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Sentoku M, Endo M, Takei M, Hanamoto W, Yasuda K. Geometrical constraint change determines organized collective migration of follower cells. Sci Rep 2025; 15:8199. [PMID: 40065059 PMCID: PMC11894221 DOI: 10.1038/s41598-025-93283-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Accepted: 03/05/2025] [Indexed: 03/14/2025] Open
Abstract
Spatial confinement plays a critical role in shaping collective cell migration, particularly in regulating interactions between leader and follower cells and among follower cells themselves. However, how changes in confinement geometry influence migration dynamics and cell-to-cell interactions remains poorly understood. This study leverages a novel microchannel design to systematically dissect the interplay between spatial confinement and collective cell behavior in endothelial-like cells (MILE SVEN 1). In a single-cell-wide T-shaped branching structure, rear cells selected alternate pathways, avoiding direct alignment with preceding cells. This highlights how spatial geometry mediates follower-follower interactions by encouraging dynamic rearrangements within the cell train. Ladder-like branching structures with consistent total pathway widths showed that dividing and reassembling cell trains had minimal impact on migration velocity, provided no compression or expansion occurred. Wide-narrow-wide patterns demonstrated distinct effects: stepwise transitions accelerated cells in narrow sections, increasing directional alignment driven by spatial restriction, followed by decreased alignment in wider regions. Gradual transitions maintained stable alignment and minimized disruptions, emphasizing the importance of smooth geometrical transitions in preserving robust collective behavior. These findings reveal how spatial confinement integrates follower-follower interactions and dynamic realignment. By linking geometric transitions to collective cell dynamics, our study advances the understanding of physical guidance mechanisms and offers a platform for investigating spatial influences on migrating cellular systems.
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Affiliation(s)
- Mitsuru Sentoku
- Department of Pure and Applied Physics, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, 169-8555, Japan
| | - Masaharu Endo
- Department of Pure and Applied Physics, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, 169-8555, Japan
| | - Miki Takei
- Department of Pure and Applied Physics, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, 169-8555, Japan
| | - Wataru Hanamoto
- Department of Physics, School of Advanced Science and Engineering, Waseda University, Tokyo, 169-8555, Japan
| | - Kenji Yasuda
- Department of Pure and Applied Physics, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, 169-8555, Japan.
- Department of Physics, School of Advanced Science and Engineering, Waseda University, Tokyo, 169-8555, Japan.
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Alsaab HO, Almutairy B, Almobarki AO, Mughaedh MAA, Alzahrani MS. Exosome's role in ovarian disease pathogenesis and therapy; Focus on ovarian cancer and failure. J Reprod Immunol 2025; 167:104403. [PMID: 39662240 DOI: 10.1016/j.jri.2024.104403] [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: 10/28/2024] [Revised: 11/16/2024] [Accepted: 11/28/2024] [Indexed: 12/13/2024]
Abstract
In the eukaryotic system, exosomes are categorized as unique extracellular vesicles with dimensions ranging from 30 to 150 nm. These vesicles contain a variety of endogenous molecules, such as proteins, DNA, mRNA, microRNA, and circular RNA. They are essential for a wide range of metabolic events and have the potential to be used as therapeutic or diagnostic targets for a number of diseases, including ovarian diseases. By inducing changes in the surrounding environment, the donor exosomes transfer their contents to the receiving cells, so demonstrating the biological implications of major interactions between cells. Mesenchymal stem cells (MSCs) have produced exosomes have shown promise as a treatment for premature organ failure (POF or POI). Furthermore, exosomal transport has many complexities, and contributes to the pathophysiology of ovarian cancer by affecting cell growth, migration, metastastsis and etc. Owing to these facts, in this paper, we present the progress developed in the understanding of exosomes as a viable therapeutic avenue and indisputable prognostic targets in ovarian disorders.
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Affiliation(s)
- Hashem O Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, Taif University, Taif 21944, Saudi Arabia.
| | - Bandar Almutairy
- Department of Pharmacology, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia.
| | | | | | - Mohammad S Alzahrani
- Department of Clinical Pharmacy, College of Pharmacy, Taif University, P.O. Box 11099, Taif , Saudi Arabia
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3
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Alqahtani NF, Alfaifi MY, Shati A A, Elbehairi SEI, Saleh AM, Kotb ES, Serag WM, Elshaarawy RFM, Alhamdi HW, Hassan YA. Molecular docking and in vivo/ in vitro studies of a novel thiadiazole Schiff base as a hepatoprotective drug against angiogenesis induced by breast cancer. RSC Adv 2024; 14:39027-39039. [PMID: 39659603 PMCID: PMC11629753 DOI: 10.1039/d4ra06398h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 10/17/2024] [Indexed: 12/12/2024] Open
Abstract
Two new thiadiazole imidazolium salicylidene Schiff bases (TISSBs) were successfully synthesized, and their structures were analyzed comprehensively using spectroscopic techniques. The results of the MTT assay showed that TISSB2 was the safest and most effective anti-breast cancer agent. The anti-angiogenic activity of TISSB2 was evaluated using in vivo tests in Ehrlich ascites carcinoma (EAC)-bearing Swiss albino mice. The degree of angiogenesis was assessed by measuring the levels of vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), and transforming growth factor-β1 (TGF-β1). The results of biochemical, immunohistochemical, and histopathological examinations indicated that TISSB2 could restore the normal functional indices of the injured liver, as evident from the downregulated TGF-β1, TNF-α, and VEGF levels reverting to normal values. Moreover, in the molecular docking study, TISSB2 exhibited stronger interactions with VEGFR-2 and NF-κB proteins, with binding affinity scores of -11.79 and -9.25 kcal mol-1, respectively. These stronger interactions involved H-bonding, ionic bonds, and hydrophobic π-interactions. Overall, TISSB2 can be a promising therapeutic option for the treatment of EAC-induced tumour angiogenesis.
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Affiliation(s)
- Norah F Alqahtani
- Department of Chemistry, College of Science, University of Jeddah Jeddah 21589 Saudi Arabia
| | - Mohammad Y Alfaifi
- King Khalid University, Faculty of Science, Biology Department Abha 9004 Saudi Arabia
- Tissue Culture and Cancer Biology Research Laboratory, King Khalid University Abha 9004 Saudi Arabia
| | - Ali Shati A
- King Khalid University, Faculty of Science, Biology Department Abha 9004 Saudi Arabia
- Tissue Culture and Cancer Biology Research Laboratory, King Khalid University Abha 9004 Saudi Arabia
| | - Serag Eldin I Elbehairi
- King Khalid University, Faculty of Science, Biology Department Abha 9004 Saudi Arabia
- Tissue Culture and Cancer Biology Research Laboratory, King Khalid University Abha 9004 Saudi Arabia
- Cell Culture Lab, Egyptian Organization for Biological Products and Vaccines (VACSERA Holding Company) 51 Wezaret El-Zeraa St., Agouza Giza Egypt
| | - Abdulrahman M Saleh
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University Kasr El-Aini Street Cairo 11562 Egypt
- Aweash El-Hagar Family Medicine Center, Epidemiological Surveillance Unit, MOHP Mansoura 35711 Egypt
| | - Ebtesam S Kotb
- Department of Chemistry, Faculty of Science, Suez University 43533 Suez Egypt
| | - Waleed M Serag
- Department of Chemistry, Faculty of Science, Suez University 43533 Suez Egypt
| | - Reda F M Elshaarawy
- Department of Chemistry, Faculty of Science, Suez University 43533 Suez Egypt
- Institut für Anorganische Chemie und Strukturchemie, Heinrich-Heine Universität Düsseldorf Düsseldorf Germany
| | - Heba W Alhamdi
- College of Sciences, Biology Department, King Khalid University Abha 61413 Saudi Arabia
| | - Yasser A Hassan
- Department of Pharmaceutics, Faculty of Pharmacy, Delta University for Science and Technology Gamasa Egypt
- Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Al-Kitab University Kirkuk Iraq
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Rass A, Eksteen C, Engelbrecht AM. Paracrine signalling in breast cancer: Insights into the tumour endothelial phenotype. Acta Histochem 2024; 126:152191. [PMID: 39216306 DOI: 10.1016/j.acthis.2024.152191] [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: 04/03/2024] [Revised: 08/15/2024] [Accepted: 08/16/2024] [Indexed: 09/04/2024]
Abstract
Tumour endothelial cells (TECs) are genetically and phenotypically distinct from their normal, healthy counterparts and provide various pro-tumourigenic effects. This study aimed to investigate the impact of conditioned media (CM) from non-tumourigenic MCF-12A breast epithelial cells as well as from MCF-7 and MDA-MB-231 breast cancer cells on human umbilical vein endothelial cells (HUVECs). Significant increases in cell viability were observed across all breast CM groups compared to controls, with notable differences between the MCF-12A, MCF-7, and MDA-MB-231 groups. Despite increased viability, no significant differences in MCM2 expression, a marker of cell proliferation, were detected. Morphological changes in HUVECs, including elongation, lumen formation, and branching, were more pronounced in breast cancer CM groups, especially in the MDA-MB-231 CM group. qPCR and Western blot analyses showed increased expression of TEC markers such as MDR1, LOX, and TEM8 in HUVECs treated with MCF-12A CM. The MCF-7 CM group significantly enhanced HUVEC migratory activity compared to MCF-12A CM, as evidenced by a scratch assay. These findings underscore distinct angiogenic responses elicited by non-tumourigenic and tumourigenic breast epithelial cells, with tumourigenic cells inducing a hyperactivated angiogenic response. The study highlights the differential effects of breast cancer cell paracrine signalling on endothelial cells and suggests the need for further investigation into TEC markers' role in both physiological and tumour angiogenesis.
