numbers GSE32981, GSE21257, GSE14827 and GSE14359) were downloaded from the Gene Expression Omnibus database. Following data preprocessing, module analysis was performed to identify the stable modules using the weighted gene co‑expression network analysis (WGCNA) package. The differentially expressed genes (DEGs) between metastatic samples and non‑metastatic samples were screened, followed by gene co‑expression network construction, and Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Subsequently, prognosis‑associated genes were screened and a miRNA‑target gene regulatory network was constructed. Finally, the data for critical genes were validated. WGCNA analysis identified six modules; blue and yellow modules were significantly positively associated with osteosarcoma metastasis. A total of 1,613 DEGs were screened between primary tissue samples and metastatic samples. Following comparison of the genes in the two (blue and yellow) modules, a total of 166 DEGs were identified (metastatic samples vs. non‑metastatic samples). Functional enrichment analysis demonstrated that these DEGs were mainly involved in 'defense response', 'p53 signaling pathway' and 'lysosome'. By utilizing the clinical information in GSE21257, 10 critical genes associated with osteosarcoma prognosis were obtained, including CTP synthase 2 (CTPS2), tumor protein p53 inducible protein 3 (TP53I3) and solute carrier family 1 member 1 (SLC1A1). In addition, hsa‑miR‑422a and hsa‑miR‑194 were highlighted in the miRNA‑target gene network. Finally, matrix metallopeptidase 3 (MMP3) and vascular endothelial growth factor B (VEGFB) were predicted as critical genes in osteosarcoma metastasis. CTPS2, TP53I3 and SLC1A1 may serve major roles in osteosarcoma development, and hsa‑miR‑422a, hsa‑miR‑194, MMP3 and VEGFB may be associated with osteosarcoma metastasis.
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Affiliation(s)
- Hongwu Fan
- Department of Orthopedics, China Japan Union Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Shan Lu
- Department of Anesthesiology, China Japan Union Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Shengqun Wang
- Department of Orthopedics, China Japan Union Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Shanyong Zhang
- Department of Spinal Surgery, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
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Shantha Kumara HMC, Yan XH, Pettke E, Cekic V, Gandhi ND, Bellini GA, Whelan RL. Plasma and wound fluid levels of eight proangiogenic proteins are elevated after colorectal resection. World J Gastrointest Oncol 2019; 11:470-488. [PMID: 31236198 PMCID: PMC6580318 DOI: 10.4251/wjgo.v11.i6.470] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 03/07/2019] [Accepted: 03/16/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Colorectal resection is associated with 3-5 wk long elevations in the plasma levels of at least 11 proangiogenic proteins that may stimulate tumor angiogenesis post-surgery. The increases during the first week after surgery may be related to the acute inflammatory response; the cause(s) of the week 2-5 increases is unknown. The wounds are a possible source because of the important role that angiogenesis plays in the healing process. The main hypothesis of the study is that wound fluid levels of the proteins studied will be elevated well beyond plasma levels which, in turn, are elevated from preoperative baseline levels.
AIM To determine plasma and wound fluid levels of 8 proangiogenic proteins after colorectal resection for cancer and benign pathology.
METHODS Blood and wound fluid samples were taken simultaneously on postoperative (postop) day 1, 3, and later time points until wound drain removal in 35 colorectal cancer patients and 31 benign disease patients undergoing colorectal resection in whom closed wound drains had been placed in either the pelvis or the subcutaneous space of the abdominal incision. Postop plasma levels were compared to preop plasma and postop wound fluid levels (separate analyses for cancer and benign groups).
RESULTS Sixty-six colorectal disease patients were studied (35 cancer, 31 benign pathology). Most patients underwent minimally invasive surgery (open surgery in 11% of cancer and 6% of benign patients). The majority in the cancer group had rectal resections while in the benign group sigmoid or right colectomy predominated. Plasma levels of all 8 proteins were significantly elevated from baseline (P < 0.05) at all post-operative time points in the cancer group and at 90% of time points (29/32) in the benign group. Wound levels of all 8 proteins were 3-106 times higher (P < 0.05) than plasma levels at 87-90 percent of postop time points; of note, wound levels were more than 10 times higher at 47-50% of time points.
