|
1
|
Devinat M, Thevenard-Devy J, Ghilane F, Devy J, Chazee L, Terryn C, Duca L, Devarenne-Charpentier E, El Btaouri H. Xanthohumol Sensitizes Melanoma Cells to Vemurafenib by Lowering Membrane Cholesterol and Increasing Membrane Fluidity. Int J Mol Sci 2025; 26:2290. [PMID: 40076912 PMCID: PMC11901044 DOI: 10.3390/ijms26052290] [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: 02/05/2025] [Revised: 02/26/2025] [Accepted: 02/28/2025] [Indexed: 03/14/2025] Open
Abstract
Chemoresistance remains one of the major obstacles to cancer treatment. The search for specific molecules that could improve cancer treatment has become one of the objectives of biomedical research. Identifying new natural molecules to enhance chemotherapy treatment or improve sensitization to conventional therapies has become a key objective. Here, we evaluated the effect of Xanthohumol (XN) extracted from hop on SKMEL-28 melanoma cells and their sensitization to vemurafenib (VEM) treatment. We measured the XN effect on cell viability and apoptosis. We also assessed the effect of XN on membrane fluidity and membrane cholesterol levels. Finally, we studied the impact of XN on cell sensitization to VEM. Here, we showed that XN reduced SKMEL-28 cell viability through an apoptotic mechanism. Our results demonstrated the potential role of XN in sensitizing cancer cells to VEM with a less toxic effect on non-tumor cells. A study of XN's molecular mechanism showed that XN was able to induce cholesterol depletion and increased fluidity in SKMEL-28 cancer cells. This leads to an increase in VEM incorporation. Here, we describe the importance of the strategy to modulate membrane fluidity by XN in order to significantly improve anticancer therapy.
Collapse
Affiliation(s)
- Marine Devinat
- UMR-CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), UFR Sciences Exactes et Naturelles, Université de Reims Champagne Ardenne, Moulin de la Housse, BP 1039, 51687 Reims, CEDEX, France; (M.D.); (J.T.-D.); (J.D.); (L.C.); (L.D.); (E.D.-C.)
| | - Jessica Thevenard-Devy
- UMR-CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), UFR Sciences Exactes et Naturelles, Université de Reims Champagne Ardenne, Moulin de la Housse, BP 1039, 51687 Reims, CEDEX, France; (M.D.); (J.T.-D.); (J.D.); (L.C.); (L.D.); (E.D.-C.)
| | - Fatiha Ghilane
- Laboratoire de Biologie des Pathologies Humaines, Université Mohammed V de Rabat, 4 Avenue Ibn Battouta, Rabat B.P. 1014 RP, Morocco;
| | - Jerome Devy
- UMR-CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), UFR Sciences Exactes et Naturelles, Université de Reims Champagne Ardenne, Moulin de la Housse, BP 1039, 51687 Reims, CEDEX, France; (M.D.); (J.T.-D.); (J.D.); (L.C.); (L.D.); (E.D.-C.)
| | - Lise Chazee
- UMR-CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), UFR Sciences Exactes et Naturelles, Université de Reims Champagne Ardenne, Moulin de la Housse, BP 1039, 51687 Reims, CEDEX, France; (M.D.); (J.T.-D.); (J.D.); (L.C.); (L.D.); (E.D.-C.)
| | - Christine Terryn
- Plateau Technique en Imagerie Cellulaire et Tissulaire (PICT) Pôle Santé, UFR Pharmacie, Université de Reims Champagne Ardenne, 51 Rue Cognacq Jay, 51096 Reims, France;
| | - Laurent Duca
- UMR-CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), UFR Sciences Exactes et Naturelles, Université de Reims Champagne Ardenne, Moulin de la Housse, BP 1039, 51687 Reims, CEDEX, France; (M.D.); (J.T.-D.); (J.D.); (L.C.); (L.D.); (E.D.-C.)
| | - Emmanuelle Devarenne-Charpentier
- UMR-CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), UFR Sciences Exactes et Naturelles, Université de Reims Champagne Ardenne, Moulin de la Housse, BP 1039, 51687 Reims, CEDEX, France; (M.D.); (J.T.-D.); (J.D.); (L.C.); (L.D.); (E.D.-C.)
| | - Hassan El Btaouri
- UMR-CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), UFR Sciences Exactes et Naturelles, Université de Reims Champagne Ardenne, Moulin de la Housse, BP 1039, 51687 Reims, CEDEX, France; (M.D.); (J.T.-D.); (J.D.); (L.C.); (L.D.); (E.D.-C.)
| |
Collapse
|
|
2
|
Daya T, Breytenbach A, Gu L, Kaur M. Cholesterol metabolism in pancreatic cancer and associated therapeutic strategies. Biochim Biophys Acta Mol Cell Biol Lipids 2025; 1870:159578. [PMID: 39542394 DOI: 10.1016/j.bbalip.2024.159578] [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: 07/24/2024] [Revised: 10/31/2024] [Accepted: 11/10/2024] [Indexed: 11/17/2024]
Abstract
Pancreatic cancer remains one of the most lethal cancers due to late diagnosis and high chemoresistance. Despite recent progression in the development of chemotherapies, immunotherapies, and potential nanoparticles-based approaches, the success rate of therapeutic response is limited which is further compounded by cancer drug resistance. Understanding of emerging biological and molecular pathways causative of pancreatic cancer's aggressive and chemoresistance is vital to improve the effectiveness of existing therapeutics and to develop new therapies. One such under-investigated and relatively less explored area of research is documenting the effect that lipids, specifically cholesterol, and its metabolism, impose on pancreatic cancer. Dysregulated cholesterol metabolism has a profound role in supporting cellular proliferation, survival, and promoting chemoresistance and this has been well established in various other cancers. Thus, we aimed to provide an in-depth review focusing on the significance of cholesterol metabolism in pancreatic cancer and relevant genes at play, molecular processes contributing to cellular cholesterol homeostasis, and current research efforts to develop new cholesterol-targeting therapeutics. We highlight the caveats, weigh in different experimental therapeutic strategies, and provide possible suggestions for future research highlighting cholesterol's importance as a therapeutic target against pancreatic cancer resistance and cancer progression.
Collapse
Affiliation(s)
- Tasvi Daya
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, WITS, 2050 Johannesburg, South Africa
| | - Andrea Breytenbach
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, WITS, 2050 Johannesburg, South Africa
| | - Liang Gu
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, WITS, 2050 Johannesburg, South Africa
| | - Mandeep Kaur
- School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, WITS, 2050 Johannesburg, South Africa.
| |
Collapse
|
|
3
|
Li K, Wu Y, Hu Y, Yue Y, Ma X, Wang S, Gan X, Xu X. Bipolar Electrode-Based Precise Manipulation and Selective Electroporation of Cells. Anal Chem 2025; 97:3908-3919. [PMID: 39950441 DOI: 10.1021/acs.analchem.4c05041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/26/2025]
Abstract
The intracellular delivery toward a specific type of single cell shows great potential in single-cell-specific therapeutic and diagnostic applications. Most of the current methods require high-precision micromanipulators or require multiple steps for motor fabrication, which hinders their practical application. Herein, we for the first time report a method for precise manipulation and selective electroporation of cells using a bipolar electrode. We achieved the precise control of the position of target cells via dielectrophoresis (DEP) at the edge of a bipolar electrode and selective electroporation of specific cells by the local intensified electric field obtained by the gap between the driving electrodes under a direct current (DC) pulse train. Active cell targeting and electroporation of cells are demonstrated using a rotating electric field to drive the cells and a train of pulses to transfect the cells. By harnessing pDEP and twDEP, our device offers the ability to precisely control the movement and placement of specific cells under a rotating electric field and enables the targeted cells to be driven toward regions where the electric field strength is optimized for efficient electroporation. Our method was demonstrated to be applicable across a wide range of cell types, by selective electroporation of different cells including yeast cells, K562 cells, THP-1 cells, 293T cells, and SNU-1 cells. In addition to the injection of fluorescence dye molecules, we also further demonstrated the introduction of plasmids into the SNU-1 cells successfully. This approach is generic and applicable to bacteria and a wide range of cell types, offering an important and novel experimental tool for targeted delivery and single-cell analysis.
Collapse
Affiliation(s)
- Kemu Li
- School of Integrated Circuits, Southeast University, Sipailou 2, Nanjing 210096, P. R. China
- School of Microelectronics, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, P. R. China
| | - Yupan Wu
- School of Integrated Circuits, Southeast University, Sipailou 2, Nanjing 210096, P. R. China
- School of Microelectronics, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, P. R. China
- Yulin Environmental Monitoring Station, Yulin, Shanxi 719000, P. R. China
- Yangtze River Delta Research Institute of NPU, Taicang, Suzhou, Jiangsu 215400, P. R. China
| | - Yan Hu
- The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Taicang, Suzhou, Jiangsu 215400, P. R. China
| | - Yuanbo Yue
- School of Microelectronics, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, P. R. China
| | - Xun Ma
- School of Microelectronics, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, P. R. China
| | - Shaoxi Wang
- School of Microelectronics, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, P. R. China
| | - Xuetao Gan
- School of Microelectronics, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, P. R. China
| | - Xiaohui Xu
- The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Taicang, Suzhou, Jiangsu 215400, P. R. China
| |
Collapse
|
|
4
|
Sun C, Li S, Ding J. Biomaterials-mediated biomineralization for tumor blockade therapy. Nanomedicine (Lond) 2025; 20:417-425. [PMID: 39800898 PMCID: PMC11812332 DOI: 10.1080/17435889.2025.2451018] [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: 09/25/2024] [Accepted: 01/06/2025] [Indexed: 02/12/2025] Open
Abstract
Recent advancements in tumor therapy have underscored the potential of biomaterials-mediated biomineralization for tumor blockade. By precisely regulating biomineralization and constructing nanomineralized structures at the cellular level, this therapy achieves multi-dimensional targeted inhibition of tumors. Mineralized precursor molecules are engineered to selectively recognize and bind to proteins on the tumor cell membrane, obstructing signal transduction. Biomineralized materials directly target the tumor cell membrane, disrupting its biological functions and inducing cell apoptosis. Additionally, these materials infiltrate the mitochondria of tumor cells, disrupting energy metabolism through mineralization and significantly impairing tumor viability. This biomaterials-mediated approach enhances treatment precision and efficacy while mitigating side effects, offering a unique approach to tumor therapy.
Collapse
Affiliation(s)
- Chao Sun
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, P. R. China
- Department of Orthopedic Surgery, Orthopedic Center, The First Hospital of Jilin University, Jilin University, Changchun, P. R. China
| | - Shuqiang Li
- Department of Orthopedic Surgery, Orthopedic Center, The First Hospital of Jilin University, Jilin University, Changchun, P. R. China
| | - Jianxun Ding
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, P. R. China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, P. R. China
| |
Collapse
|
|
5
|
Lin BJ, Fujie H, Yamazaki M, Sakamoto N. The dual effect of fiber density and matrix stiffness on A549 tumor multicellular migration. Biochem Biophys Res Commun 2024; 741:151018. [PMID: 39579534 DOI: 10.1016/j.bbrc.2024.151018] [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: 10/21/2024] [Accepted: 11/17/2024] [Indexed: 11/25/2024]
Abstract
The tumor microenvironment features dynamic biomechanical interactions between extracellular matrix physics and tumor progression. Tumor growth compresses the supportive matrix, and the stiffness-gradient guides tumor invasion. From the mechanical perspective, the complexity of the matrix topology involving durotaxis-driven metastasis remains lacking in a comprehensive description. In this study, A549 adenocarcinoma spheroids were exposed to a stiffness-and fiber-adjusted collagen matrix to examine the influence of collective motility. Centrifugated compression on the collagen constructs was adopted to mimic the matrix deformation in response to solid tumor development. Centrifugated compression physically stiffened and condensed collagen constructs simultaneously. Cultured with A549 spheroids for 7 days, compressed collagen constructs disadvantaged spheroid expansion without the effect of tumor proliferation potency but promoted matrix metalloproteinase activity corresponding to softened rigidity. Results suggested that the fibrous structure may counterbalance the matrix stiffness-induced motility.
Collapse
Affiliation(s)
- Bo-Jiang Lin
- Department of Mechanical Systems Engineering, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji, Tokyo, 1920397, Japan.
| | - Hiromichi Fujie
- Department of Mechanical Systems Engineering, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji, Tokyo, 1920397, Japan; Research Center for Medicine-Engineering Collaboration, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji, Tokyo, 1920397, Japan.
| | - Masashi Yamazaki
- Department of Mechanical Systems Engineering, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji, Tokyo, 1920397, Japan; Research Center for Medicine-Engineering Collaboration, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji, Tokyo, 1920397, Japan.
| | - Naoya Sakamoto
- Department of Mechanical Systems Engineering, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji, Tokyo, 1920397, Japan; Research Center for Medicine-Engineering Collaboration, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji, Tokyo, 1920397, Japan.
| |
Collapse
|
|
6
|
Kozole SL, Beningo KA. Myosin Light Chains in the Progression of Cancer. Cells 2024; 13:2081. [PMID: 39768172 PMCID: PMC11674124 DOI: 10.3390/cells13242081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 12/06/2024] [Accepted: 12/11/2024] [Indexed: 01/11/2025] Open
Abstract
The myosin light chains (MLCs) of non-muscle myosin II are known to regulate cellular architecture and generate cellular forces; they also have an increasingly emerging role in the progression of cancer. The phosphorylation state of the myosin light chains controls the activity of myosins that are implicated in invasion and proliferation. In cancers, when proliferation is greatly increased, cytokinesis relies on phosphorylated light chains to activate the contractile forces used to separate the cells. Likewise, during metastasis, kinase pathways culminate in aligning MLC structures for enhanced cell motility through stress fiber contraction and the accumulation of myosin filaments at the leading edge. This review summarizes the myosin light chain family members known to promote cancer progression and evidence of how their altered activities change the behavior of cells involving the mechanical-based processes of proliferation and cell movements during metastasis. In addition, myosin light chains impact the immune response to cancers and currently serve as biomarkers in staging this disease; a brief summary of these topics is provided at the end of the review.