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Affiliation(s)
- Atarah Rass
- Department of Physiological Sciences, Stellenbosch University, 2nd floor, Mike De Vries Building, Cnr. Merriman Ave & Bosman Street, Stellenbosch, South Africa.
| | - Carla Eksteen
- Department of Physiological Sciences, Stellenbosch University, 2nd floor, Mike De Vries Building, Cnr. Merriman Ave & Bosman Street, Stellenbosch, South Africa
| | - Anna-Mart Engelbrecht
- Department of Physiological Sciences, Stellenbosch University, 2nd floor, Mike De Vries Building, Cnr. Merriman Ave & Bosman Street, Stellenbosch, South Africa; African Cancer Institute (ACI), Department of Global Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa
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5
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Czarczynska-Goslinska B, Goslinski T, Roszak A, Froelich A, Szyk P, Mlynarczyk DT, Sobotta L, Budnik I, Kordyl O, Osmałek T. Microneedle System Coated with Hydrogels Containing Protoporphyrin IX for Potential Application in Pharmaceutical Technology. Methods Protoc 2024; 7:73. [PMID: 39311374 PMCID: PMC11417702 DOI: 10.3390/mps7050073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 09/08/2024] [Accepted: 09/10/2024] [Indexed: 09/26/2024] Open
Abstract
The article aims to outline the potential of treating malignant skin cancer with microneedles covered with polymer layers containing a photosensitizer-protoporphyrin IX disodium salt (PPIX). The usefulness of stereolithography (SLA), which is a form of 3D-printing technology, for the preparation of a microneedle system with protoporphyrin IX was demonstrated. The SLA method allowed for pyramid-shaped microneedles to be printed that were covered with three different 0.1% PPIX hydrogels based on sodium alginate, xanthan, and poloxamer. Rheological tests and microscopic analysis of the hydrogels were performed. Microneedles coated with two layers of poloxamer-based hydrogel containing 0.1% PPIX were subjected to release tests in Franz diffusion cells. The release profile of PPIX initially increased and then remained relatively constant. The amount of substance released after a four-hour test in three Franz cells was 0.2569 ± 0.0683 mg/cm2. Moreover, the acute toxicity of this type of microneedle was assessed using the Microtox system. The obtained results show the usefulness of further development studies on microneedles as carriers of photosensitizing agents.
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Affiliation(s)
- Beata Czarczynska-Goslinska
- Chair and Department of Pharmaceutical Technology, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland; (A.R.); (T.O.)
| | - Tomasz Goslinski
- Chair and Department of Chemical Technology of Drugs, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland; (P.S.); (D.T.M.)
| | - Agata Roszak
- Chair and Department of Pharmaceutical Technology, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland; (A.R.); (T.O.)
| | - Anna Froelich
- 3D Printing Division, Chair and Department of Pharmaceutical Technology, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland; (A.F.); (I.B.); (O.K.)
| | - Piotr Szyk
- Chair and Department of Chemical Technology of Drugs, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland; (P.S.); (D.T.M.)
- Doctoral School, Poznan University of Medical Sciences, Bukowska 70, 60-812 Poznan, Poland
| | - Dariusz T. Mlynarczyk
- Chair and Department of Chemical Technology of Drugs, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland; (P.S.); (D.T.M.)
| | - Lukasz Sobotta
- Chair and Department of Inorganic and Analytical Chemistry, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland;
| | - Irena Budnik
- 3D Printing Division, Chair and Department of Pharmaceutical Technology, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland; (A.F.); (I.B.); (O.K.)
| | - Oliwia Kordyl
- 3D Printing Division, Chair and Department of Pharmaceutical Technology, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland; (A.F.); (I.B.); (O.K.)
| | - Tomasz Osmałek
- Chair and Department of Pharmaceutical Technology, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland; (A.R.); (T.O.)
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Zhang J, Xu X, Deng H, Liu L, Xiang Y, Feng J. Overcoming cancer drug-resistance calls for novel strategies targeting abnormal alternative splicing. Pharmacol Ther 2024; 261:108697. [PMID: 39025436 DOI: 10.1016/j.pharmthera.2024.108697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 05/12/2024] [Accepted: 07/15/2024] [Indexed: 07/20/2024]
Abstract
Abnormal gene alternative splicing (AS) events are strongly associated with cancer progression. Here, we summarize AS events that contribute to the development of drug resistance and classify them into three categories: alternative cis-splicing (ACS), alternative trans-splicing (ATS), and alternative back-splicing (ABS). The regulatory mechanisms underlying AS processes through cis-acting regulatory elements and trans-acting factors are comprehensively described, and the distinct functions of spliced variants, including linear spliced variants derived from ACS, chimeric spliced variants arising from ATS, and circRNAs generated through ABS, are discussed. The identification of dysregulated spliced variants, which contribute to drug resistance and hinder effective cancer treatment, suggests that abnormal AS processes may together serve as a precise regulatory mechanism enabling drug-resistant cancer cell survival or, alternatively, represent an evolutionary pathway for cancer cells to adapt to changes in the external environment. Moreover, this review summarizes recent advancements in treatment approaches targeting AS-associated drug resistance, focusing on cis-acting regulatory elements, trans-acting factors, and specific spliced variants. Collectively, gaining an in-depth understanding of the mechanisms underlying aberrant alternative splicing events and developing strategies to target this process hold great promise for overcoming cancer drug resistance.
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Affiliation(s)
- Ji Zhang
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province 646000, China; Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province 646000, China
| | - Xinyu Xu
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province 646000, China; Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province 646000, China
| | - Hongwei Deng
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province 646000, China; Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province 646000, China
| | - Li Liu
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province 646000, China; Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province 646000, China
| | - Yuancai Xiang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou city, Sichuan 646000, China.
| | - Jianguo Feng
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province 646000, China; Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province 646000, China; Nucleic Acid Medicine of Luzhou Key Laboratory, Southwest Medical University, Luzhou, Sichuan Province 646000, China.
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Alamoudi JA, El-Masry TA, Nasr M, Ibrahim IT, Ibrahim HA, Saad HM, El-Nagar MMF, Alshawwa SZ, Alrashidi A, El Zahaby EI. Fabrication of Nanocrystals for Enhanced Distribution of a Fatty Acid Synthase Inhibitor (Orlistat) as a Promising Method to Relieve Solid Ehrlich Carcinoma-Induced Hepatic Damage in Mice. Pharmaceuticals (Basel) 2024; 17:96. [PMID: 38256929 PMCID: PMC10820129 DOI: 10.3390/ph17010096] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 12/06/2023] [Accepted: 12/11/2023] [Indexed: 01/24/2024] Open
Abstract
BACKGROUND Orlistat (ORL) is an effective irreversible inhibitor of the lipase enzyme, and it possesses anticancer effects and limited aqueous solubility. This study was designed to improve the aqueous solubility, oral absorption, and tissue distribution of ORL via the formulation of nanocrystals (NCs). METHODS ORL-NC was prepared using the liquid antisolvent precipitation method (bottom-up technology), and it demonstrated significantly improved solubility compared with that of the blank crystals (ORL-BCs) and untreated ORL powder. The biodistribution and relative bioavailability of ORL-NC were investigated via the radiolabeling technique using Technetium-99m (99mTc). Female Swiss albino mice were used to examine the antitumor activity of ORL-NC against solid Ehrlich carcinoma (SEC)-induced hepatic damage in mice. RESULTS The prepared NCs improved ORL's solubility, bioavailability, and tissue distribution, with evidence of 258.70% relative bioavailability. In the in vivo study, the ORL-NC treatment caused a reduction in all tested liver functions (total and direct bilirubin, AST, ALT, and ALP) and improved modifications in liver sections that were marked using hematoxylin and eosin staining (H&E) and immunohistochemical staining (Ki-67 and ER-α) compared with untreated SEC mice. CONCLUSIONS The developed ORL-NC could be considered a promising formulation approach to enhance the oral absorption tissue distribution of ORL and suppress the liver damage caused by SEC.