CONCLUSION Plasma protein levels were elevated for 3 weeks after surgery; wound fluid levels were much greater than corresponding blood levels. Healing wounds may be the source of the plasma increases.
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Affiliation(s)
- HMC Shantha Kumara
- Division of Colon and Rectal Surgery, Department of Surgery, Mount Sinai West Hospital, New York, NY 10019, United States
| | - Xiao-Hong Yan
- Division of Colon and Rectal Surgery, Department of Surgery, Mount Sinai West Hospital, New York, NY 10019, United States
| | - Erica Pettke
- Division of Colon and Rectal Surgery, Department of Surgery, Mount Sinai West Hospital, New York, NY 10019, United States
| | - Vesna Cekic
- Division of Colon and Rectal Surgery, Department of Surgery, Mount Sinai West Hospital, New York, NY 10019, United States
| | - Nipa Dilip Gandhi
- Division of Colon and Rectal Surgery, Department of Surgery, Mount Sinai West Hospital, New York, NY 10019, United States
| | - Geoffrey A Bellini
- Division of Colon and Rectal Surgery, Department of Surgery, Mount Sinai West Hospital, New York, NY 10019, United States
| | - Richard L Whelan
- Division of Colon and Rectal Surgery, Department of Surgery, Mount Sinai West Hospital, New York, NY 10019, United States
- Department of Surgery, Mount Sinai Icahn School of Medicine, New York, NY 10029, United States
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Li P, Liu Y, Liu W, Li G, Tang Q, Zhang Q, Leng F, Sheng F, Hu C, Lai W, Liu Y, Zhou M, Huang J, Zhou H, Zhang R, Zhao Y. IR-783 inhibits breast cancer cell proliferation and migration by inducing mitochondrial fission. Int J Oncol 2019; 55:415-424. [PMID: 31173174 PMCID: PMC6615916 DOI: 10.3892/ijo.2019.4821] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 05/31/2019] [Indexed: 12/14/2022] Open
Abstract
IR-783, a near-infrared heptamethine cyanine dye, has been reported to possess cancer targeting and anticancer effects; However, the molecular mechanism by which IR-783 exhibits anti-breast cancer activity is unclear. In the present study, the inhibitory effects of IR-783 on the proliferation and migration of breast cancer cells were investigated. Our results revealed that IR-783 inhibited MDA-MB-231 and MCF-7 cell proliferation in a dose- and time-dependent manner by inducing cell cycle arrest at the G0/G1 phase. In addition, a Transwell assay demonstrated that IR-783 treatment suppressed the migratory ability of MDA-MB-231 and MCF-7 cells. Furthermore, IR-783 treatment decreased the expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 in MDA-MB-231 cells. Furthermore, IR-783 induced MDA-MB-231 and MCF-7 cell mitochondrial fission, and also decreased the levels of ATP. This was accompanied with a decrease in polymerized filamentous actin, which is the fundamental component of filopodia at the cell surface. Collectively, the results of the present study demonstrated that IR-783 inhibited the proliferation and migration of MDA-MB-231 and MCF-7 cells by inducing mitochondrial fission and subsequently decreasing ATP levels, resulting in cell cycle arrest and filopodia formation suppression. These findings suggest that IR-783 may be developed into an effective novel drug for treating breast cancer.