Collapse
Affiliation(s)
| | - Karen A. Beningo
- Department of Biological Sciences, Wayne State University, Detroit, MI 48202, USA;
| |
Collapse
|
|
7
|
Matsuzaki T, Fujii M, Noro H, Togo S, Watanabe M, Suganuma M, Sharma S, Kobayashi N, Kawamura R, Nakabayashi S, Yoshikawa HY. Simultaneous visualization of membrane fluidity and morphology defines adhesion signatures of cancer cells. Proc Natl Acad Sci U S A 2024; 121:e2412914121. [PMID: 39636859 DOI: 10.1073/pnas.2412914121] [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: 06/27/2024] [Accepted: 10/27/2024] [Indexed: 12/07/2024] Open
Abstract
We developed an advanced optical microscope for the simultaneous visualization of membrane fluidity and morphology to define cell adhesion signatures. This microscope combines ratiometric spectral imaging of membrane fluidity and interferometric imaging of membrane morphology. As a preliminary demonstration, we simultaneously visualized the interface between a giant unilamellar vesicle (GUV) and a glass substrate at different temperatures. We identified more fluid regions of the membrane and membrane adhesion sites (conversely, low-fluidic, ordered membrane domains correlate with nonadhered regions). This microscopic system was applied to human breast cancer cell lines with different malignancies; then, we identified adhesion signature of cancer cells: 1) low-fluidic, ordered membrane domains at the cell periphery and 2) large fluidic deviation at the nonadhered region. Inhibition of the cholesterol synthesis pathway suppresses the ordered membrane domains at the cancer cell periphery; thus, high level of cholesterol supports the appearance. Furthermore, an inhibitor of the unsaturated lipid synthesis pathway suppressed the large fluidic deviation at the nonadhered region; variation of unsaturated lipids contributes to heterogeneity of the cancer membrane. Therefore, our advanced optical microscopy enables us to couple membrane physical properties with cell adhesion, leading to definition of adhesion signatures of broad cell types, not just for cancer cells, that regulate life phenomena.
Collapse
Affiliation(s)
- Takahisa Matsuzaki
- Department of Applied Physics, Graduate School of Engineering, Osaka University, Suita 565-0871, Japan
- Division of Precision Engineering and Applied Physics, Center for Future Innovation, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
| | - Mai Fujii
- Department of Chemistry, Saitama University, Sakura-Ku, Saitama 338-8570, Japan
| | - Hayata Noro
- Department of Chemistry, Saitama University, Sakura-Ku, Saitama 338-8570, Japan
| | - Shodai Togo
- Department of Chemistry, Saitama University, Sakura-Ku, Saitama 338-8570, Japan
| | - Mami Watanabe
- Department of Chemistry, Saitama University, Sakura-Ku, Saitama 338-8570, Japan
| | - Masami Suganuma
- Division of Strategic Research and Development, Graduate School of Science and Engineering, Saitama University, Sakura-Ku, Saitama 338-8570, Japan
| | - Shivani Sharma
- Directorate of Engineering, US National Science Foundation, Alexandria, VA 22314
| | - Naritaka Kobayashi
- Division of Strategic Research and Development, Graduate School of Science and Engineering, Saitama University, Sakura-Ku, Saitama 338-8570, Japan
| | - Ryuzo Kawamura
- Department of Chemistry, Saitama University, Sakura-Ku, Saitama 338-8570, Japan
| | - Seiichiro Nakabayashi
- Department of Chemistry, Saitama University, Sakura-Ku, Saitama 338-8570, Japan
- Division of Strategic Research and Development, Graduate School of Science and Engineering, Saitama University, Sakura-Ku, Saitama 338-8570, Japan
| | - Hiroshi Y Yoshikawa
- Department of Applied Physics, Graduate School of Engineering, Osaka University, Suita 565-0871, Japan
| |
Collapse
|
|
8
|
Gong T, Sun W, Li X, Cai J, Zhao N, Lu M, Xu J, Liu Z, Chen H. TMSB4Y restrains sphingomyelin synthesis via de novo purine synthesis to exert a tumor suppressor function in male esophageal squamous cell carcinoma. Oncogene 2024; 43:3660-3672. [PMID: 39443723 DOI: 10.1038/s41388-024-03193-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 10/09/2024] [Accepted: 10/10/2024] [Indexed: 10/25/2024]
Abstract
Y chromosome genes play a vital role in sex difference of cancer. The dysregulation and functional implications of Y chromosome genes in esophageal squamous cell carcinoma (ESCC) remains elusive. Here, we analyze the Y chromosome gene signature and identify TMSB4Y as an emerging prognostic predictor in male ESCC. Functional analyses show that TMSB4Y inhibits the proliferation, invasion and metastasis of male ESCC cells. Mechanistically, we demonstrate that TMSB4Y interacts with PAICS, wherein TMSB4Y disrupts the formation of the PAICS octamer to inhibit purine de novo synthesis, leading to a decrease in the AMP/ATP ratio, subsequently impeding AMPK phosphorylation. Furthermore, we uncover a regulatory cascade orchestrated by the TMSB4Y/PAICS-AMPK axis, which exerts a suppressive effect on sphingomyelin metabolism by inhibiting the expression of sphingomyelin synthases (SMSs). Notably, Malabaricone C, an inhibitor of SMS1 and SMS2, effectively suppresses male ESCC cell proliferation and xenograft tumor growth. Collectively, these findings reveal the regulation of sphingomyelin metabolism by TMSB4Y/PAICS-AMPK axis and underscore the potential of targeting SMSs as a promising therapeutic approach for the treatment of male ESCC.
Collapse
Affiliation(s)
- Tongyang Gong
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Thoracic Surgery II, Peking University Cancer Hospital & Institute, Beijing, PR China
| | - Wanyuan Sun
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
| | - Xukun Li
- Central Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, PR China
| | - Jiahui Cai
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
- Clinical Biobank, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, PR China
| | - Ning Zhao
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
| | - Minyi Lu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
| | - Juan Xu
- Department of Stomatology, The First Medical Center, Chinese PLA General Hospital, Beijing, PR China
| | - Zhihua Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China.
| | - Hongyan Chen
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China.
| |
Collapse
|
|
9
|
Nicoletti A, Vitale F, Quero G, Paratore M, Fiorillo C, Negri M, Carlino A, Inzani F, Gasbarrini A, Alfieri S, Zileri Dal Verme L. Immunohistochemical Evaluation of the Expression of Specific Membrane Antigens in Patients with Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2023; 15:4586. [PMID: 37760554 PMCID: PMC10526869 DOI: 10.3390/cancers15184586] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/26/2023] [Accepted: 09/01/2023] [Indexed: 09/29/2023] Open
Abstract
(1) Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. The lack of validated disease biomarkers makes timely diagnosis challenging in most cases. Cell membrane and surface proteins play a crucial role in several routes of oncogenesis. The aim of this study was to evaluate the expression of six membrane antigens on PDAC (CA 19-9, mucin 1 and 4 (MUC1, MUC4), mesothelin (MSLN), Annexin A10 (ANXA10), Glypican-1 (GPC-1)) and their correlation with oncologic outcomes. (2) Methods: Immunohistochemical staining for CA 19.9, MUC1, MUC4, MSLN, ANXA10, and GPC-1 of surgical samples of 50 consecutive patients with PDAC was performed. Antigen expression for tumor, ductal, and acinar tissues was classified according to the histo-score (H-score) by two pathologists. (3) Results: Recurrence rate was 47% and 18 patients (36%) deceased (median follow-up 21.5 months). Immunostaining for CA 19-9 and MUC1 showed a significantly higher expression in the neoplastic tissue compared to non-tumor ductal and acinar tissues (p < 0.001). MUC4, MSLN, ANXA10, and GPC-1 were selectively expressed in the neoplastic tissue (p < 0.001). A CA 19-9 H-score value >270 was independently associated with a worse overall survival (p = 0.05) and disease-free survival (p = 0.05). (4) Conclusions: CA 19-9 and MUC1 are highly expressed in PDAC cells. The histological expression of CA 19-9 may predict prognosis. MUC4, MSLN, ANXA10, and GPC-1 are selectively expressed by neoplastic tissue and may represent a potential histological biomarker of disease.
Collapse
Affiliation(s)
- Alberto Nicoletti
- Pancreas Unit, CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (A.N.); (F.V.); (M.P.); (M.N.); (L.Z.D.V.)
| | - Federica Vitale
- Pancreas Unit, CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (A.N.); (F.V.); (M.P.); (M.N.); (L.Z.D.V.)
| | - Giuseppe Quero
- Chirurgia Digestiva, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (G.Q.); (C.F.); (S.A.)
| | - Mattia Paratore
- Pancreas Unit, CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (A.N.); (F.V.); (M.P.); (M.N.); (L.Z.D.V.)
| | - Claudio Fiorillo
- Chirurgia Digestiva, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (G.Q.); (C.F.); (S.A.)
| | - Marcantonio Negri
- Pancreas Unit, CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (A.N.); (F.V.); (M.P.); (M.N.); (L.Z.D.V.)
| | - Angela Carlino
- Anatomia Patologica, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (A.C.); (F.I.)
| | - Frediano Inzani
- Anatomia Patologica, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (A.C.); (F.I.)
| | - Antonio Gasbarrini
- Pancreas Unit, CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (A.N.); (F.V.); (M.P.); (M.N.); (L.Z.D.V.)
| | - Sergio Alfieri
- Chirurgia Digestiva, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (G.Q.); (C.F.); (S.A.)
| | - Lorenzo Zileri Dal Verme
- Pancreas Unit, CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (A.N.); (F.V.); (M.P.); (M.N.); (L.Z.D.V.)
| |
Collapse
|
|
10
|
Jiang X, Wu L, Zhang M, Zhang T, Chen C, Wu Y, Yin C, Gao J. Biomembrane nanostructures: Multifunctional platform to enhance tumor chemoimmunotherapy via effective drug delivery. J Control Release 2023; 361:510-533. [PMID: 37567505 DOI: 10.1016/j.jconrel.2023.08.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 07/02/2023] [Accepted: 08/04/2023] [Indexed: 08/13/2023]
Abstract
Chemotherapeutic drugs have been found to activate the immune response against tumors by inducing immunogenic cell death, in addition to their direct cytotoxic effects toward tumors, therefore broadening the application of chemotherapy in tumor immunotherapy. The combination of other therapeutic strategies, such as phototherapy or radiotherapy, could further strengthen the therapeutic effects of immunotherapy. Nanostructures can facilitate multimodal tumor therapy by integrating various active agents and combining multiple types of therapeutics in a single nanostructure. Biomembrane nanostructures (e.g., exosomes and cell membrane-derived nanostructures), characterized by superior biocompatibility, intrinsic targeting ability, intelligent responsiveness and immune-modulating properties, could realize superior chemoimmunotherapy and represent next-generation nanostructures for tumor immunotherapy. This review summarizes recent advances in biomembrane nanostructures in tumor chemoimmunotherapy and highlights different types of engineering approaches and therapeutic mechanisms. A series of engineering strategies for combining different biomembrane nanostructures, including liposomes, exosomes, cell membranes and bacterial membranes, are summarized. The combination strategy can greatly enhance the targeting, intelligence and functionality of biomembrane nanostructures for chemoimmunotherapy, thereby serving as a stronger tumor therapeutic method. The challenges associated with the clinical translation of biomembrane nanostructures for chemoimmunotherapy and their future perspectives are also discussed.
Collapse
Affiliation(s)
- Xianghe Jiang
- Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, China; College of Life Science, Mudanjiang Medical University, Mudanjiang 157011, China
| | - Lili Wu
- Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, China
| | - Mengya Zhang
- Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, China
| | - Tinglin Zhang
- Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, China
| | - Cuimin Chen
- Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, China
| | - Yan Wu
- College of Life Science, Mudanjiang Medical University, Mudanjiang 157011, China.
| | - Chuan Yin
- Department of Gastroenterology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China.
| | - Jie Gao
- Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, China.
| |
Collapse
|
|
11
|
Henning P, Köster T, Haack F, Burrage K, Uhrmacher AM. Implications of different membrane compartmentalization models in particle-based in silico studies. ROYAL SOCIETY OPEN SCIENCE 2023; 10:221177. [PMID: 37416823 PMCID: PMC10320350 DOI: 10.1098/rsos.221177] [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: 09/08/2022] [Accepted: 06/12/2023] [Indexed: 07/08/2023]
Abstract
Studying membrane dynamics is important to understand the cellular response to environmental stimuli. A decisive spatial characteristic of the plasma membrane is its compartmental structure created by the actin-based membrane-skeleton (fences) and anchored transmembrane proteins (pickets). Particle-based reaction-diffusion simulation of the membrane offers a suitable temporal and spatial resolution to analyse its spatially heterogeneous and stochastic dynamics. Fences have been modelled via hop probabilities, potentials or explicit picket fences. Our study analyses the different approaches' constraints and their impact on simulation results and performance. Each of the methods comes with its own constraints; the picket fences require small timesteps, potential fences might induce a bias in diffusion in crowded systems, and probabilistic fences, in addition to carefully scaling the probability with the timesteps, induce higher computational costs for each propagation step.