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Affiliation(s)
- Jawaher Abdullah Alamoudi
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia; (J.A.A.); (S.Z.A.); (A.A.)
| | - Thanaa A. El-Masry
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt; (T.A.E.-M.); (H.A.I.)
| | - Mohamed Nasr
- Department of Pharmaceutics, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 35712, Egypt; (M.N.); (E.I.E.Z.)
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Helwan University, Cairo 11790, Egypt
| | - Ismail T. Ibrahim
- Labeled Compounds Department, Hot Laboratory Centre, Egyptian Atomic Energy Authority, Cairo 13759, Egypt;
- Department of Pharmacy, Al-Huda University College, Anbar 31001, Iraq
| | - Hanaa A. Ibrahim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt; (T.A.E.-M.); (H.A.I.)
| | - Hebatallah M. Saad
- Department of Pathology, Faculty of Veterinary Medicine, Matrouh University, Cairo 51511, Egypt;
| | - Maysa M. F. El-Nagar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt; (T.A.E.-M.); (H.A.I.)
| | - Samar Zuhair Alshawwa
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia; (J.A.A.); (S.Z.A.); (A.A.)
| | - Amal Alrashidi
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia; (J.A.A.); (S.Z.A.); (A.A.)
| | - Enas I. El Zahaby
- Department of Pharmaceutics, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 35712, Egypt; (M.N.); (E.I.E.Z.)
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Senrung A, Tripathi T, Aggarwal N, Janjua D, Chhokar A, Yadav J, Chaudhary A, Thakur K, Singh T, Bharti AC. Anti-angiogenic Potential of Trans-chalcone in an In Vivo Chick Chorioallantoic Membrane Model: An ATP Antagonist to VEGFR with Predicted Blood-brain Barrier Permeability. Cardiovasc Hematol Agents Med Chem 2024; 22:187-211. [PMID: 37936455 DOI: 10.2174/0118715257250417231019102501] [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: 02/24/2023] [Revised: 08/26/2023] [Accepted: 09/08/2023] [Indexed: 11/09/2023]
Abstract
BACKGROUND Glioblastoma multiforme (GBM) is characterized by massive tumorinduced angiogenesis aiding tumorigenesis. Vascular endothelial growth factor A (VEGF-A) via VEGF receptor 2 (VEGFR-2) constitutes majorly to drive this process. Putting a halt to tumordriven angiogenesis is a major clinical challenge, and the blood-brain barrier (BBB) is the prime bottleneck in GBM treatment. Several phytochemicals show promising antiangiogenic activity across different models, but their ability to cross BBB remains unexplored. METHODS We screened over 99 phytochemicals having anti-angiogenic properties reported in the literature and evaluated them for their BBB permeability, molecular interaction with VEGFR-2 domains, ECD2-3 (extracellular domains 2-3) and TKD (tyrosine kinase domain) at VEGF-A and ATP binding site, cell membrane permeability, and hepatotoxicity using in silico tools. Furthermore, the anti-angiogenic activity of predicted lead Trans-Chalcone (TC) was evaluated in the chick chorioallantoic membrane. RESULTS Out of 99 phytochemicals, 35 showed an efficient ability to cross BBB with a probability score of > 0.8. Docking studies revealed 30 phytochemicals crossing benchmark binding affinity < -6.4 kcal/mol of TKD with the native ligand ATP alone. Out of 30 phytochemicals, 12 showed moderate to low hepatotoxicity, and 5 showed a violation of Lipinski's rule of five. Our in silico analysis predicted TC as a BBB permeable anti-angiogenic compound for use in GBM therapy. TC reduced vascularization in the CAM model, which was associated with the downregulation of VEGFR-2 transcript expression. CONCLUSION The present study showed TC to possess anti-angiogenic potential via the inhibition of VEGFR-2. In addition, the study predicted TC to cross BBB as well as a safe alternative for GBM therapy, which needs further investigation.
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Affiliation(s)
- Anna Senrung
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
- Neuropharmacology & Drug Delivery Laboratory, Zoology Department, Daulat Ram College, University of Delhi, Delhi, 110007, India
| | - Tanya Tripathi
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
| | - Nikita Aggarwal
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
| | - Divya Janjua
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
| | - Arun Chhokar
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
- Department of Zoology, Deshbandhu College, University of Delhi, Delhi, 110019, India
| | - Joni Yadav
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
| | - Apoorva Chaudhary
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
| | - Kulbhushan Thakur
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
| | - Tejveer Singh
- Department of Zoology, Hansraj College, University of Delhi, Delhi, India
| | - Alok Chandra Bharti
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi (North Campus), Delhi, 110007, India
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Senrung A, Tripathi T, Aggarwal N, Janjua D, Yadav J, Chaudhary A, Chhokar A, Joshi U, Bharti AC. Phytochemicals Showing Antiangiogenic Effect in Pre-clinical Models and their Potential as an Alternative to Existing Therapeutics. Curr Top Med Chem 2024; 24:259-300. [PMID: 37867279 DOI: 10.2174/0115680266264349231016094456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 07/25/2023] [Accepted: 08/10/2023] [Indexed: 10/24/2023]
Abstract
Angiogenesis, the formation of new blood vessels from a pre-existing vascular network, is an important hallmark of several pathological conditions, such as tumor growth and metastasis, proliferative retinopathies, including proliferative diabetic retinopathy and retinopathy of prematurity, age-related macular degeneration, rheumatoid arthritis, psoriasis, and endometriosis. Putting a halt to pathology-driven angiogenesis is considered an important therapeutic strategy to slow down or reduce the severity of pathological disorders. Considering the attrition rate of synthetic antiangiogenic compounds from the lab to reaching the market due to severe side effects, several compounds of natural origin are being explored for their antiangiogenic properties. Employing pre-clinical models for the evaluation of novel antiangiogenic compounds is a promising strategy for rapid screening of antiangiogenic compounds. These studies use a spectrum of angiogenic model systems that include HUVEC two-dimensional culture, nude mice, chick chorioallantoic membrane, transgenic zebrafish, and dorsal aorta from rats and chicks, depending upon available resources. The present article emphasizes the antiangiogenic activity of the phytochemicals shown to exhibit antiangiogenic behavior in these well-defined existing angiogenic models and highlights key molecular targets. Different models help to get a quick understanding of the efficacy and therapeutics mechanism of emerging lead molecules. The inherent variability in assays and corresponding different phytochemicals tested in each study prevent their immediate utilization in clinical studies. This review will discuss phytochemicals discovered using suitable preclinical antiangiogenic models, along with a special mention of leads that have entered clinical evaluation.
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Affiliation(s)
- Anna Senrung
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
- Neuropharmacology and Drug Delivery Laboratory, Daulat Ram College, University of Delhi, Delhi, India
| | - Tanya Tripathi
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
| | - Nikita Aggarwal
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
| | - Divya Janjua
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
| | - Joni Yadav
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
| | - Apoorva Chaudhary
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
| | - Arun Chhokar
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
- Deshbandhu College, University of Delhi, Delhi, India
| | - Udit Joshi
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
| | - Alok Chandra Bharti
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
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10
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Thapa K, Khan H, Kaur G, Kumar P, Singh TG. Therapeutic targeting of angiopoietins in tumor angiogenesis and cancer development. Biochem Biophys Res Commun 2023; 687:149130. [PMID: 37944468 DOI: 10.1016/j.bbrc.2023.149130] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 10/12/2023] [Accepted: 10/17/2023] [Indexed: 11/12/2023]
Abstract
The formation and progression of tumors in humans are linked to the abnormal development of new blood vessels known as neo-angiogenesis. Angiogenesis is a broad word that encompasses endothelial cell migration, proliferation, tube formation, and intussusception, as well as peri-EC recruitment and extracellular matrix formation. Tumor angiogenesis is regulated by angiogenic factors, out of which some of the most potent angiogenic factors such as vascular endothelial growth factor and Angiopoietins (ANGs) in the body are produced by macrophages and other immune cells within the tumor microenvironment. ANGs have a distinct function in tumor angiogenesis and behavior. ANG1, ANG 2, ANG 3, and ANG 4 are the family members of ANG out of which ANG2 has been extensively investigated owing to its unique role in modifying angiogenesis and its tight association with tumor progression, growth, and invasion/metastasis, which makes it an excellent candidate for therapeutic intervention in human malignancies. ANG modulators have demonstrated encouraging outcomes in the treatment of tumor development, either alone or in conjunction with VEGF inhibitors. Future development of more ANG modulators targeting other ANGs is needed. The implication of ANG1, ANG3, and ANG4 as probable therapeutic targets for anti-angiogenesis treatment in tumor development should be also evaluated. The article has described the role of ANG in tumor angiogenesis as well as tumor growth and the treatment strategies modulating ANGs in tumor angiogenesis as demonstrated in clinical studies. The pharmacological modulation of ANGs and ANG-regulated pathways that are responsible for tumor angiogenesis and cancer development should be evaluated for the development of future molecular therapies.