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Affiliation(s)
- Pantong Li
- Department of Pharmacy, The University-Town Hospital of Chongqing Medical University, Chongqing 401331, P.R. China
| | - Yu Liu
- Department of Pharmacy, The University-Town Hospital of Chongqing Medical University, Chongqing 401331, P.R. China
| | - Wuyi Liu
- Department of Pharmacy, Xinqiao Hospital, Army Medical University, Chongqing, 400037, P.R. China
| | - Guobing Li
- Department of Pharmacy, Xinqiao Hospital, Army Medical University, Chongqing, 400037, P.R. China
| | - Qin Tang
- Department of Pharmacy, Xinqiao Hospital, Army Medical University, Chongqing, 400037, P.R. China
| | - Qian Zhang
- Department of Pharmacy, Xinqiao Hospital, Army Medical University, Chongqing, 400037, P.R. China
| | - Faning Leng
- Department of Pharmacy, Xinqiao Hospital, Army Medical University, Chongqing, 400037, P.R. China
| | - Fangfang Sheng
- Department of Pharmacy, Xinqiao Hospital, Army Medical University, Chongqing, 400037, P.R. China
| | - Changpeng Hu
- Department of Pharmacy, Xinqiao Hospital, Army Medical University, Chongqing, 400037, P.R. China
| | - Wenjing Lai
- Department of Pharmacy, Xinqiao Hospital, Army Medical University, Chongqing, 400037, P.R. China
| | - Yali Liu
- Department of Pharmacy, Xinqiao Hospital, Army Medical University, Chongqing, 400037, P.R. China
| | - Min Zhou
- Department of Pharmacy, Xinqiao Hospital, Army Medical University, Chongqing, 400037, P.R. China
| | - Jingbin Huang
- Department of Pharmacy, Xinqiao Hospital, Army Medical University, Chongqing, 400037, P.R. China
| | - Huyue Zhou
- Department of Pharmacy, Xinqiao Hospital, Army Medical University, Chongqing, 400037, P.R. China
| | - Rong Zhang
- Department of Pharmacy, Xinqiao Hospital, Army Medical University, Chongqing, 400037, P.R. China
| | - Yu Zhao
- Department of Pharmacy, The University-Town Hospital of Chongqing Medical University, Chongqing 401331, P.R. China
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Walter C, Davis JT, Mathur J, Pathak A. Physical defects in basement membrane-mimicking collagen-IV matrices trigger cellular EMT and invasion. Integr Biol (Camb) 2019; 10:342-355. [PMID: 29790537 DOI: 10.1039/c8ib00034d] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In fibrosis and cancer, degradation of basement membrane (BM) and cell invasion are considered as key outcomes of a cellular transformation called epithelial-mesenchymal transition (EMT). Here, we pose a converse question - can preexisting physical defects in the BM matrix cause EMT in normal epithelial cells? On a BM-mimicking matrix of collagen-IV-coated polyacrylamide (PA) gel, we have discovered a reverse phenomenon in which preexisting defects trigger EMT in normal epithelial cells. Through spatiotemporal measurements and simulations in silico, we demonstrate that the EMT precedes cellular mechanoactivation on defective matrices, but they occur concurrently on stiff matrices. The defect-dependent EMT caused cell invasion though a stroma-mimicking collagen-I layer, which could be disabled through MMP9 inhibition. Our findings reveal that the known BM degradation caused by cellular EMT and invasion is not a one-way process. Instead, normal epithelial cells can exploit physical defects in the BM matrix to undergo disease-like cellular transformations.