Collapse
Affiliation(s)
- Philipp Henning
- Institute for Visual and Analytic Computing, University of Rostock, Rostock, Germany
| | - Till Köster
- Institute for Visual and Analytic Computing, University of Rostock, Rostock, Germany
| | - Fiete Haack
- Institute for Visual and Analytic Computing, University of Rostock, Rostock, Germany
| | - Kevin Burrage
- School of Mathematical Sciences, Queensland University of Technology, Brisbane, Australia
- Visiting Professor, Department of Computer Science, University of Oxford, Oxford, UK
| | - Adelinde M. Uhrmacher
- Institute for Visual and Analytic Computing, University of Rostock, Rostock, Germany
| |
Collapse
|
|
12
|
Nicolson GL, Ferreira de Mattos G. The Fluid-Mosaic model of cell membranes: A brief introduction, historical features, some general principles, and its adaptation to current information. BIOCHIMICA ET BIOPHYSICA ACTA. BIOMEMBRANES 2023; 1865:184135. [PMID: 36746313 DOI: 10.1016/j.bbamem.2023.184135] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/27/2023] [Accepted: 01/30/2023] [Indexed: 02/07/2023]
Abstract
The Fluid-Mosaic Membrane (FMM) model was originally proposed as a general, nanometer-scale representation of cell membranes (Singer and Nicolson, 1972). The FMM model was based on some general principles, such as thermodynamic considerations, intercalation of globular proteins into a lipid bilayer, independent protein and lipid dynamics, cooperativity and other characteristics. Other models had trimolecular structures or membrane globular lipoprotein units. These latter models were flawed, because they did not allow autonomous lipids, membrane domains or discrete lateral dynamics. The FMM model was also consistent with membrane asymmetry, cis- and trans-membrane linkages and associations of membrane components into multi-molecular complexes and domains. It has remained useful for explaining the basic organizational principles and properties of various biological membranes. New information has been added, such as membrane-associated cytoskeletal assemblies, extracellular matrix interactions, transmembrane controls, specialized lipid-protein domains that differ in compositions, rotational and lateral mobilities, lifetimes, functions, and other characteristics. The presence of dense, structured membrane domains has reduced significantly the extent of fluid-lipid membrane areas, and the FMM model is now considered to be more mosaic and dense than the original proposal.
Collapse
Affiliation(s)
- Garth L Nicolson
- Department of Molecular Pathology, The Institute for Molecular Medicine, Huntington Beach, CA 92647, USA.
| | - Gonzalo Ferreira de Mattos
- Laboratory of Ion Channels, Biological Membranes and Cell Signaling, Department of Biophysics, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
| |
Collapse
|
|
13
|
Diniz Filho JFS, de Barros AODS, Pijeira MSO, Ricci-Junior E, Midlej V, Baroni MPMA, dos Santos CC, Alencar LMR, Santos-Oliveira R. Ultrastructural Analysis of Cancer Cells Treated with the Radiopharmaceutical Radium Dichloride ([ 223Ra]RaCl 2): Understanding the Effect on Cell Structure. Cells 2023; 12:451. [PMID: 36766793 PMCID: PMC9913731 DOI: 10.3390/cells12030451] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/10/2023] [Accepted: 01/30/2023] [Indexed: 02/01/2023] Open
Abstract
The use of alpha-particle (α-particle) radionuclides, especially [223Ra]RaCl2 (radium dichloride), for targeted alpha therapy is steadily increasing. Despite the positive clinical outcomes of this therapy, very little data are available about the effect on the ultrastructure of cells. The purpose of this study was to evaluate the nanomechanical and ultrastructure effect of [223Ra] RaCl2 on cancer cells. To analyze the effect of [223Ra]RaCl2 on tumor cells, human breast cancer cells (lineage MDA-MB-231) were cultured and treated with the radiopharmaceutical at doses of 2 µCi and 0.9 µCi. The effect was evaluated using atomic force microscopy (AFM) and transmission electron microscopy (TEM) combined with Raman spectroscopy. The results showed massive destruction of the cell membrane but preservation of the nucleus membrane. No evidence of DNA alteration was observed. The data demonstrated the formation of lysosomes and phagosomes. These findings help elucidate the main mechanism involved in cell death during α-particle therapy.
Collapse
Affiliation(s)
- Joel Félix Silva Diniz Filho
- Biophysics and Nanosystems Laboratory, Department of Physics, Federal University of Maranhão, São Luis 65065690, MA, Brazil
| | - Aline Oliveira da Silva de Barros
- Laboratory of Nanoradiopharmacy and Synthesis of New Radiopharmaceuticals, Brazilian Nuclear Energy Commission, Nuclear Engineering Institute, Rio de Janeiro 21941906, RJ, Brazil
| | - Martha Sahylí Ortega Pijeira
- Laboratory of Nanoradiopharmacy and Synthesis of New Radiopharmaceuticals, Brazilian Nuclear Energy Commission, Nuclear Engineering Institute, Rio de Janeiro 21941906, RJ, Brazil
| | - Eduardo Ricci-Junior
- School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21941900, RJ, Brazil
| | - Victor Midlej
- Laboratory of Structural Biology, Oswaldo Cruz Institute (FIOCRUZ), Rio de Janeiro 21040900, RJ, Brazil
| | | | - Clenilton Costa dos Santos
- Biophysics and Nanosystems Laboratory, Department of Physics, Federal University of Maranhão, São Luis 65065690, MA, Brazil
| | | | - Ralph Santos-Oliveira
- Laboratory of Nanoradiopharmacy and Synthesis of New Radiopharmaceuticals, Brazilian Nuclear Energy Commission, Nuclear Engineering Institute, Rio de Janeiro 21941906, RJ, Brazil
- Laboratory of Radiopharmacy and Nanoradiopharmaceuticals, State University of Rio de Janeiro, Rio de Janeiro 23070200, RJ, Brazil
| |
Collapse
|
|
14
|
Shi J, Yang Y, He W, Moses M, Gu YH, Li N, Di W. Correlation between CD44 and membrane fluidity-a study on biopsies of high-grade serous ovarian tumor. Acta Biochim Biophys Sin (Shanghai) 2022; 54:1928-1930. [PMID: 36789687 PMCID: PMC10157600 DOI: 10.3724/abbs.2022190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- Jun Shi
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.,Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yang Yang
- Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200032, China
| | - Wei He
- Department of Pathology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Munika Moses
- Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yi-Hua Gu
- Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200032, China
| | - Ningli Li
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Wen Di
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| |
Collapse
|
|
15
|
Maja M, Tyteca D. Alteration of cholesterol distribution at the plasma membrane of cancer cells: From evidence to pathophysiological implication and promising therapy strategy. Front Physiol 2022; 13:999883. [PMID: 36439249 PMCID: PMC9682260 DOI: 10.3389/fphys.2022.999883] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 10/10/2022] [Indexed: 11/11/2022] Open
Abstract
Cholesterol-enriched domains are nowadays proposed to contribute to cancer cell proliferation, survival, death and invasion, with important implications in tumor progression. They could therefore represent promising targets for new anticancer treatment. However, although diverse strategies have been developed over the years from directly targeting cholesterol membrane content/distribution to adjusting sterol intake, all approaches present more or less substantial limitations. Those data emphasize the need to optimize current strategies, to develop new specific cholesterol-targeting anticancer drugs and/or to combine them with additional strategies targeting other lipids than cholesterol. Those objectives can only be achieved if we first decipher (i) the mechanisms that govern the formation and deformation of the different types of cholesterol-enriched domains and their interplay in healthy cells; (ii) the mechanisms behind domain deregulation in cancer; (iii) the potential generalization of observations in different types of cancer; and (iv) the specificity of some alterations in cancer vs. non-cancer cells as promising strategy for anticancer therapy. In this review, we will discuss the current knowledge on the homeostasis, roles and membrane distribution of cholesterol in non-tumorigenic cells. We will then integrate documented alterations of cholesterol distribution in domains at the surface of cancer cells and the mechanisms behind their contribution in cancer processes. We shall finally provide an overview on the potential strategies developed to target those cholesterol-enriched domains in cancer therapy.
Collapse
|
|
16
|
Xu Y, Jin Y, Gao S, Wang Y, Qu C, Wu Y, Ding N, Dai Y, Jiang L, Liu S. Prognostic Signature and Therapeutic Value Based on Membrane Lipid Biosynthesis-Related Genes in Breast Cancer. JOURNAL OF ONCOLOGY 2022; 2022:7204415. [PMID: 36059802 PMCID: PMC9436593 DOI: 10.1155/2022/7204415] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/12/2022] [Accepted: 07/13/2022] [Indexed: 11/30/2022]
Abstract
There is a need to improve diagnostic and therapeutic approaches to enhance the prognosis of breast cancer, the most common malignancy worldwide. Membrane lipid biosynthesis is a hot biological pathway in current cancer research. It is unclear whether membrane lipid biosynthesis is involved in the prognosis of BRCA. With LASSO regression, a 14-gene prediction model was constructed using data from the TCGA-BRCA cohort. The prediction model includes GPAA1, PIGF, ST3GAL1, ST6GALNAC4, PLPP2, ELOVL1, HACD1, SGPP1, PRKD2, VAPB, CERS2, SGMS2, ALDH3B2, and HACD3. BRCA patients from the TCGA-BRCA cohort were divided into two risk subgroups based on the model. Kaplan-Meier survival curves showed that patients with lower risk scores had significantly improved overall survival (P=2.49e - 09). In addition, risk score, age, stage, and TNM classification were used to predict mortality in BRCA patients. In addition, the 14 genes in the risk model were analyzed for gene variation, methylation level, drug sensitivity, and immune cell infiltration, and the miRNA-mRNA network was constructed. Afterward, the THPA website then analyzed the protein expression of 14 of these risk model genes in normal and pathological BRCA tissues. In conclusion, the membrane lipid biosynthesis-related risk model and nomogram can be used to predict BRCA clinical prognosis.
Collapse
Affiliation(s)
- Yingkun Xu
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Yudi Jin
- Department of Pathology, Chongqing University Cancer Hospital, Chongqing 400045, China
| | - Shun Gao
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Yuan Wang
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Chi Qu
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Yinan Wu
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Nan Ding
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Yuran Dai
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Linshan Jiang
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Shengchun Liu
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| |
Collapse
|
|
17
|
Fifty Years of the Fluid–Mosaic Model of Biomembrane Structure and Organization and Its Importance in Biomedicine with Particular Emphasis on Membrane Lipid Replacement. Biomedicines 2022; 10:biomedicines10071711. [PMID: 35885016 PMCID: PMC9313417 DOI: 10.3390/biomedicines10071711] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 07/06/2022] [Accepted: 07/10/2022] [Indexed: 12/29/2022] Open
Abstract
The Fluid–Mosaic Model has been the accepted general or basic model for biomembrane structure and organization for the last 50 years. In order to establish a basic model for biomembranes, some general principles had to be established, such as thermodynamic assumptions, various molecular interactions, component dynamics, macromolecular organization and other features. Previous researchers placed most membrane proteins on the exterior and interior surfaces of lipid bilayers to form trimolecular structures or as lipoprotein units arranged as modular sheets. Such membrane models were structurally and thermodynamically unsound and did not allow independent lipid and protein lateral movements. The Fluid–Mosaic Membrane Model was the only model that accounted for these and other characteristics, such as membrane asymmetry, variable lateral movements of membrane components, cis- and transmembrane linkages and dynamic associations of membrane components into multimolecular complexes. The original version of the Fluid–Mosaic Membrane Model was never proposed as the ultimate molecular description of all biomembranes, but it did provide a basic framework for nanometer-scale biomembrane organization and dynamics. Because this model was based on available 1960s-era data, it could not explain all of the properties of various biomembranes discovered in subsequent years. However, the fundamental organizational and dynamic aspects of this model remain relevant to this day. After the first generation of this model was published, additional data on various structures associated with membranes were included, resulting in the addition of membrane-associated cytoskeletal, extracellular matrix and other structures, specialized lipid–lipid and lipid–protein domains, and other configurations that can affect membrane dynamics. The presence of such specialized membrane domains has significantly reduced the extent of the fluid lipid membrane matrix as first proposed, and biomembranes are now considered to be less fluid and more mosaic with some fluid areas, rather than a fluid matrix with predominantly mobile components. However, the fluid–lipid matrix regions remain very important in biomembranes, especially those involved in the binding and release of membrane lipid vesicles and the uptake of various nutrients. Membrane phospholipids can associate spontaneously to form lipid structures and vesicles that can fuse with various cellular membranes to transport lipids and other nutrients into cells and organelles and expel damaged lipids and toxic hydrophobic molecules from cells and tissues. This process and the clinical use of membrane phospholipid supplements has important implications for chronic illnesses and the support of healthy mitochondria, plasma membranes and other cellular membrane structures.
Collapse
|
|
18
|
Kreiser RP, Wright AK, Sasser LR, Rinauro DJ, Gabriel JM, Hsu CM, Hurtado JA, McKenzie TL, Errico S, Albright JA, Richardson L, Jaffett VA, Riegner DE, Nguyen LT, LeForte K, Zasloff M, Hollows JE, Chiti F, Vendruscolo M, Limbocker R. A Brain-Permeable Aminosterol Regulates Cell Membranes to Mitigate the Toxicity of Diverse Pore-Forming Agents. ACS Chem Neurosci 2022; 13:1219-1231. [PMID: 35404569 PMCID: PMC9026273 DOI: 10.1021/acschemneuro.1c00840] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
![]()
The molecular composition
of the plasma membrane plays a key role
in mediating the susceptibility of cells to perturbations induced
by toxic molecules. The pharmacological regulation of the properties
of the cell membrane has therefore the potential to enhance cellular
resilience to a wide variety of chemical and biological compounds.