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Affiliation(s)
- Komal Thapa
- Chitkara School of Pharmacy, Chitkara University, 174103, Himachal Pradesh, India
| | - Heena Khan
- Chitkara College of Pharmacy, Chitkara University, 140401, Punjab, India
| | - Gagandeep Kaur
- Chitkara School of Pharmacy, Chitkara University, 174103, Himachal Pradesh, India
| | - Puneet Kumar
- Department of Pharmacology, Central University of Punjab, Ghudda, 151401, Bathinda, India
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11
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Senrung A, Tripathi T, Yadav J, Janjua D, Chaudhary A, Chhokar A, Aggarwal N, Joshi U, Goswami N, Bharti AC. In vivo antiangiogenic effect of nimbolide, trans-chalcone and piperine for use against glioblastoma. BMC Cancer 2023; 23:1173. [PMID: 38036978 PMCID: PMC10691152 DOI: 10.1186/s12885-023-11625-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 11/09/2023] [Indexed: 12/02/2023] Open
Abstract
BACKGROUND Angiogenesis is an important hallmark of Glioblastoma (GBM) marked by elevated vascular endothelial growth factor-A (VEGF-A) and its receptor 2 (VEGFR-2). As previously reported nimbolide (NBL), trans-chalcone (TC) and piperine (PPR) possess promising antiangiogenic activity in several cancers however, their comparative efficacy and mechanism of antiangiogenic activity in GBM against VEGFR-2 has not been elucidated. METHODS 2D and 3D spheroids cultures of U87 (Uppsala 87 Malignant Glioma) were used for evaluation of non-cytotxoic dose for anti-angiogenic activity. The antiangiogenic effect was investigated by the GBM U87 cell line bearing chick CAM model. Excised U87 xenografts were histologically examined for blood vascular density by histochemistry. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to detect the presence of avian and human VEGF-A and VEGFR-2 mRNA transcripts. RESULTS Using 2D and 3D spheroid models, the non-cytotoxic dose of NBL, TC and PPR was ≤ 11 µM. We found NBL, TC and PPR inhibit U87-induced neoangiogenesis in a dose-dependent manner in the CAM stand-alone model as well as in CAM U87 xenograft model. The results also indicate that these natural compounds inhibit the expression of notable angiogenic factors, VEGF-A and VEGFR-2. A positive correlation was found between blood vascular density and VEGF-A as well as VEGFR-2 transcripts. CONCLUSION Taken together, NBL, TC and PPR can suppress U87-induced neoangiogenesis via a reduction in VEGF-A and its receptor VEGFR-2 transcript expression at noncytotoxic concentrations. These phytochemicals showed their utility as adjuvants to GBM therapy, with Piperine demonstrating superior effectiveness among them all.
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Affiliation(s)
- Anna Senrung
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
- Neuropharmacology and Drug Delivery Laboratory, Daulat Ram College, University of Delhi, Delhi, India
| | - Tanya Tripathi
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
| | - Joni Yadav
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
| | - Divya Janjua
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
| | - Apoorva Chaudhary
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
| | - Arun Chhokar
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
- Deshbandhu College, University of Delhi, Delhi, India
| | - Nikita Aggarwal
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
| | - Udit Joshi
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India
| | - Nidhi Goswami
- Neuropharmacology and Drug Delivery Laboratory, Daulat Ram College, University of Delhi, Delhi, India
| | - Alok Chandra Bharti
- Department of Zoology, Molecular Oncology Laboratory, University of Delhi (North Campus), Delhi, 110007, India.
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12
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Hernández-Aceves JA, Cervantes-Torres J, Torres-García D, Zuñiga-Flores FJ, Patiño-Chávez OJ, Peña Agudelo JA, Aguayo-Flores JE, Garfias Y, Montero-León L, Romero-Romero L, Pérez-Torres A, Fragoso G, Sciutto E. GK-1 effectively reduces angiogenesis and prevents T cell exhaustion in a breast cancer murine experimental model. Cancer Immunol Immunother 2023; 72:3825-3838. [PMID: 37736849 PMCID: PMC10576684 DOI: 10.1007/s00262-023-03538-9] [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: 06/15/2023] [Accepted: 08/28/2023] [Indexed: 09/23/2023]
Abstract
Breast cancer is the leading malignancy in women worldwide, both in terms of incidence and mortality. Triple-negative breast cancer (TNBC) is the type with the worst clinical outcomes and with fewer therapeutic options than other types of breast cancer. GK-1 is a peptide that in the experimental model of the metastatic 4T1 breast cancer has demonstrated anti-tumor and anti-metastatic properties. Herein, GK-1 (5 mg/kg, i.v.) weekly administrated not only decreases tumor growth and the number of lung macro-metastases but also lung and lymph nodes micro-metastases. Histological analysis reveals that GK-1 reduced 57% of the intra-tumor vascular areas, diminished the leukemoid reaction's progression, and the spleens' weight and length. A significant reduction in VEGF-C, SDF-1, angiopoietin-2, and endothelin-1 angiogenic factors was induced. Moreover, GK-1 prevents T cell exhaustion in the tumor-infiltrating lymphocytes (TILs) decreasing PD-1 expression. It also increased IFN-γ and granzyme-B expression and the cytotoxic activity of CD8+ TILs cells against tumor cells. All these features were found to be associated with a better antitumor response and prognosis. Altogether, these results reinforce the potential of GK-1 to improve the clinical outcome of triple-negative breast cancer immunotherapy. Translation research is ongoing towards its evaluation in humans.
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Affiliation(s)
- Juan A Hernández-Aceves
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Jacquelynne Cervantes-Torres
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Diana Torres-García
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Francisco J Zuñiga-Flores
- Departamento de Biología Celular y Tisular, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Osiris J Patiño-Chávez
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Jorge A Peña Agudelo
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | | | - Yonathan Garfias
- Unidad de Investigación, Conde de Valenciana, Instituto de Oftalmología, Mexico City, Mexico
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad Universitaria, Mexico City, Mexico
| | - Laura Montero-León
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Laura Romero-Romero
- Departamento de Patología, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autónoma de México, Circuito Escolar, Ciudad Universitaria, Mexico City, Mexico
| | - Armando Pérez-Torres
- Departamento de Biología Celular y Tisular, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico.
| | - Gladis Fragoso
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.
| | - Edda Sciutto
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.
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13
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Furuhata K, Masuda H, Sato A, Miyata K, Shinyashiki N, Kita R, Imagawa K, Akamatsu T, Yagihara S. Aberrant Water Structure Dynamics in B16 Melanoma-Bearing Mice by Time Domain Refractometry Analysis. BIOLOGY 2023; 12:1250. [PMID: 37759649 PMCID: PMC10525127 DOI: 10.3390/biology12091250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/11/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023]
Abstract
Living bodies comprise approximately 55-75% water to maintain homeostasis. However, little is known about the comprehensive differences in in vivo water molecule dynamics (water structure dynamics; WSD) between physiological and pathophysiological statuses. Here, we examined the WSD of ex vivo tumor tissues and organs from tumor-bearing mice with engrafted mouse malignant melanoma cells (B16-F10) in the right flanks to compare with those in healthy mice, using time domain reflectometry of dielectric spectroscopy at days 9, 11, and 14 after engrafting. The relaxation parameters of relaxation time (τ), relaxation time distribution parameter (β), and relaxation strength (∆ε) were measured on tumor tissues and lung, liver, kidney, and skin tissues. Immediately afterward, the water contents (%) in the tumor and the other organs were calculated by measuring their weights before and after freeze-drying. Each parameter of the tumor was compared to that of pooled values of other organs in tumor-bearing (TO) and healthy mice (HO). The tumor water content temporarily increased compared to that of HO at day 11; the tumor volume was also prone to increase. In contrast, tumor tissues exhibited significantly higher values of β close to 1 of ultrapure water and ∆ε compared to TO and HO at all times. Moreover, β in the viscera of TO was prone to increase compared to that of HO with significantly higher levels at day 11. Conclusively, tumor-bearing mice exhibited systemically aberrant WSD, unlike healthy mice. Thus, dielectric spectroscopy in terms of WSD may provide novel pathophysiological perspectives in tumor-bearing living bodies.