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Affiliation(s)
- Christopher Walter
- Department of Biomedical Engineering, Washington University, St. Louis, USA
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Zhuang S, Liu F, Wu P. Retracted
: Upregulation of long noncoding RNA TUG1 contributes to the development of laryngocarcinoma by targeting miR‐145‐5p/ROCK1 axis. J Cell Biochem 2019; 120:13392-13402. [DOI: 10.1002/jcb.28614] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 01/18/2019] [Accepted: 01/24/2019] [Indexed: 01/06/2023]
Affiliation(s)
- Shenfa Zhuang
- Department of Otolaryngology Jining First People's Hospital of Shandong Province Jining Shandong China
| | - Fengxian Liu
- Department of Otolaryngology The Third People's Hospital of Qingdao Qingdao Shandong China
| | - Pingping Wu
- Department of Otolaryngology Jining First People's Hospital of Shandong Province Jining Shandong China
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Aftab Q, Mesnil M, Ojefua E, Poole A, Noordenbos J, Strale PO, Sitko C, Le C, Stoynov N, Foster LJ, Sin WC, Naus CC, Chen VC. Cx43-Associated Secretome and Interactome Reveal Synergistic Mechanisms for Glioma Migration and MMP3 Activation. Front Neurosci 2019; 13:143. [PMID: 30941001 PMCID: PMC6433981 DOI: 10.3389/fnins.2019.00143] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 02/07/2019] [Indexed: 12/23/2022] Open
Abstract
Extracellular matrix (ECM) remodeling, degradation and glioma cell motility are critical aspects of glioblastoma multiforme (GBM). Despite being a rich source of potential biomarkers and targets for therapeutic advance, the dynamic changes occurring within the extracellular environment that are specific to GBM motility have yet to be fully resolved. The gap junction protein connexin43 (Cx43) increases glioma migration and invasion in a variety of in vitro and in vivo models. In this study, the upregulation of Cx43 in C6 glioma cells induced morphological changes and the secretion of proteins associated with cell motility. Demonstrating the selective engagement of ECM remodeling networks, secretome analysis revealed the near-binary increase of osteopontin and matrix metalloproteinase-3 (MMP3), with gelatinase and NFF-3 assays confirming the proteolytic activities. Informatic analysis of interactome and secretome downstream of Cx43 identifies networks of glioma motility that appear to be synergistically engaged. The data presented here implicate ECM remodeling and matrikine signals downstream of Cx43/MMP3/osteopontin and ARK1B10 inhibition as possible avenues to inhibit GBM.
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Affiliation(s)
- Qurratulain Aftab
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Marc Mesnil
- Signalisation et Transports Ioniques Membranaires (STIM), CNRS ERL 7003, University of Poitiers, Poitiers, France
| | - Emmanuel Ojefua
- Department of Chemistry, Brandon University, Brandon, MB, Canada
| | - Alisha Poole
- Department of Chemistry, Brandon University, Brandon, MB, Canada
| | - Jenna Noordenbos
- Department of Chemistry, Brandon University, Brandon, MB, Canada
| | - Pierre-Olivier Strale
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Chris Sitko
- Department of Chemistry, Brandon University, Brandon, MB, Canada
| | - Caitlin Le
- Department of Chemistry, Brandon University, Brandon, MB, Canada
| | - Nikolay Stoynov
- Department of Biochemistry and Molecular Biology, Centre for High-Throughput Biology, University of British Columbia, Vancouver, BC, Canada
| | - Leonard J Foster
- Department of Biochemistry and Molecular Biology, Centre for High-Throughput Biology, University of British Columbia, Vancouver, BC, Canada
| | - Wun-Chey Sin
- Signalisation et Transports Ioniques Membranaires (STIM), CNRS ERL 7003, University of Poitiers, Poitiers, France
| | - Christian C Naus
- Signalisation et Transports Ioniques Membranaires (STIM), CNRS ERL 7003, University of Poitiers, Poitiers, France
| | - Vincent C Chen
- Department of Chemistry, Brandon University, Brandon, MB, Canada
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Zhou X, Xu C, Zou Z, Shen X, Xie T, Zhang R, Liao L, Dong J. aThe characteristics of glucose metabolism in the sulfonylurea receptor 1 knockout rat model. Mol Med 2019; 25:2. [PMID: 30616503 PMCID: PMC6322298 DOI: 10.1186/s10020-018-0067-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 12/11/2018] [Indexed: 12/26/2022] Open
Abstract