In this study, we investigate the ability of claramine, a blood–brain
barrier permeable small molecule in the aminosterol class, to neutralize
the toxicity of acute biological threat agents, including melittin
from honeybee venom and α-hemolysin from Staphylococcus
aureus. Our results show that claramine neutralizes
the toxicity of these pore-forming agents by preventing their interactions
with cell membranes without perturbing their structures in a detectable
manner. We thus demonstrate that the exogenous administration of an
aminosterol can tune the properties of lipid membranes and protect
cells from diverse biotoxins, including not just misfolded protein
oligomers as previously shown but also biological protein-based toxins.
Our results indicate that the investigation of regulators of the physicochemical
properties of cell membranes offers novel opportunities to develop
countermeasures against an extensive set of cytotoxic effects associated
with cell membrane disruption.
Collapse
Affiliation(s)
- Ryan P. Kreiser
- Department of Chemistry and Life Science, United States Military Academy, West Point, New York 10996, United States
| | - Aidan K. Wright
- Department of Chemistry and Life Science, United States Military Academy, West Point, New York 10996, United States
| | - Liam R. Sasser
- Department of Chemistry and Life Science, United States Military Academy, West Point, New York 10996, United States
| | - Dillon J. Rinauro
- Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K
| | - Justus M. Gabriel
- Department of Chemistry and Life Science, United States Military Academy, West Point, New York 10996, United States
| | - Claire M. Hsu
- Department of Chemistry and Life Science, United States Military Academy, West Point, New York 10996, United States
| | - Jorge A. Hurtado
- Department of Chemistry and Life Science, United States Military Academy, West Point, New York 10996, United States
| | - Tristan L. McKenzie
- Department of Chemistry and Life Science, United States Military Academy, West Point, New York 10996, United States
| | - Silvia Errico
- Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
| | - J. Alex Albright
- Department of Chemistry and Life Science, United States Military Academy, West Point, New York 10996, United States
| | - Lance Richardson
- Department of Chemistry and Life Science, United States Military Academy, West Point, New York 10996, United States
| | - Victor A. Jaffett
- Department of Chemistry and Life Science, United States Military Academy, West Point, New York 10996, United States
| | - Dawn E. Riegner
- Department of Chemistry and Life Science, United States Military Academy, West Point, New York 10996, United States
| | - Lam T. Nguyen
- Department of Chemistry and Life Science, United States Military Academy, West Point, New York 10996, United States
| | - Kathleen LeForte
- Department of Chemistry and Life Science, United States Military Academy, West Point, New York 10996, United States
| | - Michael Zasloff
- MedStar-Georgetown Transplant Institute, Georgetown University School of Medicine, Washington, District of Columbia 20010, United States
| | - Jared E. Hollows
- Department of Chemistry and Life Science, United States Military Academy, West Point, New York 10996, United States
| | - Fabrizio Chiti
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
| | - Michele Vendruscolo
- Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K
| | - Ryan Limbocker
- Department of Chemistry and Life Science, United States Military Academy, West Point, New York 10996, United States
| |
Collapse
|
|
19
|
Mbikay M, Chrétien M. Isoquercetin as an Anti-Covid-19 Medication: A Potential to Realize. Front Pharmacol 2022; 13:830205. [PMID: 35308240 PMCID: PMC8924057 DOI: 10.3389/fphar.2022.830205] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 01/26/2022] [Indexed: 12/30/2022] Open
Abstract
Isoquercetin and quercetin are secondary metabolites found in a variety of plants, including edible ones. Isoquercetin is a monoglycosylated derivative of quercetin. When ingested, isoquercetin accumulates more than quercetin in the intestinal mucosa where it is converted to quercetin; the latter is absorbed into enterocytes, transported to the liver, released in circulation, and distributed to tissues, mostly as metabolic conjugates. Physiologically, isoquercetin and quercetin exhibit antioxidant, anti-inflammatory, immuno-modulatory, and anticoagulant activities. Generally isoquercetin is less active than quercetin in vitro and ex vivo, whereas it is equally or more active in vivo, suggesting that it is primarily a more absorbable precursor to quercetin, providing more favorable pharmacokinetics to the latter. Isoquercetin, like quercetin, has shown broad-spectrum antiviral activities, significantly reducing cell infection by influenza, Zika, Ebola, dengue viruses among others. This ability, together with their other physiological properties and their safety profile, has led to the proposition that administration of these flavonols could prevent infection by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), or arrest the progression to severity and lethality of resulting coronavirus disease of 2019 (Covid-19). In silico screening of small molecules for binding affinity to proteins involved SARS-CoV-2 life cycle has repeatedly situated quercetin and isoquercetin near to top of the list of likely effectors. If experiments in cells and animals confirm these predictions, this will provide additional justifications for the conduct of clinical trials to evaluate the prophylactic and therapeutic efficacy of these flavonols in Covid-19.
Collapse
Affiliation(s)
- Majambu Mbikay
- Functional Endoproteolysis Laboratory, Montreal Clinical Research Institute, Montreal, QC, Canada
| | - Michel Chrétien
- Functional Endoproteolysis Laboratory, Montreal Clinical Research Institute, Montreal, QC, Canada
| |
Collapse
|
|
20
|
Quantifying the cell morphology and predicting biological behavior of signet ring cell carcinoma using deep learning. Sci Rep 2022; 12:183. [PMID: 34997025 PMCID: PMC8741938 DOI: 10.1038/s41598-021-03984-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 11/10/2021] [Indexed: 12/21/2022] Open
Abstract
Signet ring cell carcinoma (SRCC) is a malignant tumor of the digestive system. This tumor has long been considered to be poorly differentiated and highly invasive because it has a higher rate of metastasis than well-differentiated adenocarcinoma. But some studies in recent years have shown that the prognosis of some SRCC is more favorable than other poorly differentiated adenocarcinomas, which suggests that SRCC has different degrees of biological behavior. Therefore, we need to find a histological stratification that can predict the biological behavior of SRCC. Some studies indicate that the morphological status of cells can be linked to the invasiveness potential of cells, however, the traditional histopathological examination can not objectively define and evaluate them. Recent improvements in biomedical image analysis using deep learning (DL) based neural networks could be exploited to identify and analyze SRCC. In this study, we used DL to identify each cancer cell of SRCC in whole slide images (WSIs) and quantify their morphological characteristics and atypia. Our results show that the biological behavior of SRCC can be predicted by quantifying the morphology of cancer cells by DL. This technique could be used to predict the biological behavior and may change the stratified treatment of SRCC.
Collapse
|
|
21
|
Yates AG, Pink RC, Erdbrügger U, Siljander PR, Dellar ER, Pantazi P, Akbar N, Cooke WR, Vatish M, Dias‐Neto E, Anthony DC, Couch Y. In sickness and in health: The functional role of extracellular vesicles in physiology and pathology in vivo: Part II: Pathology: Part II: Pathology. J Extracell Vesicles 2022; 11:e12190. [PMID: 35041301 PMCID: PMC8765328 DOI: 10.1002/jev2.12190] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 09/03/2021] [Accepted: 09/15/2021] [Indexed: 02/06/2023] Open
Abstract
It is clear from Part I of this series that extracellular vesicles (EVs) play a critical role in maintaining the homeostasis of most, if not all, normal physiological systems. However, the majority of our knowledge about EV signalling has come from studying them in disease. Indeed, EVs have consistently been associated with propagating disease pathophysiology. The analysis of EVs in biofluids, obtained in the clinic, has been an essential of the work to improve our understanding of their role in disease. However, to interfere with EV signalling for therapeutic gain, a more fundamental understanding of the mechanisms by which they contribute to pathogenic processes is required. Only by discovering how the EV populations in different biofluids change-size, number, and physicochemical composition-in clinical samples, may we then begin to unravel their functional roles in translational models in vitro and in vivo, which can then feedback to the clinic. In Part II of this review series, the functional role of EVs in pathology and disease will be discussed, with a focus on in vivo evidence and their potential to be used as both biomarkers and points of therapeutic intervention.
Collapse
Affiliation(s)
- Abi G. Yates
- Department of PharmacologyUniversity of OxfordOxfordUK
- School of Biomedical SciencesFaculty of MedicineUniversity of QueenslandSt LuciaAustralia
| | - Ryan C. Pink
- Department of Biological and Medical SciencesFaculty of Health and Life SciencesOxford Brookes UniversityOxfordUK
| | - Uta Erdbrügger
- Department of Medicine, Division of NephrologyUniversity of VirginiaCharlottesvilleVirginiaUSA
| | - Pia R‐M. Siljander
- Molecular and Integrative Biosciences Research ProgrammeFaculty of Biological and Environmental SciencesUniversity of HelsinkiHelsinkiFinland
| | - Elizabeth R. Dellar
- Department of Biological and Medical SciencesFaculty of Health and Life SciencesOxford Brookes UniversityOxfordUK
| | - Paschalia Pantazi
- Department of Biological and Medical SciencesFaculty of Health and Life SciencesOxford Brookes UniversityOxfordUK
| | - Naveed Akbar
- Division of Cardiovascular Medicine, Radcliffe Department of MedicineUniversity of OxfordOxfordUK
| | - William R. Cooke
- Nuffield Department of Women's and Reproductive HealthJohn Radcliffe Hospital, HeadingtonOxfordUK
| | - Manu Vatish
- Nuffield Department of Women's and Reproductive HealthJohn Radcliffe Hospital, HeadingtonOxfordUK
| | - Emmanuel Dias‐Neto
- Laboratory of Medical Genomics. A.C. Camargo Cancer CentreSão PauloBrazil
- Laboratory of Neurosciences (LIM‐27) Institute of PsychiatrySão Paulo Medical SchoolSão PauloBrazil
| | | | - Yvonne Couch
- Acute Stroke Programme ‐ Radcliffe Department of MedicineUniversity of OxfordOxfordUK
| |
Collapse
|
|
22
|
Nicolson GL, Ferreira de Mattos G. A Brief Introduction to Some Aspects of the Fluid-Mosaic Model of Cell Membrane Structure and Its Importance in Membrane Lipid Replacement. MEMBRANES 2021; 11:947. [PMID: 34940448 PMCID: PMC8708848 DOI: 10.3390/membranes11120947] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 11/18/2021] [Accepted: 11/22/2021] [Indexed: 12/15/2022]
Abstract
Early cell membrane models placed most proteins external to lipid bilayers in trimolecular structures or as modular lipoprotein units. These thermodynamically untenable structures did not allow lipid lateral movements independent of membrane proteins. The Fluid-Mosaic Membrane Model accounted for these and other properties, such as membrane asymmetry, variable lateral mobilities of membrane components and their associations with dynamic complexes. Integral membrane proteins can transform into globular structures that are intercalated to various degrees into a heterogeneous lipid bilayer matrix. This simplified version of cell membrane structure was never proposed as the ultimate biomembrane description, but it provided a basic nanometer scale framework for membrane organization. Subsequently, the structures associated with membranes were considered, including peripheral membrane proteins, and cytoskeletal and extracellular matrix components that restricted lateral mobility. In addition, lipid-lipid and lipid-protein membrane domains, essential for cellular signaling, were proposed and eventually discovered. The presence of specialized membrane domains significantly reduced the extent of the fluid lipid matrix, so membranes have become more mosaic with some fluid areas over time. However, the fluid regions of membranes are very important in lipid transport and exchange. Various lipid globules, droplets, vesicles and other membranes can fuse to incorporate new lipids or expel damaged lipids from membranes, or they can be internalized in endosomes that eventually fuse with other internal vesicles and membranes. They can also be externalized in a reverse process and released as extracellular vesicles and exosomes. In this Special Issue, the use of membrane phospholipids to modify cellular membranes in order to modulate clinically relevant host properties is considered.
Collapse
Affiliation(s)
- Garth L. Nicolson
- Department of Molecular Pathology, The Institute for Molecular Medicine, Huntington Beach, CA 92647, USA
| | - Gonzalo Ferreira de Mattos
- Laboratory of Ion Channels, Biological Membranes and Cell Signaling, Department of Biophysics, Facultad de Medicina, Universidad de la República, Montevideo 11600, Uruguay;
| |
Collapse
|
|
23
|
Tallima H, Azzazy HME, El Ridi R. Cell surface sphingomyelin: key role in cancer initiation, progression, and immune evasion. Lipids Health Dis 2021; 20:150. [PMID: 34717628 PMCID: PMC8557557 DOI: 10.1186/s12944-021-01581-y] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 10/15/2021] [Indexed: 12/16/2022] Open
Abstract
Cell surface biochemical changes, notably excessive increase in outer leaflet sphingomyelin (SM) content, are important in cancer initiation, growth, and immune evasion. Innumerable reports describe methods to initiate, promote, or enhance immunotherapy of clinically detected cancer, notwithstanding the challenges, if not impossibility, of identification of tumor-specific, or associated antigens, the lack of tumor cell surface membrane expression of major histocompatibility complex (MHC) class I alpha and β2 microglobulin chains, and lack of expression or accessibility of Fas and other natural killer cell immune checkpoint molecules. Conversely, SM synthesis and hydrolysis are increasingly implicated in initiation of carcinogenesis and promotion of metastasis. Surface membrane SM readily forms inter- and intra- molecular hydrogen bond network, which excessive tightness would impair cell-cell contact inhibition, inter- and intra-cellular signals, metabolic pathways, and susceptibility to host immune cells and mediators. The present review aims at clarifying the tumor immune escape mechanisms, which face common immunotherapeutic approaches, and attracting attention to an entirely different, neglected, key aspect of tumorigenesis associated with biochemical changes in the cell surface that lead to failure of contact inhibition, an instrumental tumorigenesis mechanism. Additionally, the review aims to provide evidence for surface membrane SM levels and roles in cells resistance to death, failure to respond to growth suppressor signals, and immune escape, and to suggest possible novel approaches to cancer control and cure.