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Affiliation(s)
- Kahori Furuhata
- Department of Physiology, School of Medicine, Isehara Campus, Tokai University, 143 Shimokasuya, Isehara 259-1193, Japan; (K.F.); (A.S.); (K.M.)
| | - Haruchika Masuda
- Department of Physiology, School of Medicine, Isehara Campus, Tokai University, 143 Shimokasuya, Isehara 259-1193, Japan; (K.F.); (A.S.); (K.M.)
- Regenerative Medicine Research Division, Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura 247-8533, Japan
- Department of Plastic Surgery, School of Medicine, Isehara Campus, Tokai University, 143 Shimokasuya, Isehara 259-1193, Japan; (K.I.); (T.A.)
- Department of Nutritional Science, Faculty of Applied Biosciences, Setagaya Campus, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Tokyo 156-8502, Japan
| | - Atsuko Sato
- Department of Physiology, School of Medicine, Isehara Campus, Tokai University, 143 Shimokasuya, Isehara 259-1193, Japan; (K.F.); (A.S.); (K.M.)
| | - Kumiko Miyata
- Department of Physiology, School of Medicine, Isehara Campus, Tokai University, 143 Shimokasuya, Isehara 259-1193, Japan; (K.F.); (A.S.); (K.M.)
| | - Naoki Shinyashiki
- Department of Physics, School of Science, Shonan Campus, Tokai University, 4-1-1 Kitakaname, Hiratsuka 259-1292, Japan; (N.S.); (R.K.); (S.Y.)
- Micro/Nano Technology Center, Shonan Campus, Tokai University, 4-1-1 Kitakaname, Hiratsuka 259-1292, Japan
| | - Rio Kita
- Department of Physics, School of Science, Shonan Campus, Tokai University, 4-1-1 Kitakaname, Hiratsuka 259-1292, Japan; (N.S.); (R.K.); (S.Y.)
- Micro/Nano Technology Center, Shonan Campus, Tokai University, 4-1-1 Kitakaname, Hiratsuka 259-1292, Japan
| | - Kotaro Imagawa
- Department of Plastic Surgery, School of Medicine, Isehara Campus, Tokai University, 143 Shimokasuya, Isehara 259-1193, Japan; (K.I.); (T.A.)
| | - Tadashi Akamatsu
- Department of Plastic Surgery, School of Medicine, Isehara Campus, Tokai University, 143 Shimokasuya, Isehara 259-1193, Japan; (K.I.); (T.A.)
| | - Shin Yagihara
- Department of Physics, School of Science, Shonan Campus, Tokai University, 4-1-1 Kitakaname, Hiratsuka 259-1292, Japan; (N.S.); (R.K.); (S.Y.)
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14
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Haskell J, Hubbard T, Murray C, Gardner B, Ives C, Ferguson D, Stone N. High wavenumber Raman spectroscopy for intraoperative assessment of breast tumour margins. Analyst 2023; 148:4373-4385. [PMID: 37594446 DOI: 10.1039/d3an00574g] [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: 08/19/2023]
Abstract
Optimal oncological results and patient outcomes are achieved in surgery for early breast cancer with breast conserving surgery (BCS) where this is appropriate. A limitation of BCS occurs when cancer is present at, or close, to the resection margin - termed a 'positive' margin - and re-excision is recommended to reduce recurrence rate. This is occurs in 17% of BCS in the UK and there is therefore a critical need for a way to assess margin status intraoperatively to ensure complete excision with adequate margins at the first operation. This study presents the potential of high wavenumber (HWN) Raman spectroscopy to address this. Freshly excised specimens from thirty patients undergoing surgery for breast cancer were measured using a surface Raman probe, and a multivariate classification model to predict normal versus tumour was developed from the data. This model achieved 77.1% sensitivity and 90.8% specificity following leave one patient out cross validation, with the defining features being differences in water content and lipid versus protein content. This demonstrates the feasibility of HWN Raman spectroscopy to facilitate future intraoperative margin assessment at specific locations. Clinical utility of the approach will require further research.
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Affiliation(s)
- Jennifer Haskell
- Physics and Astronomy, Faculty of Environment, Science and Economy, University of Exeter, Exeter, Devon, UK.
- Royal Devon University Healthcare NHS Foundation Trust, Exeter, Devon, UK
| | - Thomas Hubbard
- Physics and Astronomy, Faculty of Environment, Science and Economy, University of Exeter, Exeter, Devon, UK.
- Royal Devon University Healthcare NHS Foundation Trust, Exeter, Devon, UK
| | - Claire Murray
- Royal Devon University Healthcare NHS Foundation Trust, Exeter, Devon, UK
| | - Benjamin Gardner
- Physics and Astronomy, Faculty of Environment, Science and Economy, University of Exeter, Exeter, Devon, UK.
- Royal Devon University Healthcare NHS Foundation Trust, Exeter, Devon, UK
| | - Charlotte Ives
- Physics and Astronomy, Faculty of Environment, Science and Economy, University of Exeter, Exeter, Devon, UK.
- Royal Devon University Healthcare NHS Foundation Trust, Exeter, Devon, UK
| | - Douglas Ferguson
- Physics and Astronomy, Faculty of Environment, Science and Economy, University of Exeter, Exeter, Devon, UK.
- Royal Devon University Healthcare NHS Foundation Trust, Exeter, Devon, UK
| | - Nick Stone
- Physics and Astronomy, Faculty of Environment, Science and Economy, University of Exeter, Exeter, Devon, UK.
- Royal Devon University Healthcare NHS Foundation Trust, Exeter, Devon, UK
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15
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Shamsabadipour A, Pourmadadi M, Davodabadi F, Rahdar A, Romanholo Ferreira LF. Applying thermodynamics as an applicable approach to cancer diagnosis, evaluation, and therapy: A review. J Drug Deliv Sci Technol 2023; 86:104681. [DOI: 10.1016/j.jddst.2023.104681] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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16
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Agnihotri TG, Salave S, Shinde T, Srikanth I, Gyanani V, Haley JC, Jain A. Understanding the role of endothelial cells in brain tumor formation and metastasis: a proposition to be explored for better therapy. JOURNAL OF THE NATIONAL CANCER CENTER 2023; 3:222-235. [PMID: 39035200 PMCID: PMC11256543 DOI: 10.1016/j.jncc.2023.08.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 07/31/2023] [Accepted: 08/02/2023] [Indexed: 07/23/2024] Open
Abstract
Glioblastoma is one of the most devastating central nervous system disorders. Being a highly vascular brain tumor, it is distinguished by aberrant vessel architecture. This lends credence to the idea that endothelial cells (ECs) linked with glioblastoma vary fundamentally from ECs seen in the healthy human brain. To effectively design an antiangiogenic treatment, it is crucial to identify the functional and phenotypic characteristics of tumor-associated ECs. The ECs associated with glioblastoma are less prone to apoptosis than control cells and are resistant to cytotoxic treatments. Additionally, ECs associated with glioblastoma migrate more quickly than control ECs and naturally produce large amounts of growth factors such as endothelin-1, interleukin-8, and vascular endothelial growth factor (VEGF). For designing innovative antiangiogenic drugs that particularly target tumor-related ECs in gliomas, it is critical to comprehend these distinctive features of ECs associated with gliomas. This review discusses the process of angiogenesis, other factors involved in the genesis of tumors, and the possibility of ECs as a potential target in combating glioblastoma. It also sheds light on the association of tumor microenvironment and ECs with immunotherapy. This review, thus gives us the hope that neuro endothelial targeting with growth factors and angiogenesis regulators combined with gene therapy would open up new doorways and change our traditional perspective of treating cancer.