Background Sulfonylurea receptor 1 (SUR1) is primarily responsible for glucose regulation in normal conditions. Here, we sought to investigate the glucose metabolism characteristics of SUR1−/− rats. Methods The TALEN technique was used to construct a SUR1 gene deficiency rat model. Rats were grouped by SUR1 gene knockout or not and sex difference. Body weight; glucose metabolism indicators, including IPGTT, IPITT, glycogen contents and so on; and other molecule changes were examined. Results Insulin secretion was significantly inhibited by knocking out the SUR1 gene. SUR1−/− rats showed lower body weights compared to wild-type rats, and even SUR1−/− males weighed less than wild-type females. Upon SUR1 gene knockout, the rats showed a peculiar plasma glucose profile. During IPGTT, plasma glucose levels were significantly elevated in SUR1−/− rats at 15 min, which could be explained by SUR1 mainly working in the first phase of insulin secretion. Moreover, SUR1−/− male rats showed obviously impaired glucose tolerance than before and a better insulin sensitivity in the 12th week compared with females, which might be related with excess androgen secretion in adulthood. Increased glycogen content and GLUT4 expression and the inactivation of GSK3 were also observed in SUR1−/− rats, which suggested an enhancement of insulin sensitivity. Conclusions These results reconfirm the role of SUR1 in systemic glucose metabolism. More importantly, our SUR1−/− rat model might be applied in other fields, such as for exploring other hypoglycaemic functions of sulfonylureas. Electronic supplementary material The online version of this article (10.1186/s10020-018-0067-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xiaojun Zhou
- Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, 250014, People's Republic of China
| | - Chunmei Xu
- Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, 250014, People's Republic of China
| | - Zhiwei Zou
- Department of Endocrinology, Qilu Hospital of Shandong University, Shandong University, Jinan, Shandong, 250012, People's Republic of China
| | - Xue Shen
- Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Tianyue Xie
- Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Rui Zhang
- Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, 250014, People's Republic of China
| | - Lin Liao
- Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, 250014, People's Republic of China.
| | - Jianjun Dong
- Department of Endocrinology, Qilu Hospital of Shandong University, Shandong University, Jinan, Shandong, 250012, People's Republic of China.
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Long-term characterization of activated microglia/macrophages facilitating the development of experimental brain metastasis through intravital microscopic imaging. J Neuroinflammation 2019; 16:4. [PMID: 30616691 PMCID: PMC6323850 DOI: 10.1186/s12974-018-1389-9] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Accepted: 12/11/2018] [Indexed: 01/17/2023] Open
Abstract
Background Microglia/macrophages (M/Ms) with multiple functions derived from distinct activation states are key surveillants maintaining brain homeostasis. However, their activation status and role during the brain metastasis of malignant tumors have been poorly characterized. Methods Heterozygous CX3CR1-GFP transgenic mice were used to visualize the dynamic changes of M/Ms during the development of experimental brain metastasis through long-term intravital imaging equipped with redesigned bilateral cranial windows. The occurrence of experimental brain metastasis was evaluated after M/Ms were depleted with PLX3397, a CSF-1R inhibitor. The possible mediators of M/Ms in facilitating the brain metastasis were determined using reverse transcription-PCR, immunofluorescence, correlational analysis, and MMP inhibition. Results Here, we showed that M/Ms were persistently activated and facilitated the formation of melanoma brain metastasis in vivo. We observed that M/Ms gradually and massively accumulated in the metastasis, with a 2.89-fold increase. To precisely depict the dynamic changes in the activation state of M/Ms, we defined the branching parameter to quantify their morphological alterations. The quantitative data showed that the extent of activation of M/Ms in metastatic foci was enhanced, with a 2.27-fold increase from day 1 to day 21. Along with the activation, the M/Ms increased their moving velocity (4.15-fold) and established a rapid, confined, and discontinuous motility behavior. The occurrence of melanoma brain metastasis was significantly hindered under M/M elimination, indicating the key role of M/Ms in the experimental brain metastasis. Interestingly, we found that M/Ms highly expressed matrix metalloproteinase 3 (MMP3), which were strongly correlated with M/M activation and the decrease of tight junction protein zonula occludens-1 (ZO-1). An MMP inhibitor moderately decreased the occurrence of melanoma brain metastasis, suggesting that MMP3 secreted by M/Ms may facilitate melanoma cell growth. Conclusions Our results indicated that the activated M/Ms were essential in the development of melanoma brain metastasis, suggesting that M/Ms are a potential therapeutic target for tumor brain metastasis. Electronic supplementary material The online version of this article (10.1186/s12974-018-1389-9) contains supplementary material, which is available to authorized users.