Collapse
Affiliation(s)
- Hatem Tallima
- Department of Chemistry, School of Science and Engineering, The American University in Cairo, New Cairo, Cairo, 11835, Egypt. .,Zoology Department, Faculty of Science, Cairo University, Giza, 12613, Egypt.
| | - Hassan M E Azzazy
- Department of Chemistry, School of Science and Engineering, The American University in Cairo, New Cairo, Cairo, 11835, Egypt
| | - Rashika El Ridi
- Zoology Department, Faculty of Science, Cairo University, Giza, 12613, Egypt
| |
Collapse
|
|
24
|
Actin Cytoskeletal Dynamics in Single-Cell Wound Repair. Int J Mol Sci 2021; 22:ijms221910886. [PMID: 34639226 PMCID: PMC8509258 DOI: 10.3390/ijms221910886] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 10/04/2021] [Accepted: 10/04/2021] [Indexed: 11/17/2022] Open
Abstract
The plasma membrane protects the eukaryotic cell from its surroundings and is essential for cell viability; thus, it is crucial that membrane disruptions are repaired quickly to prevent immediate dyshomeostasis and cell death. Accordingly, cells have developed efficient repair mechanisms to rapidly reseal ruptures and reestablish membrane integrity. The cortical actin cytoskeleton plays an instrumental role in both plasma membrane resealing and restructuring in response to damage. Actin directly aids membrane repair or indirectly assists auxiliary repair mechanisms. Studies investigating single-cell wound repair have often focused on the recruitment and activation of specialized repair machinery, despite the undeniable need for rapid and dynamic cortical actin modulation; thus, the role of the cortical actin cytoskeleton during wound repair has received limited attention. This review aims to provide a comprehensive overview of membrane repair mechanisms directly or indirectly involving cortical actin cytoskeletal remodeling.
Collapse
|
|
25
|
Cortés-Hernández LE, Eslami-S Z, Costa-Silva B, Alix-Panabières C. Current Applications and Discoveries Related to the Membrane Components of Circulating Tumor Cells and Extracellular Vesicles. Cells 2021; 10:2221. [PMID: 34571870 PMCID: PMC8465935 DOI: 10.3390/cells10092221] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/23/2021] [Accepted: 08/26/2021] [Indexed: 12/13/2022] Open
Abstract
In cancer, many analytes can be investigated through liquid biopsy. They play fundamental roles in the biological mechanisms underpinning the metastatic cascade and provide clinical information that can be monitored in real time during the natural course of cancer. Some of these analytes (circulating tumor cells and extracellular vesicles) share a key feature: the presence of a phospholipid membrane that includes proteins, lipids and possibly nucleic acids. Most cell-to-cell and cell-to-matrix interactions are modulated by the cell membrane composition. To understand cancer progression, it is essential to describe how proteins, lipids and nucleic acids in the membrane influence these interactions in cancer cells. Therefore, assessing such interactions and the phospholipid membrane composition in different liquid biopsy analytes might be important for future diagnostic and therapeutic strategies. In this review, we briefly describe some of the most important surface components of circulating tumor cells and extracellular vesicles as well as their interactions, putting an emphasis on how they are involved in the different steps of the metastatic cascade and how they can be exploited by the different liquid biopsy technologies.
Collapse
Affiliation(s)
- Luis Enrique Cortés-Hernández
- Laboratory of Rare Human Circulating Cells (LCCRH), University Medical Centre of Montpellier, CEDEX 5, 34295 Montpellier, France; (L.E.C.-H.); (Z.E.-S.)
- CREEC/CANECEV, MIVEGEC (CREES), Université de Montpellier, CNRS, IRD, 34000 Montpellier, France
| | - Zahra Eslami-S
- Laboratory of Rare Human Circulating Cells (LCCRH), University Medical Centre of Montpellier, CEDEX 5, 34295 Montpellier, France; (L.E.C.-H.); (Z.E.-S.)
- CREEC/CANECEV, MIVEGEC (CREES), Université de Montpellier, CNRS, IRD, 34000 Montpellier, France
| | - Bruno Costa-Silva
- Champalimaud Research, Champalimaud Centre for the Unknown, 1400-038 Lisbon, Portugal;
| | - Catherine Alix-Panabières
- Laboratory of Rare Human Circulating Cells (LCCRH), University Medical Centre of Montpellier, CEDEX 5, 34295 Montpellier, France; (L.E.C.-H.); (Z.E.-S.)
- CREEC/CANECEV, MIVEGEC (CREES), Université de Montpellier, CNRS, IRD, 34000 Montpellier, France
| |
Collapse
|
|
26
|
Hong W, Liu CC, Zhang H, Chen Z, Xiao M, Xu L. Cancer Cell Preferential Penetration and pH-Responsive Drug Delivery of Oligorutin. Biomacromolecules 2021; 22:3679-3691. [PMID: 34383480 DOI: 10.1021/acs.biomac.1c00268] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
We report herein a novel delivery system, derived from the facile enzymatic synthesis of oligorutin (OR), for cancer cell targeting and pH-responsive drug delivery. In this study, we demonstrate that OR could preferentially penetrate cancer cells via the lipid raft-mediated endocytosis pathway, and cell membrane cholesterol was critical to the internalization of OR. The accumulation of OR in the tumor region was further confirmed by an in vivo biodistribution study. Considering the tumor-targeting property of OR, a pH-responsive drug delivery system (OR-BTZ) was developed by covalent conjugation of the catechol groups on OR with antitumor drug bortezomib (BTZ) through a pH-sensitive borate ester bond. OR-BTZ exerted cytotoxicity as well as inhibition of the migration and invasion to hepatoma carcinoma cells and showed no apparent cytotoxicity with liver normal cells. The OR-BTZs also presented significant therapeutic efficacy and low systematic toxicity in the murine hepatocellular carcinoma model. To our knowledge, this study presents the first attempt to exploit the potential of oligoflavonoids for cancer cell-targeted drug delivery and will motivate the development of flavonoids and their derivatives as a new type of biomaterials for tumor-targeted therapy.
Collapse
Affiliation(s)
- Weiying Hong
- National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-Based Medicine, Shandong University, Qingdao 266237, China
| | - Chang-Cheng Liu
- National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-Based Medicine, Shandong University, Qingdao 266237, China
| | - Henan Zhang
- National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-Based Medicine, Shandong University, Qingdao 266237, China
| | - Zhiyong Chen
- Shandong Provincial Key Laboratory of Fluorine Chemistry and Chemical Materials, School of Chemistry and Chemical Engineering, Jinan University, Jinan 250022, China
| | - Min Xiao
- National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-Based Medicine, and State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China
| | - Li Xu
- National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-Based Medicine, Shandong University, Qingdao 266237, China
| |
Collapse
|
|
27
|
Li X, Chen Z, Li Y, Liang H, Wang H, Li M. Optical tweezers study of membrane fluidity in small cell lung cancer cells. OPTICS EXPRESS 2021; 29:11976-11986. [PMID: 33984967 DOI: 10.1364/oe.420288] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 03/23/2021] [Indexed: 06/12/2023]
Abstract
The fluidity of the cell membrane is closely related to cancer metastasis/invasion. To test the relationship of membrane fluidity and invasiveness, we first demonstrated that transfection of small RNA miR-92b-3p can significantly increase invasiveness of the small cell lung cancer cell line SHP77. Then optical tweezers were used to measure membrane fluidity. This study employed continuous and step-like stretching methods to examine fluidity changes in SHP77 cell membranes before and after miR-92b-3p transfection. A newly developed physical model was used to derive the effective viscosity and static tension of the cell membrane from relaxation curves obtained via step-like stretching. Experiments showed that invasiveness and fluidity increased significantly after miR-92b-3p transfection. This study paved the way toward a better understanding of cancer cell invasion and membrane mechanical characteristics.
Collapse
|
|
28
|
Choromańska A, Chwiłkowska A, Kulbacka J, Baczyńska D, Rembiałkowska N, Szewczyk A, Michel O, Gajewska-Naryniecka A, Przystupski D, Saczko J. Modifications of Plasma Membrane Organization in Cancer Cells for Targeted Therapy. Molecules 2021; 26:1850. [PMID: 33806009 PMCID: PMC8037978 DOI: 10.3390/molecules26071850] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 03/18/2021] [Accepted: 03/23/2021] [Indexed: 12/11/2022] Open
Abstract
Modifications of the composition or organization of the cancer cell membrane seem to be a promising targeted therapy. This approach can significantly enhance drug uptake or intensify the response of cancer cells to chemotherapeutics. There are several methods enabling lipid bilayer modifications, e.g., pharmacological, physical, and mechanical. It is crucial to keep in mind the significance of drug resistance phenomenon, ion channel and specific receptor impact, and lipid bilayer organization in planning the cell membrane-targeted treatment. In this review, strategies based on cell membrane modulation or reorganization are presented as an alternative tool for future therapeutic protocols.
Collapse
Affiliation(s)
- Anna Choromańska
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland; (J.K.); (D.B.); (N.R.); (A.S.); (O.M.); (A.G.-N.); (J.S.)
| | - Agnieszka Chwiłkowska
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland; (J.K.); (D.B.); (N.R.); (A.S.); (O.M.); (A.G.-N.); (J.S.)
| | - Julita Kulbacka
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland; (J.K.); (D.B.); (N.R.); (A.S.); (O.M.); (A.G.-N.); (J.S.)
| | - Dagmara Baczyńska
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland; (J.K.); (D.B.); (N.R.); (A.S.); (O.M.); (A.G.-N.); (J.S.)
| | - Nina Rembiałkowska
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland; (J.K.); (D.B.); (N.R.); (A.S.); (O.M.); (A.G.-N.); (J.S.)
| | - Anna Szewczyk
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland; (J.K.); (D.B.); (N.R.); (A.S.); (O.M.); (A.G.-N.); (J.S.)
| | - Olga Michel
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland; (J.K.); (D.B.); (N.R.); (A.S.); (O.M.); (A.G.-N.); (J.S.)
| | - Agnieszka Gajewska-Naryniecka
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland; (J.K.); (D.B.); (N.R.); (A.S.); (O.M.); (A.G.-N.); (J.S.)
| | - Dawid Przystupski
- Department of Paediatric Bone Marrow Transplantation, Oncology and Haematology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland;
| | - Jolanta Saczko
- Department of Molecular and Cellular Biology, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland; (J.K.); (D.B.); (N.R.); (A.S.); (O.M.); (A.G.-N.); (J.S.)
| |
Collapse
|
|
29
|
Vona R, Iessi E, Matarrese P. Role of Cholesterol and Lipid Rafts in Cancer Signaling: A Promising Therapeutic Opportunity? Front Cell Dev Biol 2021; 9:622908. [PMID: 33816471 PMCID: PMC8017202 DOI: 10.3389/fcell.2021.622908] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 02/15/2021] [Indexed: 12/11/2022] Open
Abstract
Cholesterol is a lipid molecule that plays an essential role in a number of biological processes, both physiological and pathological. It is an essential structural constituent of cell membranes, and it is fundamental for biosynthesis, integrity, and functions of biological membranes, including membrane trafficking and signaling. Moreover, cholesterol is the major lipid component of lipid rafts, a sort of lipid-based structures that regulate the assembly and functioning of numerous cell signaling pathways, including those related to cancer, such as tumor cell growth, adhesion, migration, invasion, and apoptosis. Considering the importance of cholesterol metabolism, its homeostasis is strictly regulated at every stage: import, synthesis, export, metabolism, and storage. The alterations of this homeostatic balance are known to be associated with cardiovascular diseases and atherosclerosis, but mounting evidence also connects these behaviors to increased cancer risks. Although there is conflicting evidence on the role of cholesterol in cancer development, most of the studies consistently suggest that a dysregulation of cholesterol homeostasis could lead to cancer development. This review aims to discuss the current understanding of cholesterol homeostasis in normal and cancerous cells, summarizing key findings from recent preclinical and clinical studies that have investigated the role of major players in cholesterol regulation and the organization of lipid rafts, which could represent promising therapeutic targets.
Collapse
Affiliation(s)
- Rosa Vona
- Center for Gender-Specific Medicine, Istituto Superiore di Sanità [Italian National Institute of Health], Rome, Italy
| | - Elisabetta Iessi
- Center for Gender-Specific Medicine, Istituto Superiore di Sanità [Italian National Institute of Health], Rome, Italy
| | - Paola Matarrese
- Center for Gender-Specific Medicine, Istituto Superiore di Sanità [Italian National Institute of Health], Rome, Italy
| |
Collapse
|
|
30
|
Calaf GM, Bleak TC, Roy D. Signs of carcinogenicity induced by parathion, malathion, and estrogen in human breast epithelial cells (Review). Oncol Rep 2021; 45:24. [PMID: 33649804 PMCID: PMC7905528 DOI: 10.3892/or.2021.7975] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 01/29/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer development is a multistep process that may be induced by a variety of compounds. Environmental substances, such as pesticides, have been associated with different human diseases. Organophosphorus pesticides (OPs) are among the most commonly used insecticides. Despite the fact that organophosphorus has been associated with an increased risk of cancer, particularly hormone-mediated cancer, few prospective studies have examined the use of individual insecticides. Reported results have demonstrated that OPs and estrogen induce a cascade of events indicative of the transformation of human breast epithelial cells. In vitro studies analyzing an immortalized non-tumorigenic human breast epithelial cell line may provide us with an approach to analyzing cell transformation under the effects of OPs in the presence of estrogen. The results suggested hormone-mediated effects of these insecticides on the risk of cancer among women. It can be concluded that, through experimental models, the initiation of cancer can be studied by analyzing the steps that transform normal breast cells to malignant ones through certain substances, such as pesticides and estrogen. Such substances cause genomic instability, and therefore tumor formation in the animal, and signs of carcinogenesis in vitro. Cancer initiation has been associated with an increase in genomic instability, indicated by the inactivation of tumor-suppressor genes and activation of oncogenes in the presence of malathion, parathion, and estrogen. In the present study, a comprehensive summary of the impact of OPs in human and rat breast cancer, specifically their effects on the cell cycle, signaling pathways linked to epidermal growth factor, drug metabolism, and genomic instability in an MCF-10F estrogen receptor-negative breast cell line is provided.