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Affiliation(s)
- Tejas Girish Agnihotri
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, India
| | - Sagar Salave
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, India
| | - Tanuja Shinde
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, India
| | - Induri Srikanth
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, India
| | - Vijay Gyanani
- Long Acting Drug Delivery, Celanese Corporation, Irving, United States
| | - Jeffrey C. Haley
- Long Acting Drug Delivery, Celanese Corporation, Irving, United States
| | - Aakanchha Jain
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, India
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17
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Morales-Sánchez P, Lambert C, Ares-Blanco J, Suárez-Gutiérrez L, Villa-Fernández E, Garcia AV, García-Villarino M, Tejedor JR, Fraga MF, Torre EM, Pujante P, Delgado E. Circulating miRNA expression in long-standing type 1 diabetes mellitus. Sci Rep 2023; 13:8611. [PMID: 37244952 DOI: 10.1038/s41598-023-35836-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 05/24/2023] [Indexed: 05/29/2023] Open
Abstract
Type 1 diabetes is a chronic autoimmune disease which results in inefficient regulation of glucose homeostasis and can lead to different vascular comorbidities through life. In this study we aimed to analyse the circulating miRNA expression profile of patients with type 1 diabetes, and with no other associated pathology. For this, fasting plasma was obtained from 85 subjects. Next generation sequencing analysis was firstly performed to identify miRNAs that were differentially expressed between groups (20 patients vs. 10 controls). hsa-miR-1-3p, hsa-miR-200b-3p, hsa-miR-9-5p, and hsa-miR-1200 expression was also measured by Taqman RT-PCR to validate the observed changes (34 patients vs. 21 controls). Finally, through a bioinformatic approach, the main pathways affected by the target genes of these miRNAs were studied. Among the studied miRNAs, hsa-miR-1-3p expression was found significantly increased in patients with type 1 diabetes compared to controls, and positively correlated with glycated haemoglobin levels. Additionally, by using a bioinformatic approach, we could observe that changes in hsa-miR-1-3p directly affect genes involved in vascular development and cardiovascular pathologies. Our results suggest that, circulating hsa-miR-1-3p in plasma, together with glycaemic control, could be used as prognostic biomarkers in type 1 diabetes, helping to prevent the development of vascular complications in these patients.
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Affiliation(s)
- Paula Morales-Sánchez
- Endocrinology, Nutrition, Diabetes and Obesity Group (ENDO), Health Research Institute of the Principality of Asturias (ISPA), Av. Hospital Universitario s/n, 33011, Oviedo, Asturias, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Carmen Lambert
- Endocrinology, Nutrition, Diabetes and Obesity Group (ENDO), Health Research Institute of the Principality of Asturias (ISPA), Av. Hospital Universitario s/n, 33011, Oviedo, Asturias, Spain.
- University of Barcelona, Barcelona, Spain.
| | - Jessica Ares-Blanco
- Endocrinology, Nutrition, Diabetes and Obesity Group (ENDO), Health Research Institute of the Principality of Asturias (ISPA), Av. Hospital Universitario s/n, 33011, Oviedo, Asturias, Spain
- Endocrinology and Nutrition Department, Asturias Central University Hospital, Oviedo, Asturias, Spain
- Medicine Department, University of Oviedo, Oviedo, Asturias, Spain
| | - Lorena Suárez-Gutiérrez
- Endocrinology, Nutrition, Diabetes and Obesity Group (ENDO), Health Research Institute of the Principality of Asturias (ISPA), Av. Hospital Universitario s/n, 33011, Oviedo, Asturias, Spain
- Endocrinology and Nutrition Department, Asturias Central University Hospital, Oviedo, Asturias, Spain
| | - Elsa Villa-Fernández
- Endocrinology, Nutrition, Diabetes and Obesity Group (ENDO), Health Research Institute of the Principality of Asturias (ISPA), Av. Hospital Universitario s/n, 33011, Oviedo, Asturias, Spain
| | - Ana Victoria Garcia
- Endocrinology, Nutrition, Diabetes and Obesity Group (ENDO), Health Research Institute of the Principality of Asturias (ISPA), Av. Hospital Universitario s/n, 33011, Oviedo, Asturias, Spain
| | - Miguel García-Villarino
- Endocrinology, Nutrition, Diabetes and Obesity Group (ENDO), Health Research Institute of the Principality of Asturias (ISPA), Av. Hospital Universitario s/n, 33011, Oviedo, Asturias, Spain
| | - Juan Ramón Tejedor
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
- Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Health Research Institute of Asturias (ISPA), Oviedo, Asturias, Spain
- Institute of Oncology of Asturias (IUOPA), Oviedo, Asturias, Spain
- Department of Organisms and Systems Biology (B.O.S), University of Oviedo, Oviedo, Asturias, Spain
| | - Mario F Fraga
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
- Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Health Research Institute of Asturias (ISPA), Oviedo, Asturias, Spain
- Institute of Oncology of Asturias (IUOPA), Oviedo, Asturias, Spain
- Department of Organisms and Systems Biology (B.O.S), University of Oviedo, Oviedo, Asturias, Spain
| | - Edelmiro Menéndez Torre
- Endocrinology, Nutrition, Diabetes and Obesity Group (ENDO), Health Research Institute of the Principality of Asturias (ISPA), Av. Hospital Universitario s/n, 33011, Oviedo, Asturias, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
- Endocrinology and Nutrition Department, Asturias Central University Hospital, Oviedo, Asturias, Spain
- Medicine Department, University of Oviedo, Oviedo, Asturias, Spain
| | - Pedro Pujante
- Endocrinology, Nutrition, Diabetes and Obesity Group (ENDO), Health Research Institute of the Principality of Asturias (ISPA), Av. Hospital Universitario s/n, 33011, Oviedo, Asturias, Spain.
- Endocrinology and Nutrition Department, Asturias Central University Hospital, Oviedo, Asturias, Spain.
| | - Elías Delgado
- Endocrinology, Nutrition, Diabetes and Obesity Group (ENDO), Health Research Institute of the Principality of Asturias (ISPA), Av. Hospital Universitario s/n, 33011, Oviedo, Asturias, Spain.
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
- Endocrinology and Nutrition Department, Asturias Central University Hospital, Oviedo, Asturias, Spain.
- Medicine Department, University of Oviedo, Oviedo, Asturias, Spain.
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18
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Liu Y, Tang H, Zhang Y, Wang Q, Li S, Wang Z, Shi X. Circular RNA hsa_circ_0000519 contributes to angiogenesis and tumor progression in hepatocellular carcinoma through the miR-1296/E2F7 axis. Hum Cell 2023; 36:738-751. [PMID: 36627545 DOI: 10.1007/s13577-022-00854-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 12/23/2022] [Indexed: 01/12/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Uncontrolled angiogenesis plays a critical role in hepatocellular tumor growth and metastasis. In this study, we aimed to investigate the effects of circular RNA hsa_circ_0000519 and the potential involvement of microRNA (miR)-1296 and E2F transcription factor 7 (E2F7) in HCC development. Hsa_circ_0000519 was highly expressed in HCC cells and hepatocellular tumor tissues, and correlated with poor prognosis of HCC patients. Knockdown of hsa_circ_0000519 significantly reduced HCC cell viability, suppressed cell proliferation, and induced cell cycle arrest in G0/G1. Downregulation of hsa_circ_0000519 also inhibited formation of capillary-like endothelial structures in vitro and impeded microvessel formation in mice bearing HCC tumors. The migration and invasive capacities of HCC cells were markedly reduced by hsa_circ_0000519 knockdown. Hsa_circ_0000519 possessed a binding site for microRNA (miR)-1296. Upregulation of hsa_circ_0000519 significantly decreased the miR-1296 expression in both HCC cells and mouse xenografts. Furthermore, E2F7 was a target of miR-1296. Hsa_circ_0000519 positively regulated E2F7 via acting as a miR-1296 sponge. Upregulation of E2F7 abolished the inhibitory effects of hsa_circ_0000519 knockdown on HCC cell proliferation and angiogenesis. In conclusion, hsa_circ_0000519 promoted tumor progression and angiogenesis in HCC through the miR-1296/E2F7 axis. These data suggest the potential clinical application of hsa_circ_0000519 in HCC treatment.
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Affiliation(s)
- Yi Liu
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, No. 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China
| | - Hui Tang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Yaling Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, No. 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China
| | - Qian Wang
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, No. 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China
| | - Shiying Li
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, No. 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China.
| | - Zhiyi Wang
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, No. 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China
| | - Xiaofeng Shi
- Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, No. 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China
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19
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Barrionuevo E, Cornier PG, Delpiccolo CML, Mata EG, Roguin LP, Blank VC. Antiangiogenic activity of the penicillin derivative TAP7f in melanoma. J Mol Med (Berl) 2023; 101:249-263. [PMID: 36688961 DOI: 10.1007/s00109-023-02287-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 12/19/2022] [Accepted: 01/16/2023] [Indexed: 01/24/2023]
Abstract
Previously , we demonstrated that the non-antibiotic penicillin derivative TAP7f inhibited melanoma metastasis in vitro and in vivo through the downregulation of β-catenin and integrin αVβ3. As angiogenesis is required for tumor growth and metastasis, we decided to explore the possible antiangiogenic effect of TAP7f. We found that TAP7f inhibited proliferation, migration, tube formation, and actin cytoskeleton organization of human endothelial cells. In a gel plug assay, an in vivo model for angiogenesis, TAP7f also blocked vascular formation induced by fibroblast growth factor 2. Furthermore, when murine B16-F10 melanoma cells pre-treated with TAP7f were injected intradermally in mice, we observed a decrease in the number and thickness of the capillaries surrounding the tumor. Additionally, TAP7f downregulated vascular endothelial growth factor (VEGF) and platelet-derived growth factor-B (PDGF-B) expression in B16-F10 cells and VEGF receptor expression in HMEC-1 endothelial cells. When the antitumor effect of TAP7f was studied in C57BL/6 J mice challenged with B16-F10 melanoma cells, a significant reduction of tumor growth was observed. Furthermore, a decreased expression of VEGF, PDGF-B, and the endothelial cell marker CD34 was observed in tumors from TAP7f-treated mice. Together, our results suggest that the antiangiogenic activity of TAP7f contributes to its antitumor and antimetastatic action and positions this penicillin derivative as an alternative or complementary agent for the treatment of melanoma. KEY MESSAGES: • TAP7f inhibits proliferation, migration, tube formation, and actin cytoskeleton organization of endothelial cells. • TAP7f downregulates VEGF receptor expression in endothelial cells. • TAP7f downregulates VEGF and PDGF expression in melanoma cells. • TAP7f inhibits angiogenesis in vivo.