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Tao J, Gao Z, Huang R, Li H. Therapeutic effect of combined hyperbaric oxygen and radiation therapy for single brain metastasis and its influence on osteopontin and MMP-9. Exp Ther Med 2019; 17:465-471. [PMID: 30651823 PMCID: PMC6307382 DOI: 10.3892/etm.2018.6930] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 06/15/2018] [Indexed: 12/21/2022] Open
Abstract
The present study aimed to investigate the therapeutic effect of combined hyperbaric oxygen and radiation therapy for the treatment of single brain metastasis (SBM), as well as its influence on osteopontin (OPN) and matrix metalloproteinase-9 (MMP-9). A total of 86 patients with SBM were admitted to Hongqi Hospital from January 2013 to January 2016 and those included within the study were randomly divided into two groups. The control group was only treated with whole brain radiotherapy, while the observation group was treated with hyperbaric oxygenation combined with whole brain radiotherapy. OPN and MMP-9 expression was measured in each group by ELISA and the results prior to and following treatment were compared. The total effective rate (patients with complete remission, partial remission or stabilized lesions) in the observation group (95.3%) was significantly increased compared with the control group (67.4%). However, the OPN and MMP-9 protein levels observed in the observation group were significantly reduced compared with the control group (P<0.05). In addition, the quality of life and the incidence of adverse reactions in the observation group were significantly improved compared with the control group (P<0.05). For patients with SBM, hyperbaric oxygenation combined with radiotherapy may improve the efficiency of treatment and should be considered for further investigation and use within a clinical setting.
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Affiliation(s)
- Jing Tao
- Department of Hyperbaric Oxygen Therapy, Affiliated Hongqi Hospital, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
| | - Zhaoyu Gao
- Department of Hyperbaric Oxygen Therapy, Affiliated Hongqi Hospital, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
| | - Rui Huang
- Department of Academic Theory, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
| | - Hong Li
- Department of Hyperbaric Oxygen Therapy, Affiliated Hongqi Hospital, Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
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Miller JJ, Grist JT, Serres S, Larkin JR, Lau AZ, Ray K, Fisher KR, Hansen E, Tougaard RS, Nielsen PM, Lindhardt J, Laustsen C, Gallagher FA, Tyler DJ, Sibson N. 13C Pyruvate Transport Across the Blood-Brain Barrier in Preclinical Hyperpolarised MRI. Sci Rep 2018; 8:15082. [PMID: 30305655 PMCID: PMC6180068 DOI: 10.1038/s41598-018-33363-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Accepted: 09/26/2018] [Indexed: 01/01/2023] Open
Abstract
Hyperpolarised MRI with Dynamic Nuclear Polarisation overcomes the fundamental thermodynamic limitations of conventional magnetic resonance, and is translating to human studies with several early-phase clinical trials in progress including early reports that demonstrate the utility of the technique to observe lactate production in human brain cancer patients. Owing to the fundamental coupling of metabolism and tissue function, metabolic neuroimaging with hyperpolarised [1-13C]pyruvate has the potential to be revolutionary in numerous neurological disorders (e.g. brain tumour, ischemic stroke, and multiple sclerosis). Through the use of [1-13C]pyruvate and ethyl-[1-13C]pyruvate in naïve brain, a rodent model of metastasis to the brain, or porcine brain subjected to mannitol osmotic shock, we show that pyruvate transport across the blood-brain barrier of anaesthetised animals is rate-limiting. We show through use of a well-characterised rat model of brain metastasis that the appearance of hyperpolarized [1-13C]lactate production corresponds to the point of blood-brain barrier breakdown in the disease. With the more lipophilic ethyl-[1-13C]pyruvate, we observe pyruvate production endogenously throughout the entire brain and lactate production only in the region of disease. In the in vivo porcine brain we show that mannitol shock permeabilises the blood-brain barrier sufficiently for a dramatic 90-fold increase in pyruvate transport and conversion to lactate in the brain, which is otherwise not resolvable. This suggests that earlier reports of whole-brain metabolism in anaesthetised animals may be confounded by partial volume effects and not informative enough for translational studies. Issues relating to pyruvate transport and partial volume effects must therefore be considered in pre-clinical studies investigating neuro-metabolism in anaesthetised animals, and we additionally note that these same techniques may provide a distinct biomarker of blood-brain barrier permeability in future studies.