Collapse
Affiliation(s)
- Gloria M Calaf
- Instituto de Alta Investigación, Universidad de Tarapacá, Arica 1000000, Chile
| | - Tammy C Bleak
- Instituto de Alta Investigación, Universidad de Tarapacá, Arica 1000000, Chile
| | - Debasish Roy
- Department of Natural Sciences, Hostos Community College of The City University of New York, Bronx, NY 10451, USA
| |
Collapse
|
|
31
|
Zhang T, Hu W, Chen W. Plasma Membrane Integrates Biophysical and Biochemical Regulation to Trigger Immune Receptor Functions. Front Immunol 2021; 12:613185. [PMID: 33679752 PMCID: PMC7933204 DOI: 10.3389/fimmu.2021.613185] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 01/06/2021] [Indexed: 11/23/2022] Open
Abstract
Plasma membrane provides a biophysical and biochemical platform for immune cells to trigger signaling cascades and immune responses against attacks from foreign pathogens or tumor cells. Mounting evidence suggests that the biophysical-chemical properties of this platform, including complex compositions of lipids and cholesterols, membrane tension, and electrical potential, could cooperatively regulate the immune receptor functions. However, the molecular mechanism is still unclear because of the tremendous compositional complexity and spatio-temporal dynamics of the plasma membrane. Here, we review the recent significant progress of dynamical regulation of plasma membrane on immune receptors, including T cell receptor, B cell receptor, Fc receptor, and other important immune receptors, to proceed mechano-chemical sensing and transmembrane signal transduction. We also discuss how biophysical-chemical cues couple together to dynamically tune the receptor's structural conformation or orientation, distribution, and organization, thereby possibly impacting their in-situ ligand binding and related signal transduction. Moreover, we propose that electrical potential could potentially induce the biophysical-chemical coupling change, such as lipid distribution and membrane tension, to inevitably regulate immune receptor activation.
Collapse
Affiliation(s)
- Tongtong Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wei Hu
- Department of Cell Biology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wei Chen
- Department of Cell Biology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory for Biomedical Engineering of Ministry of Education, State Key Laboratory for Modern Optical Instrumentation, College of Biomedical Engineering and Instrument Science, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
| |
Collapse
|
|
32
|
Plasma membrane integrity in health and disease: significance and therapeutic potential. Cell Discov 2021; 7:4. [PMID: 33462191 PMCID: PMC7813858 DOI: 10.1038/s41421-020-00233-2] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 10/23/2020] [Indexed: 12/13/2022] Open
Abstract
Maintenance of plasma membrane integrity is essential for normal cell viability and function. Thus, robust membrane repair mechanisms have evolved to counteract the eminent threat of a torn plasma membrane. Different repair mechanisms and the bio-physical parameters required for efficient repair are now emerging from different research groups. However, less is known about when these mechanisms come into play. This review focuses on the existence of membrane disruptions and repair mechanisms in both physiological and pathological conditions, and across multiple cell types, albeit to different degrees. Fundamentally, irrespective of the source of membrane disruption, aberrant calcium influx is the common stimulus that activates the membrane repair response. Inadequate repair responses can tip the balance between physiology and pathology, highlighting the significance of plasma membrane integrity. For example, an over-activated repair response can promote cancer invasion, while the inability to efficiently repair membrane can drive neurodegeneration and muscular dystrophies. The interdisciplinary view explored here emphasises the widespread potential of targeting plasma membrane repair mechanisms for therapeutic purposes.
Collapse
|
|
33
|
Hou W, Ma D, He X, Han W, Ma J, Wang H, Xu C, Xie R, Fan Q, Ye F, Hu S, Li M, Lu Y. Subnanometer-Precision Measurements of Transmembrane Motions of Biomolecules in Plasma Membranes Using Quenchers in Extracellular Environment. NANO LETTERS 2021; 21:485-491. [PMID: 33280386 DOI: 10.1021/acs.nanolett.0c03941] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Characterization of biomolecular dynamics at cellular membranes lags far behind that in solutions because of challenges to measure transmembrane trafficking with subnanometer precision. Herein, by introducing nonfluorescent quenchers into extracellular environment of live cells, we adopted Förster resonance energy transfer from one donor to multiple quenchers to measure positional changes of biomolecules in plasma membranes. We demonstrated the method by monitoring flip-flops of individual lipids and by capturing transient states of the host defense peptide LL-37 in plasma membranes. The method was also applied to investigate the interaction of the necroptosis-associated protein MLKL with plasma membranes, showing a few distinct depths of MLKL insertion. Our method is especially powerful to quantitate the dynamics of proteins at the cytosolic leaflets of plasma membranes which are usually not accessible by conventional techniques. The method will find wide applications in the systematic analysis of fundamental cellular processes at plasma membranes.
Collapse
Affiliation(s)
- Wenqing Hou
- Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China
- Songshan Lake Materials Laboratory, Dongguan, Guangdong 523808, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Dongfei Ma
- Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China
- Songshan Lake Materials Laboratory, Dongguan, Guangdong 523808, China
| | - Xiaolong He
- Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China
| | - Weijing Han
- Songshan Lake Materials Laboratory, Dongguan, Guangdong 523808, China
| | - Jianbing Ma
- Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China
- Songshan Lake Materials Laboratory, Dongguan, Guangdong 523808, China
| | - Hao Wang
- Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China
- Songshan Lake Materials Laboratory, Dongguan, Guangdong 523808, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Chunhua Xu
- Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China
| | - Ruipei Xie
- Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Qihui Fan
- Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China
| | - Fangfu Ye
- Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China
- Songshan Lake Materials Laboratory, Dongguan, Guangdong 523808, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Shuxin Hu
- Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China
| | - Ming Li
- Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China
- Songshan Lake Materials Laboratory, Dongguan, Guangdong 523808, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ying Lu
- Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China
- Songshan Lake Materials Laboratory, Dongguan, Guangdong 523808, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| |
Collapse
|
|
34
|
Guan C, Lu C, Xiao M, Chen W. EHD2 Overexpression Suppresses the Proliferation, Migration, and Invasion in Human Colon Cancer. Cancer Invest 2021; 39:297-309. [PMID: 33356637 DOI: 10.1080/07357907.2020.1870125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Background: To investigate how EHD2 influences the development of colon cancer.Methods: Immunohistochemistry of 90 colon cancer tissue specimens were determined the expression of EHD2. The lentivirus-EHD2-transfected colon cancer cells were conducted to evaluate the biological behaviors.Results: EHD2 was closely associated with clinic pathological parameters (p < 0.001). EHD2 upregulation was relative with a longer overall survival. The results of the univariate and multivariate analyses indicated that EHD2 could be an independent prognosis marker. EHD2 overexpression suppressed cell invasion and proliferation, but enhanced cell apoptosis and cell cycle arrest.Conclusions: EHD2 might represent a therapeutic target of colon cancer.IMPACT STATEMENTWhat is already known on this subject? Membrane trafficking is crucial for cell proliferation, differentiation and apoptosis, especially tumorigenesis and development. EHD2 proteins play an important role in the regulation of membrane trafficking in endocytosis. EHD2 has been suggested to participate in the occurrence of some malignancies.What are the new findings? EHD2 could be an independent prognosis marker in colon cancer. EHD2 overexpression suppressed cell invasion and proliferation, but enhanced cell apoptosis and cell cycle arrest in vitro. EHD2 overexpression markedly increased the expression of EMT marker E-cadherin in colon cancer.How might it impact on clinical practice in the foreseeable future? EHD2 overexpression may inhibit tumorigenesis in colon cancer through the modulation of E-cadherin, the critical marker of EMT which is closely related to invasion and distant metastasis of tumor cells.
Collapse
Affiliation(s)
- Chengqi Guan
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.,Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Cuihua Lu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Mingbing Xiao
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Weichang Chen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| |
Collapse
|
|
35
|
Pantazi P, Carollo E, Carter DRF, Brooks SA. A practical toolkit to study aspects of the metastatic cascade in vitro. Acta Histochem 2020; 122:151654. [PMID: 33157489 DOI: 10.1016/j.acthis.2020.151654] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 10/23/2020] [Accepted: 10/28/2020] [Indexed: 12/30/2022]
Abstract
While metastasis - the spread of cancer from the primary location to distant sites in the body - remains the principle cause of cancer death, it is incompletely understood. It is a complex process, requiring the metastatically successful cancer cell to negotiate a formidable series of interconnected steps, which are described in this paper. For each step, we review the range of in vitro assays that may be used to study them. We also provide a range of detailed, step-by-step protocols that can be undertaken in most modestly-equipped laboratories, including methods for converting qualitative observations into quantitative data for analysis. Assays include: (1) a gelatin degradation assay to study the ability of endothelial cells to degrade extracellular matrix during tumour angiogenesis; (2) the morphological characterisation of cells undergoing epithelial-mesenchymal transition (EMT) as they acquire motility; (3) a 'scratch' or 'wound-healing' assay to study cancer cell migration; (4) a transwell assay to study cancer cell invasion through extracellular matrix; and (5) a static adhesion assay to examine cancer cell interactions with, and adhesion to, endothelial monolayers. This toolkit of protocols will enable researchers who are interested in metastasis to begin to focus on defined aspects of the process. It is only by further understanding this complex, fascinating and clinically relevant series of events that we may ultimately devise ways of better treating, or even preventing, cancer metastasis. The assays may also be of more broad interest to researchers interested in studying aspects of cellular behaviour in relation to other developmental and disease processes.
Collapse
|
|
36
|
uPAR-expressing melanoma exosomes promote angiogenesis by VE-Cadherin, EGFR and uPAR overexpression and rise of ERK1,2 signaling in endothelial cells. Cell Mol Life Sci 2020; 78:3057-3072. [PMID: 33237352 PMCID: PMC8004497 DOI: 10.1007/s00018-020-03707-4] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 11/02/2020] [Accepted: 11/06/2020] [Indexed: 12/19/2022]
Abstract
Exosomes (Exos) have been reported to promote pre-metastatic niche formation, proliferation, angiogenesis and metastasis. We have investigated the role of uPAR in melanoma cell lines-derived Exos and their pro-angiogenic effects on human microvascular endothelial cells (HMVECs) and endothelial colony-forming cells (ECFCs). Melanoma Exos were isolated from conditioned media of A375 and M6 cells by differential centrifugation and filtration. Tunable Resistive Pulse Sensing (TRPS) and Nanoparticle tracking analysis were performed to analyze dimension and concentration of Exos. The CRISPR–Cas 9 technology was exploited to obtain a robust uPAR knockout. uPAR is expressed in melanoma Exos that are internalized by HMVECs and ECFCs, enhancing VE-Cadherin, EGFR and uPAR expression in endothelial cells that undergo a complete angiogenic program, including proliferation, migration and tube formation. uPAR loss reduced the pro-angiogenic effects of melanoma Exos in vitro and in vivo by inhibition of VE-Cadherin, EGFR and uPAR expression and of ERK1,2 signaling in endothelial cells. A similar effect was obtained with a peptide that inhibits uPAR–EGFR interaction and with the EGFR inhibitor Gefitinib, which also inhibited melanoma Exos-dependent EGFR phosphorylation. This study suggests that uPAR is required for the pro-angiogenic activity of melanoma Exos. We propose the identification of uPAR-expressing Exos as a potentially useful biomarker for assessing pro-angiogenic propensity and eventually monitoring the response to treatment in metastatic melanoma patients.
Collapse
|
|
37
|
Misiak P, Niemirowicz-Laskowska K, Markiewicz KH, Misztalewska-Turkowicz I, Wielgat P, Kurowska I, Siemiaszko G, Destarac M, Car H, Wilczewska AZ. Evaluation of Cytotoxic Effect of Cholesterol End-Capped Poly( N-Isopropylacrylamide)s on Selected Normal and Neoplastic Cells. Int J Nanomedicine 2020; 15:7263-7278. [PMID: 33061380 PMCID: PMC7533236 DOI: 10.2147/ijn.s262582] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 07/30/2020] [Indexed: 12/22/2022] Open
Abstract
Purpose Efficient intracellular delivery of a therapeutic compound is an important feature of smart drug delivery systems (SDDS). Modification of a carrier structure with a cell-penetrating ligand, ie, cholesterol moiety, is a strategy to improve cellular uptake. Cholesterol end-capped poly(N-isopropylacrylamide)s offer a promising foundation for the design of efficient thermoresponsive drug delivery systems. Methods A series of cholesterol end-capped poly(N-isopropylacrylamide)s (PNIPAAm) with number-average molar masses ranging from 3200 to 11000 g·mol–1 were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization from original xanthate-functionalized cholesterol and self-assembled into micelles. The physicochemical characteristics and cytotoxicity of cholesterol end-capped poly(N-isopropylacrylamide)s have been thoroughly investigated. Results Phase transition temperature dependence on the molecular weight and hydrophilic/hydrophobic ratio in the polymers were observed in water. Biological test results showed that the obtained materials, both in disordered and micellar form, are non-hemolytic, highly compatible with fibroblasts, and toxic to glioblastoma cells. It was found that the polymer termini dictates the mode of action of the system. Conclusion The cholesteryl moiety acts as a cell-penetrating agent, which enables disruption of the plasma membrane and in effect leads to the restriction of the tumor growth. Cholesterol end-capped PNIPAAm showing in vitro anticancer efficacy can be developed not only as drug carriers but also as components of combined/synergistic therapy.