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Affiliation(s)
- Elizabeth Barrionuevo
- Laboratorio de Oncología y Transducción de Señales, Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, CONICET, Buenos Aires, Argentina
| | - Patricia G Cornier
- Facultad de Ciencias Bioquímicas y Farmacéuticas, Instituto de Química Rosario (CONICET-UNR), Universidad Nacional de Rosario, Rosario, Argentina
| | - Carina M L Delpiccolo
- Facultad de Ciencias Bioquímicas y Farmacéuticas, Instituto de Química Rosario (CONICET-UNR), Universidad Nacional de Rosario, Rosario, Argentina
| | - Ernesto G Mata
- Facultad de Ciencias Bioquímicas y Farmacéuticas, Instituto de Química Rosario (CONICET-UNR), Universidad Nacional de Rosario, Rosario, Argentina
| | - Leonor P Roguin
- Laboratorio de Oncología y Transducción de Señales, Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, CONICET, Buenos Aires, Argentina
| | - Viviana C Blank
- Laboratorio de Oncología y Transducción de Señales, Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, CONICET, Buenos Aires, Argentina.
- , Buenos Aires, 956, C1113AAD, Argentina.
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20
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Placental Galectins in Cancer: Why We Should Pay More Attention. Cells 2023; 12:cells12030437. [PMID: 36766779 PMCID: PMC9914345 DOI: 10.3390/cells12030437] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 01/15/2023] [Accepted: 01/26/2023] [Indexed: 01/31/2023] Open
Abstract
The first studies suggesting that abnormal expression of galectins is associated with cancer were published more than 30 years ago. Today, the role of galectins in cancer is relatively well established. We know that galectins play an active role in many types of cancer by regulating cell growth, conferring cell death resistance, or inducing local and systemic immunosuppression, allowing tumor cells to escape the host immune response. However, most of these studies have focused on very few galectins, most notably galectin-1 and galectin-3, and more recently, galectin-7 and galectin-9. Whether other galectins play a role in cancer remains unclear. This is particularly true for placental galectins, a subgroup that includes galectin-13, -14, and -16. The role of these galectins in placental development has been well described, and excellent reviews on their role during pregnancy have been published. At first sight, it was considered unlikely that placental galectins were involved in cancer. Yet, placentation and cancer progression share several cellular and molecular features, including cell invasion, immune tolerance and vascular remodeling. The development of new research tools and the concomitant increase in database repositories for high throughput gene expression data of normal and cancer tissues provide a new opportunity to examine the potential involvement of placental galectins in cancer. In this review, we discuss the possible roles of placental galectins in cancer progression and why they should be considered in cancer studies. We also address challenges associated with developing novel research tools to investigate their protumorigenic functions and design highly specific therapeutic drugs.
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21
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An Update of G-Protein-Coupled Receptor Signaling and Its Deregulation in Gastric Carcinogenesis. Cancers (Basel) 2023; 15:cancers15030736. [PMID: 36765694 PMCID: PMC9913146 DOI: 10.3390/cancers15030736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 01/15/2023] [Accepted: 01/19/2023] [Indexed: 01/27/2023] Open
Abstract
G-protein-coupled receptors (GPCRs) belong to a cell surface receptor superfamily responding to a wide range of external signals. The binding of extracellular ligands to GPCRs activates a heterotrimeric G protein and triggers the production of numerous secondary messengers, which transduce the extracellular signals into cellular responses. GPCR signaling is crucial and imperative for maintaining normal tissue homeostasis. High-throughput sequencing analyses revealed the occurrence of the genetic aberrations of GPCRs and G proteins in multiple malignancies. The altered GPCRs/G proteins serve as valuable biomarkers for early diagnosis, prognostic prediction, and pharmacological targets. Furthermore, the dysregulation of GPCR signaling contributes to tumor initiation and development. In this review, we have summarized the research progress of GPCRs and highlighted their mechanisms in gastric cancer (GC). The aberrant activation of GPCRs promotes GC cell proliferation and metastasis, remodels the tumor microenvironment, and boosts immune escape. Through deep investigation, novel therapeutic strategies for targeting GPCR activation have been developed, and the final aim is to eliminate GPCR-driven gastric carcinogenesis.
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22
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Ahmad A, Nawaz MI. Molecular mechanism of VEGF and its role in pathological angiogenesis. J Cell Biochem 2022; 123:1938-1965. [PMID: 36288574 DOI: 10.1002/jcb.30344] [Citation(s) in RCA: 91] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 09/12/2022] [Accepted: 10/13/2022] [Indexed: 12/24/2022]
Abstract
Over the last seven decades, a significant scientific contribution took place in the delineation of the implications of vascular endothelial-derived growth factor (VEGF) in the processes of angiogenesis. Under pathological conditions, mainly in response to hypoxia or ischemia, elevated VEGF levels promote vascular damage and the growth of abnormal blood vessels. Indeed, the development of VEGF biology has revolutionized our understanding of its role in pathological conditions. Hence, targeting VEGF or VEGF-mediated molecular pathways could be an excellent therapeutic strategy for managing cancers and intraocular neovascular disorders. Although anti-VEGF therapies, such as monoclonal antibodies and small-molecule tyrosine kinase inhibitors, have limited clinical efficacy, they can still significantly improve the overall survival rate. This thus demands further investigation through the development of alternative strategies in the management of VEGF-mediated pathological angiogenesis. This review article focuses on the recent developments toward the delineation of the functional biology of VEGF and the role of anti-VEGF strategies in the management of tumor and eye pathologies. Moreover, therapeutic angiogenesis, an exciting frontier for the treatment of ischemic disorders, is highlighted in this review, including wound healing.
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Affiliation(s)
- Ajmal Ahmad
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.,Dr. Nasser Al-Rashid Research Chair in Ophthalmology, Abdulaziz University Hospital, Riyadh, Saudi Arabia
| | - Mohd Imtiaz Nawaz
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.,Dr. Nasser Al-Rashid Research Chair in Ophthalmology, Abdulaziz University Hospital, Riyadh, Saudi Arabia
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23
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Gao S, Zhao T, Meng F, Luo Y, Li Y, Wang Y. Circular RNAs in endometrial carcinoma (Review). Oncol Rep 2022; 48:212. [PMID: 36263622 PMCID: PMC9608256 DOI: 10.3892/or.2022.8427] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 08/17/2022] [Indexed: 11/24/2022] Open
Abstract
As one of the leading causes of death in women in Western developed countries, endometrial carcinoma (EC) is a common gynecological malignant tumor that seriously threatens women's health. In recent years, a trend has emerged of EC being manifested in younger women, and its overall incidence is gradually rising. Circular RNAs (circRNAs) are novel endogenous transcripts that have limited ability to encode proteins due to their covalent closed‑loop structure, which differs from that of other types of RNA. A growing body of evidence has demonstrated that circRNAs fulfill an important role in lung cancer, gastric cancer, breast cancer, EC and other malignant tumor types, and they can affect the occurrence and development of these malignancies through a variety of pathways, further demonstrating the potential of circRNAs as molecular biomarkers for the diagnosis, treatment and prognosis of malignant tumors. The purpose of the present review is to summarize the current understanding of the biogenesis and effects of circRNAs, and to discuss the expression, function and underlying mechanism of circRNAs in EC in order to identify potential novel biomarkers.