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Affiliation(s)
- Jack J Miller
- Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK.
- Department of Physics, Clarendon Laboratory, University of Oxford, Oxford, UK.
- Oxford Centre for Clinical Magnetic Resonance Research, John Radcliffe Hospital, Oxford, UK.
| | - James T Grist
- Department of Radiology, University of Cambridge, Cambridge, UK
| | - Sébastien Serres
- Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK
- School of Life Sciences, University of Nottingham, Nottingham, UK
| | - James R Larkin
- Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK
| | - Angus Z Lau
- Physical Sciences, Sunnybrook Research Institute, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Kevin Ray
- Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK
- Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
| | | | - Esben Hansen
- MR Research Centre, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Rasmus Stilling Tougaard
- MR Research Centre, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Cardiology, Aarhus University Hospital, Skejby, Aarhus, Denmark
| | - Per Mose Nielsen
- MR Research Centre, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Jakob Lindhardt
- MR Research Centre, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Christoffer Laustsen
- MR Research Centre, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | | | - Damian J Tyler
- Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, UK
- Oxford Centre for Clinical Magnetic Resonance Research, John Radcliffe Hospital, Oxford, UK
| | - Nicola Sibson
- Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK
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Azizidoost S, Asnafi AA, Saki N. Signaling-chemokine axis network in brain as a sanctuary site for metastasis. J Cell Physiol 2018; 234:3376-3382. [PMID: 30187487 DOI: 10.1002/jcp.27305] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 08/01/2018] [Indexed: 01/02/2023]
Abstract
BACKGROUND Brain metastasis remains a major cause of death in patients with solid cancers. The co-operation between several molecular factors such as chemokines, chemokine receptors, and signaling pathways is involved in the pathogenesis of brain metastasis mostly from solid tumors. In this review, we examine the possible role of chemokine/receptor axis, as well as signaling pathways as prognostic biomarkers in brain metastasis. METHODS Relevant English language literature were searched and retrieved from Google Scholar search engine (1993-2017). The following keywords were used: "chemokine," "signaling pathway," "brain," "metastasis," and "niche." RESULTS Increased expression of chemokines like CXCL12 and dysregulated signaling intermediates such as Notch in patients with solid tumors (e.g., breast cancer) is associated with brain metastasis. CONCLUSIONS As biomarkers for brain metastasis, chemokine, and signaling intermediates are potential prognostic factors in a number of solid tumor, including breast cancer, melanoma, and lung cancer.
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Affiliation(s)
- Shirin Azizidoost
- Thalassemia and Hemoglobinopathy Research Center, Research Institute of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ali Amin Asnafi
- Thalassemia and Hemoglobinopathy Research Center, Research Institute of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Najmaldin Saki
- Thalassemia and Hemoglobinopathy Research Center, Research Institute of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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