Collapse
Affiliation(s)
- Pawel Misiak
- Faculty of Chemistry, University of Bialystok, Bialystok, Poland
| | | | | | | | - Przemysław Wielgat
- Department of Clinical Pharmacology, Medical University of Bialystok, Bialystok, Poland
| | - Izabela Kurowska
- Faculty of Chemistry, University of Bialystok, Bialystok, Poland.,Doctoral School of Exact and Natural Sciences, University of Bialystok, Bialystok, Poland
| | | | | | - Halina Car
- Department of Experimental Pharmacology, Medical University of Bialystok, Bialystok, Poland
| | | |
Collapse
|
|
38
|
Shetty AK, Zanirati G. The Interstitial System of the Brain in Health and Disease. Aging Dis 2020; 11:200-211. [PMID: 32010493 PMCID: PMC6961771 DOI: 10.14336/ad.2020.0103] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 01/03/2020] [Indexed: 12/13/2022] Open
Abstract
The brain interstitial fluid (ISF) and the cerebrospinal fluid (CSF) cushion and support the brain cells. The ISF occupies the brain interstitial system (ISS), whereas the CSF fills the brain ventricles and the subarachnoid space. The brain ISS is an asymmetrical, tortuous, and exceptionally confined space between neural cells and the brain microvasculature. Recently, with a newly developed in vivo measuring technique, a series of discoveries have been made in the brain ISS and the drainage of ISF. The goal of this review is to confer recent advances in our understanding of the brain ISS, including its structure, function, and the various processes mediating or disrupting ISF drainage in physiological and pathological conditions. The brain ISF in the deep brain regions has recently been demonstrated to drain in a compartmentalized ISS instead of a highly connected system, together with the drainage of ISF into the cerebrospinal fluid (CSF) at the surface of the cerebral cortex and the transportation from CSF into cervical lymph nodes. Besides, accumulation of tau in the brain ISS in conditions such as Alzheimer’s disease and its link to the sleep-wake cycle and sleep deprivation, clearance of ISF in a deep sleep via increased CSF flow, novel approaches to remove beta-amyloid from the brain ISS, and obstruction to the ISF drainage in neurological conditions are deliberated. Moreover, the role of ISS in the passage of extracellular vesicles (EVs) released from neural cells and the rapid targeting of therapeutic EVs into neural cells in the entire brain following an intranasal administration, and the promise and limitations of ISS based drug delivery approaches are discussed
Collapse
Affiliation(s)
- Ashok K Shetty
- 1Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University College of Medicine, College Station, TX 77843, USA
| | - Gabriele Zanirati
- 2Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil
| |
Collapse
|
|
39
|
Li F, Guo P, Dong K, Guo P, Wang H, Lv X. Identification of Key Biomarkers and Potential Molecular Mechanisms in Renal Cell Carcinoma by Bioinformatics Analysis. J Comput Biol 2019; 26:1278-1295. [PMID: 31233342 DOI: 10.1089/cmb.2019.0145] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Renal cell carcinoma (RCC) is the most common form of kidney cancer, caused by renal epithelial cells. RCC remains to be a challenging public health problem worldwide. Metastases that are resistant to radiotherapy and chemotherapy are the major cause of death from cancer. However, the underlying molecular mechanism regulating the metastasis of RCC is poorly known. Publicly available databases of RCC were obtained from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified using GEO2R analysis, whereas the Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed by Gene Set Enrichment Analysis (GSEA) and Metascape. Protein-protein interaction (PPI) network of DEGs was analyzed by STRING online database, and Cytoscape software was used for visualizing PPI network. Survival analysis of hub genes was conducted using GEPIA online database. The expression levels of hub genes were investigated from The Human Protein Atlas online database and GEPIA online database. Finally, the comparative toxicogenomics database (CTD; http://ctdbase.org) was used to identify hub genes associated with tumor or metastasis. We identified 229 DEGs comprising 135 downregulated genes and 94 upregulated genes. Functional analysis revealed that these DEGs were associates with cell recognition, regulation of immune, negative regulation of adaptive immune response, and other functions. And these DEGs mainly related to P53 signaling pathway, cytokine-cytokine receptor interaction, Natural killer cell mediated cytotoxicity, and other pathways are involved. Ten genes were identified as hub genes through module analyses in the PPI network. Finally, survival analysis of 10 hub genes was conducted, which showed that the MMP2 (matrix metallo peptidase 2), DCN, COL4A1, CASR (calcium sensing receptor), GPR4 (G protein-coupled receptor 4), UTS2 (urotensin 2), and LDLR (low density lipoprotein receptor) genes were significant for survival. In this study, the DEGs between RCC and metastatic RCC were analyzed, which assist us in systematically understanding the pathogeny underlying metastasis of RCC. The MMP2, DCN, COL4A1, CASR, GPR4, UTS2, and LDLR genes might be used as potential targets to improve diagnosis and immunotherapy biomarkers for RCC.
Collapse
Affiliation(s)
- Feng Li
- Department of Urology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Peiyuan Guo
- School of Basic Medical Sciences, Hebei Medical University, Shijiazhuang, P.R. China
| | - Keqin Dong
- School of Basic Medical Sciences, Hebei Medical University, Shijiazhuang, P.R. China
| | - Peng Guo
- Department of Orthopedics, The Fourth Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Haoyuan Wang
- School of Basic Medical Sciences, Hebei Medical University, Shijiazhuang, P.R. China
| | - Xianqiang Lv
- Department of Urology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| |
Collapse
|
|
40
|
Alomari M, Almohazey D, Almofty SA, Khan FA, Al Hamad M, Ababneh D. Role of Lipid Rafts in Hematopoietic Stem Cells Homing, Mobilization, Hibernation, and Differentiation. Cells 2019; 8:cells8060630. [PMID: 31234505 PMCID: PMC6627378 DOI: 10.3390/cells8060630] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 06/07/2019] [Accepted: 06/14/2019] [Indexed: 12/17/2022] Open
Abstract
Hematopoietic stem cells (HSCs) are multipotent, self-renewing cells that can differentiate into myeloid or lymphoid cells. The mobilization and differentiation processes are affected by the external environment, such as extracellular matrix and soluble molecules in the niche, where the lipid rafts (LRs) of the HSCs act as the receptors and control platforms for these effectors. LRs are membrane microdomains that are enriched in cholesterol, sphingolipid, and proteins. They are involved in diverse cellular processes including morphogenesis, cytokinesis, signaling, endocytic events, and response to the environment. They are also involved in different types of diseases, such as cancer, Alzheimer's, and prion disease. LR clustering and disruption contribute directly to the differentiation, homing, hibernation, or mobilization of HSCs. Thus, characterization of LR integrity may provide a promising approach to controlling the fate of stem cells for clinical applications. In this review, we show the critical role of LR modification (clustering, disruption, protein incorporation, and signal responding) in deciding the fate of HSCs, under the effect of soluble cytokines such as stem cell factor (SCF), transforming growth factor- β (TGF-β), hematopoietic-specific phospholipase Cβ2 (PLC-β2), and granulocyte colony-stimulating factor (G-CSF).
Collapse
Affiliation(s)
- Munther Alomari
- Department of Stem Cell Biology, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Post Box No. 1982, Dammam 31441, Saudi Arabia.
| | - Dana Almohazey
- Department of Stem Cell Biology, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Post Box No. 1982, Dammam 31441, Saudi Arabia.
| | - Sarah Ameen Almofty
- Department of Stem Cell Biology, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Post Box No. 1982, Dammam 31441, Saudi Arabia.
| | - Firdos Alam Khan
- Department of Stem Cell Biology, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Post Box No. 1982, Dammam 31441, Saudi Arabia.
| | - Mohammad Al Hamad
- Department of Pathology, College of Medicine, Imam Abdulrahman Bin Faisal University, Post Box No. 1982, Dammam 31441, Saudi Arabia.
| | - Deena Ababneh
- Department of Basic Sciences and Humanities, College of Engineering, Imam Abdulrahman Bin Faisal University, Post Box No. 1982, Dammam 31441, Saudi Arabia.
| |
Collapse
|
|
41
|
Bruno S, Chiabotto G, Favaro E, Deregibus MC, Camussi G. Role of extracellular vesicles in stem cell biology. Am J Physiol Cell Physiol 2019; 317:C303-C313. [PMID: 31091143 DOI: 10.1152/ajpcell.00129.2019] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The extracellular vesicles (EVs) are membrane vesicles carrying proteins, nucleic acids, and bioactive lipids of the cell of origin. These vesicles released within the extracellular space and entering into the circulation may transfer their cargo to neighboring or distant cells and induce phenotypical and functional changes that may be relevant in several physiopathological conditions. In an attempt to define the biological properties of EVs, several investigations have focused on their cargo and on the effects elicited in recipient cells. EVs have been involved in modulation of tumor microenvironment and behavior, as well as in the immune and inflammatory response. In the present review, we address the paracrine action of EVs released by stem cells and their potential involvement in the activation of regenerative programs in injured cells.
Collapse
Affiliation(s)
- Stefania Bruno
- Department of Medical Sciences, University of Torino, Turin, Italy
| | - Giulia Chiabotto
- Department of Medical Sciences, University of Torino, Turin, Italy
| | - Enrica Favaro
- Department of Medical Sciences, University of Torino, Turin, Italy
| | | | - Giovanni Camussi
- Department of Medical Sciences, University of Torino, Turin, Italy
| |
Collapse
|
|
42
|
Michalak M, Warnken U, Schnölzer M, Gabius HJ, Kopitz J. Detection of malignancy-associated phosphoproteome changes in human colorectal cancer induced by cell surface binding of growth-inhibitory galectin-4. IUBMB Life 2018; 71:364-375. [PMID: 30550624 DOI: 10.1002/iub.1987] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 11/21/2018] [Accepted: 11/21/2018] [Indexed: 01/28/2023]
Abstract
Emerging evidence on efficient tumor growth regulation by endogenous lectins directs interest to determine on a proof-of-principle level the range of information on alterations provided by full-scale analysis using phosphoproteomics. In our pilot study, we tested galectin-4 (gal-4) that is a growth inhibitor for colon cancer cells (CRC), here working with the LS 180 line. In order to cover monitoring of short- and long-term effects stable isotope labeling by amino acids in cell culture-based quantitative phosphoproteomic analyses were conducted on LS 180 cell preparations collected 1 and 72 h after adding gal-4 to the culture medium. After short-term treatment, 981 phosphosites, all of them S/T based, were detected by phosphoproteomics. Changes higher than 1.5-fold were seen for eight sites in seven proteins. Most affected were the BET1 homolog (BET1), whose level of phosphorylation at S50 was about threefold reduced, and centromere protein F (CENPF), extent of phosphorylation at S3119 doubling in gal-4-treated cells. Phosphoproteome analysis after 72 h of treatment revealed marked changes at 33 S/T-based phosphosites from 29 proteins. Prominent increase of phosphorylation was observed for cofilin-1 at position S3. Extent of phosphorylation of the glutamine transporter SLC1A5 at position S503 was decreased by a factor of 3. Altered phosphorylation of BET1, CENPF, and cofilin-1 as well as a significant effect of gal-4 treatment on glutamine uptake by cells were substantiated by independent methods in the Vaco 432, Colo 205, CX 1, and HCT 116 cell lines. With the example of gal-4 which functions as a tumor suppressor in CRC cells, we were able to prove that cell surface binding of the lectin not only markedly influences the cell proteome, but also has a bearing on malignancy-associated intracellular protein phosphorylation. These results underscore the potential of this approach to give further work on elucidating the details of signaling underlying galectin-triggered growth inhibition a clear direction. © 2018 IUBMB Life, 71(3):364-375, 2019.
Collapse
Affiliation(s)
- Malwina Michalak
- Department of Applied Tumor Biology, Institute of Pathology, Medical School of the Ruprecht-Karls-University, Heidelberg, Germany.,Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Uwe Warnken
- Functional Proteome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Martina Schnölzer
- Functional Proteome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hans-Joachim Gabius
- Faculty of Veterinary Medicine, Institute of Physiological Chemistry, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Jürgen Kopitz
- Department of Applied Tumor Biology, Institute of Pathology, Medical School of the Ruprecht-Karls-University, Heidelberg, Germany.,Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| |
Collapse
|
|
43
|
Ruiz M, Bodhicharla R, Svensk E, Devkota R, Busayavalasa K, Palmgren H, Ståhlman M, Boren J, Pilon M. Membrane fluidity is regulated by the C. elegans transmembrane protein FLD-1 and its human homologs TLCD1/2. eLife 2018; 7:e40686. [PMID: 30509349 PMCID: PMC6279351 DOI: 10.7554/elife.40686] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 11/04/2018] [Indexed: 12/15/2022] Open
Abstract
Dietary fatty acids are the main building blocks for cell membranes in animals, and mechanisms must therefore exist that compensate for dietary variations. We isolated C. elegans mutants that improved tolerance to dietary saturated fat in a sensitized genetic background, including eight alleles of the novel gene fld-1 that encodes a homolog of the human TLCD1 and TLCD2 transmembrane proteins. FLD-1 is localized on plasma membranes and acts by limiting the levels of highly membrane-fluidizing long-chain polyunsaturated fatty acid-containing phospholipids. Human TLCD1/2 also regulate membrane fluidity by limiting the levels of polyunsaturated fatty acid-containing membrane phospholipids. FLD-1 and TLCD1/2 do not regulate the synthesis of long-chain polyunsaturated fatty acids but rather limit their incorporation into phospholipids. We conclude that inhibition of FLD-1 or TLCD1/2 prevents lipotoxicity by allowing increased levels of membrane phospholipids that contain fluidizing long-chain polyunsaturated fatty acids. Editorial note This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
Collapse
Affiliation(s)
- Mario Ruiz
- Department of Chemistry and Molecular BiologyUniversity of GothenburgGothenburgSweden
| | - Rakesh Bodhicharla
- Department of Chemistry and Molecular BiologyUniversity of GothenburgGothenburgSweden
| | - Emma Svensk
- Department of Chemistry and Molecular BiologyUniversity of GothenburgGothenburgSweden
| | - Ranjan Devkota
- Department of Chemistry and Molecular BiologyUniversity of GothenburgGothenburgSweden
| | - Kiran Busayavalasa
- Department of Chemistry and Molecular BiologyUniversity of GothenburgGothenburgSweden
| | - Henrik Palmgren
- Department of Chemistry and Molecular BiologyUniversity of GothenburgGothenburgSweden
- Diabetes Bioscience, Cardiovascular, Renal and Metabolism, IMED Biotech UnitAstraZenecaGothenburgSweden
| | - Marcus Ståhlman
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of MedicineUniversity of GothenburgGothenburgSweden
| | - Jan Boren
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of MedicineUniversity of GothenburgGothenburgSweden
| | - Marc Pilon
- Department of Chemistry and Molecular BiologyUniversity of GothenburgGothenburgSweden
| |
Collapse
|
|
44
|
Lopes-de-Araújo J, Reis S, Nunes C. Topotecan effect on the structure of normal and cancer plasma membrane lipid models: A multi-model approach. Eur J Pharm Sci 2018; 123:515-523. [DOI: 10.1016/j.ejps.2018.08.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 07/25/2018] [Accepted: 08/03/2018] [Indexed: 12/20/2022]
|
|
45
|
de Araujo Farias V, O’Valle F, Serrano-Saenz S, Anderson P, Andrés E, López-Peñalver J, Tovar I, Nieto A, Santos A, Martín F, Expósito J, Oliver FJ, de Almodóvar JMR. Exosomes derived from mesenchymal stem cells enhance radiotherapy-induced cell death in tumor and metastatic tumor foci. Mol Cancer 2018; 17:122. [PMID: 30111323 PMCID: PMC6094906 DOI: 10.1186/s12943-018-0867-0] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Accepted: 07/31/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND We have recently shown that radiotherapy may not only be a successful local and regional treatment but, when combined with MSCs, may also be a novel systemic cancer therapy. This study aimed to investigate the role of exosomes derived from irradiated MSCs in the delay of tumor growth and metastasis after treatment with MSC + radiotherapy (RT). METHODS We have measured tumor growth and metastasis formation, of subcutaneous human melanoma A375 xenografts on NOD/SCID-gamma mice, and the response of tumors to treatment with radiotherapy (2 Gy), mesenchymal cells (MSC), mesenchymal cells plus radiotherapy, and without any treatment. Using proteomic analysis, we studied the cargo of the exosomes released by the MSC treated with 2 Gy, compared with the cargo of exosomes released by MSC without treatment. RESULTS The tumor cell loss rates found after treatment with the combination of MSC and RT and for exclusive RT, were: 44.4% % and 12,1%, respectively. Concomitant and adjuvant use of RT and MSC, increased the mice surviving time 22,5% in this group, with regard to the group of mice treated with exclusive RT and in a 45,3% respect control group. Moreover, the number of metastatic foci found in the internal organs of the mice treated with MSC + RT was 60% less than the mice group treated with RT alone. We reasoned that the exosome secreted by the MSC, could be implicated in tumor growth delay and metastasis control after treatment. CONCLUSIONS Our results show that exosomes derived form MSCs, combined with radiotherapy, are determinant in the enhancement of radiation effects observed in the control of metastatic spread of melanoma cells and suggest that exosome-derived factors could be involved in the bystander, and abscopal effects found after treatment of the tumors with RT plus MSC. Radiotherapy itself may not be systemic, although it might contribute to a systemic effect when used in combination with mesenchymal stem cells owing the ability of irradiated MSCs-derived exosomes to increase the control of tumor growth and metastasis.
Collapse
Affiliation(s)
- Virgínea de Araujo Farias
- Instituto Universitario de Investigación en Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, PTS Granada and CIBERONC (Instituto de Salud Carlos III), 18016 Granada, Spain
- Instituto de Parasitología y Biomedicina “López Neyra”, Consejo Superior de Investigaciones Científicas, PTS Granada, 18016 and CIBERONC (Instituto de Salud Carlos III), Granada, Spain
| | - Francisco O’Valle
- Instituto Universitario de Investigación en Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, PTS Granada and CIBERONC (Instituto de Salud Carlos III), 18016 Granada, Spain
- Departamento de Anatomía Patológica, Facultad de Medicina, Universidad de Granada, PTS Granada, 18016 Granada, Spain
| | - Santiago Serrano-Saenz
- Instituto de Parasitología y Biomedicina “López Neyra”, Consejo Superior de Investigaciones Científicas, PTS Granada, 18016 and CIBERONC (Instituto de Salud Carlos III), Granada, Spain
| | - Per Anderson
- GENYO, Centre for Genomics and Oncological Research, Pfizer/Universidad de Granada/Junta de Andalucía, PTS Granada, 18016 Granada, Spain
| | - Eduardo Andrés
- Instituto de Parasitología y Biomedicina “López Neyra”, Consejo Superior de Investigaciones Científicas, PTS Granada, 18016 and CIBERONC (Instituto de Salud Carlos III), Granada, Spain
| | - Jesús López-Peñalver
- Instituto Universitario de Investigación en Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, PTS Granada and CIBERONC (Instituto de Salud Carlos III), 18016 Granada, Spain
- Unidad de radiología experimental, Centro de Instrumentación Científica, Centro de Investigación Biomédica, Universidad de Granada, PTS Granada, 18016 Granada, Spain
| | - Isabel Tovar
- Complejo Hospitalario de Granada, Servicio Andaluz de Salud, PTS Granada, 18016 Granada, Spain
| | - Ana Nieto
- Instituto Universitario de Investigación en Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, PTS Granada and CIBERONC (Instituto de Salud Carlos III), 18016 Granada, Spain
- Unidad de experimentación animal, Centro de Instrumentación Científica, Centro de Investigación Biomédica, Universidad de Granada, PTS Granada, 18016 Granada, Spain
| | - Ana Santos
- Instituto Universitario de Investigación en Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, PTS Granada and CIBERONC (Instituto de Salud Carlos III), 18016 Granada, Spain
- Unidad de microscopia, Centro de Instrumentación Científica, Centro de Investigación Biomédica, Universidad de Granada, PTS Granada, 18016 Granada, Spain
| | - Francisco Martín
- GENYO, Centre for Genomics and Oncological Research, Pfizer/Universidad de Granada/Junta de Andalucía, PTS Granada, 18016 Granada, Spain
| | - José Expósito
- Complejo Hospitalario de Granada, Servicio Andaluz de Salud, PTS Granada, 18016 Granada, Spain
| | - F. Javier Oliver
- Instituto de Parasitología y Biomedicina “López Neyra”, Consejo Superior de Investigaciones Científicas, PTS Granada, 18016 and CIBERONC (Instituto de Salud Carlos III), Granada, Spain
| | - José Mariano Ruiz de Almodóvar
- Instituto Universitario de Investigación en Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, PTS Granada and CIBERONC (Instituto de Salud Carlos III), 18016 Granada, Spain
- Complejo Hospitalario de Granada, Servicio Andaluz de Salud, PTS Granada, 18016 Granada, Spain
| |
Collapse
|
|
46
|
Cholesterol inhibits hepatocellular carcinoma invasion and metastasis by promoting CD44 localization in lipid rafts. Cancer Lett 2018; 429:66-77. [DOI: 10.1016/j.canlet.2018.04.038] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 04/25/2018] [Accepted: 04/26/2018] [Indexed: 02/07/2023]
|
|
47
|
Ma J, Zhang L, Yang P, Zeng ZC, Xiang ZL. Integrated analysis of long noncoding RNA expression profiles in lymph node metastasis of hepatocellular carcinoma. Gene 2018; 676:47-55. [PMID: 29981417 DOI: 10.1016/j.gene.2018.07.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Revised: 06/15/2018] [Accepted: 07/01/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and metastasis of HCC is the leading cause of poor prognosis. Among all the extrahepatic metastases, lymph node metastasis (LNM) is common, second only to lung metastasis. However, the pathogenesis of HCC LNM remains largely unknown. METHODS Microarray was performed to investigate the long noncoding RNA (lncRNA) and messenger RNA (mRNA) expression profiles in serum samples from HCC LNM patients (N = 4) and HCC non-LNM controls (N = 5). Subsequently, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was applied to validate the expression levels of randomly selected differential lncRNAs and mRNAs. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were employed to explore the potential functions of differentially expressed mRNAs. Co-expression networks were further constructed to elucidate the interactions of the differential genes and to speculate on the potential functions of the dominant lncRNAs. In this research, we attempted to illuminate the correlations between lncRNA and HCC LNM. RESULTS Compared with the non-LNM group, a total of 234 lncRNAs and 58 mRNAs were obtained as significantly dysregulated genes in LNM group (p < 0.05, fold change ≥ 2). Functional enrichment analyses showed that upregulated mRNAs are mostly enriched for glucose-6-phosphate dehydrogenase activity, biotin binding and AP-3 adaptor complex, while the downregulated mRNAs are enriched for macrophage colony-stimulating factor receptor binding, succinate-CoA ligase activity and palmitoyltransferase activity. In addition, coexpression network revealed that the dominant lncRNAs are potential participants of protein metabolic process, integral component of membrane, RNA binding, Golgi apparatus, as well as focal adhesion pathway. CONCLUSION This study first revealed the expression profiles and potential functions of dysregulated lncRNAs and mRNAs in HCC LNM, which may provide novel clues for further studies on HCC LNM.
Collapse
Affiliation(s)
- Jie Ma
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Li Zhang
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ping Yang
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhao-Chong Zeng
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Zuo-Lin Xiang
- Department of Radiation Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
| |
Collapse
|
|
48
|
Karbanová J, Lorico A, Bornhäuser M, Corbeil D, Fargeas CA. Prominin-1/CD133: Lipid Raft Association, Detergent Resistance, and Immunodetection. Stem Cells Transl Med 2017; 7:155-160. [PMID: 29271118 PMCID: PMC5788878 DOI: 10.1002/sctm.17-0223] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2017] [Accepted: 11/17/2017] [Indexed: 01/17/2023] Open
Abstract
The cell surface antigen prominin‐1 (alias CD133) has gained enormous interest in the past 2 decades and given rise to debates as to its utility as a biological stem and cancer stem cell marker. Important and yet often overlooked knowledge that is pertinent to its physiological function has been generated in other systems given its more general expression beyond primitive cells. This article briefly discusses the importance of particular biochemical features of CD133 with relation to its association with membrane microdomains (lipid rafts) and proper immunodetection. It also draws attention toward the adequate use of detergents and caveats that may apply to the interpretation of the results generated. Stem Cells Translational Medicine2018;7:155–160
Collapse
Affiliation(s)
- Jana Karbanová
- Tissue Engineering Laboratories, Biotechnology Center (BIOTEC), Dresden, Germany.,DFG Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany
| | - Aurelio Lorico
- Department of Pathology, College of Medicine, Roseman University of Health Sciences, Las Vegas, Nevada, USA
| | - Martin Bornhäuser
- DFG Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany.,Medical Clinic and Polyclinic I, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Denis Corbeil
- Tissue Engineering Laboratories, Biotechnology Center (BIOTEC), Dresden, Germany.,DFG Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany
| | - Christine A Fargeas
- Tissue Engineering Laboratories, Biotechnology Center (BIOTEC), Dresden, Germany
| |
Collapse
|
|
49
|
The brain interstitial system: Anatomy, modeling, in vivo measurement, and applications. Prog Neurobiol 2017; 157:230-246. [DOI: 10.1016/j.pneurobio.2015.12.007] [Citation(s) in RCA: 114] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 11/18/2015] [Accepted: 12/02/2015] [Indexed: 01/01/2023]
|
|
50
|
Chabanon M, Stachowiak JC, Rangamani P. Systems biology of cellular membranes: a convergence with biophysics. WILEY INTERDISCIPLINARY REVIEWS. SYSTEMS BIOLOGY AND MEDICINE 2017; 9. [PMID: 28475297 PMCID: PMC5561455 DOI: 10.1002/wsbm.1386] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 02/02/2017] [Accepted: 02/21/2017] [Indexed: 12/12/2022]
Abstract
Systems biology and systems medicine have played an important role in the last two decades in shaping our understanding of biological processes. While systems biology is synonymous with network maps and '-omics' approaches, it is not often associated with mechanical processes. Here, we make the case for considering the mechanical and geometrical aspects of biological membranes as a key step in pushing the frontiers of systems biology of cellular membranes forward. We begin by introducing the basic components of cellular membranes, and highlight their dynamical aspects. We then survey the functions of the plasma membrane and the endomembrane system in signaling, and discuss the role and origin of membrane curvature in these diverse cellular processes. We further give an overview of the experimental and modeling approaches to study membrane phenomena. We close with a perspective on the converging futures of systems biology and membrane biophysics, invoking the need to include physical variables such as location and geometry in the study of cellular membranes. WIREs Syst Biol Med 2017, 9:e1386. doi: 10.1002/wsbm.1386 For further resources related to this article, please visit the WIREs website.
Collapse
Affiliation(s)
- Morgan Chabanon
- Department of Mechanical and Aerospace Engineering, University of California San Diego, La Jolla, CA, USA
| | - Jeanne C Stachowiak
- Department of Biomedical Engineering, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX, USA
| | - Padmini Rangamani
- Department of Mechanical and Aerospace Engineering, University of California San Diego, La Jolla, CA, USA
| |
Collapse
|