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Affiliation(s)
- Shan Gao
- Department of Obstetrics and Gynecology, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning 110024, P.R. China
| | - Tianjun Zhao
- Department of Obstetrics and Gynecology, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning 110024, P.R. China
| | - Fangchi Meng
- Department of Obstetrics and Gynecology, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning 110024, P.R. China
| | - Yinzhou Luo
- Fourth Department of Orthopedic Surgery, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning 110024, P.R. China
| | - Yan Li
- Department of Obstetrics and Gynecology, Central Hospital Affiliated to Shenyang Medical College, Shenyang, Liaoning 110024, P.R. China
| | - Yong Wang
- Department of Orthopedic Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
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24
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Zalpoor H, Aziziyan F, Liaghat M, Bakhtiyari M, Akbari A, Nabi-Afjadi M, Forghaniesfidvajani R, Rezaei N. The roles of metabolic profiles and intracellular signaling pathways of tumor microenvironment cells in angiogenesis of solid tumors. Cell Commun Signal 2022; 20:186. [PMID: 36419156 PMCID: PMC9684800 DOI: 10.1186/s12964-022-00951-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 08/06/2022] [Indexed: 11/27/2022] Open
Abstract
Innate and adaptive immune cells patrol and survey throughout the human body and sometimes reside in the tumor microenvironment (TME) with a variety of cell types and nutrients that may differ from those in which they developed. The metabolic pathways and metabolites of immune cells are rooted in cell physiology, and not only provide nutrients and energy for cell growth and survival but also influencing cell differentiation and effector functions. Nowadays, there is a growing awareness that metabolic processes occurring in cancer cells can affect immune cell function and lead to tumor immune evasion and angiogenesis. In order to safely treat cancer patients and prevent immune checkpoint blockade-induced toxicities and autoimmunity, we suggest using anti-angiogenic drugs solely or combined with Immune checkpoint blockers (ICBs) to boost the safety and effectiveness of cancer therapy. As a consequence, there is significant and escalating attention to discovering techniques that target metabolism as a new method of cancer therapy. In this review, a summary of immune-metabolic processes and their potential role in the stimulation of intracellular signaling in TME cells that lead to tumor angiogenesis, and therapeutic applications is provided. Video abstract.
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Affiliation(s)
- Hamidreza Zalpoor
- grid.412571.40000 0000 8819 4698Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran ,grid.510410.10000 0004 8010 4431Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Fatemeh Aziziyan
- grid.510410.10000 0004 8010 4431Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran ,grid.412266.50000 0001 1781 3962Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mahsa Liaghat
- grid.510410.10000 0004 8010 4431Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran ,Department of Medical Laboratory Sciences, Faculty of Medical Sciences, Islamic Azad University, Kazerun Branch, Kazerun, Iran
| | - Maryam Bakhtiyari
- grid.510410.10000 0004 8010 4431Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran ,grid.412606.70000 0004 0405 433XDepartment of Medical Laboratory Sciences, Faculty of Allied Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Abdullatif Akbari
- grid.412571.40000 0000 8819 4698Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran ,grid.510410.10000 0004 8010 4431Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Mohsen Nabi-Afjadi
- grid.412266.50000 0001 1781 3962Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Razieh Forghaniesfidvajani
- grid.510410.10000 0004 8010 4431Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Nima Rezaei
- grid.510410.10000 0004 8010 4431Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran ,grid.411705.60000 0001 0166 0922Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Dr. Gharib St, Keshavarz Blvd, Tehran, Iran ,grid.411705.60000 0001 0166 0922Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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25
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Visfatin-Induced Inhibition of miR-1264 Facilitates PDGF-C Synthesis in Chondrosarcoma Cells and Enhances Endothelial Progenitor Cell Angiogenesis. Cells 2022; 11:cells11213470. [PMID: 36359873 PMCID: PMC9656973 DOI: 10.3390/cells11213470] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 10/22/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
Abstract
New treatments for chondrosarcoma are extremely important. Chondrosarcoma is a primary malignant bone tumor with a very unfavorable prognosis. High-grade chondrosarcoma has a high potential to metastasize to any organ in the body. Platelet-derived growth factor (PDGF) is a potent angiogenic factor that promotes tumor angiogenesis and metastasis. The adipocytokine visfatin promotes metastatic potential of chondrosarcoma; however, the role of visfatin in angiogenesis in human chondrosarcoma is unclear. We report that the levels of PDGF-C expression were positively correlated with tumor stages, significantly higher than the levels of expression in normal cartilage. Visfatin increased PDGF-C expression and endothelial progenitor cell (EPC) angiogenesis through the PI3K/Akt/mTOR signaling pathway, and dose-dependently down-regulated the synthesis of miR-1264, which targets the 3′-UTR of PDGF-C. Additionally, we discovered inhibition of visfatin or PDGF-C in chondrosarcoma tumors significantly reduced tumor angiogenesis and size. Our results indicate that visfatin inhibits miR-1264 production through the PI3K/Akt/mTOR signaling cascade, and thereby promotes PDGF-C expression and chondrosarcoma angiogenesis. Visfatin may be worth targeting in the treatment of chondrosarcoma angiogenesis.
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26
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Cho W, Ahn M, Kim BS, Cho D. Blood-Lymphatic Integrated System with Heterogeneous Melanoma Spheroids via In-Bath Three-Dimensional Bioprinting for Modelling of Combinational Targeted Therapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2202093. [PMID: 36026581 PMCID: PMC9561777 DOI: 10.1002/advs.202202093] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 08/15/2022] [Indexed: 05/19/2023]
Abstract
Although metastatic melanoma can be managed with chemotherapy, its heterogeneity and resistance to therapy remain poorly understood. In addition to the spread of melanoma in the bloodstream, melanoma-stroma interaction and the lymphatic system play active roles in said heterogeneity and resistance, leading to its progression and metastasis. Reproducing the complexities of the melanoma microenvironment in vitro will help understanding its progression and enhance the translatability of potential cancer therapeutics. A blood-lymphatic integrated system with heterogeneous melanoma spheroids (BLISH) using the in-bath bioprinting process is developed. The process uniformly prints size-controllable metastatic melanoma spheroids along with biomimetic blood and lymphatic vessels (LVs). The system reproduces hallmark events of metastatic melanoma, such as tumor stroma interaction, melanoma invasion, and intravasation. The application of the system to investigate the anticancer effect of combinational targeted therapy suggests that it can be used to study the pathophysiology of melanoma and improve the accuracy of drug response monitoring in skin cancer.
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Affiliation(s)
- Won‐Woo Cho
- Department of Mechanical EngineeringPohang University of Science and Technology (POSTECH)PohangKyungbuk37673Republic of Korea
| | - Minjun Ahn
- Department of Mechanical EngineeringPohang University of Science and Technology (POSTECH)PohangKyungbuk37673Republic of Korea
| | - Byoung Soo Kim
- School of Biomedical Convergence EngineeringPusan National UniversityYangsanKyungnam50612Republic of Korea
| | - Dong‐Woo Cho
- Department of Mechanical EngineeringPohang University of Science and Technology (POSTECH)PohangKyungbuk37673Republic of Korea
- Institute for Convergence Research and Education in Advanced TechnologyYonsei UniversitySeoul03722Republic of Korea
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27
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Phoenix KN, Yue Z, Yue L, Cronin CG, Liang BT, Hoeppner LH, Claffey KP. PLCβ2 Promotes VEGF-Induced Vascular Permeability. Arterioscler Thromb Vasc Biol 2022; 42:1229-1241. [PMID: 35861069 PMCID: PMC9492642 DOI: 10.1161/atvbaha.122.317645] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Regulation of vascular permeability is critical to maintaining tissue metabolic homeostasis. VEGF (vascular endothelial growth factor) is a key stimulus of vascular permeability in acute and chronic diseases including ischemia reperfusion injury, sepsis, and cancer. Identification of novel regulators of vascular permeability would allow for the development of effective targeted therapeutics for patients with unmet medical need. METHODS In vitro and in vivo models of VEGFA-induced vascular permeability, pathological permeability, quantitation of intracellular calcium release and cell entry, and phosphatidylinositol 4,5-bisphosphate levels were evaluated with and without modulation of PLC (phospholipase C) β2. RESULTS Global knock-out of PLCβ2 in mice resulted in blockade of VEGFA-induced vascular permeability in vivo and transendothelial permeability in primary lung endothelial cells. Further work in an immortalized human microvascular cell line modulated with stable knockdown of PLCβ2 recapitulated the observations in the mouse model and primary cell assays. Additionally, loss of PLCβ2 limited both intracellular release and extracellular entry of calcium following VEGF stimulation as well as reduced basal and VEGFA-stimulated levels of phosphatidylinositol 4,5-bisphosphate compared to control cells. Finally, loss of PLCβ2 in both a hyperoxia-induced lung permeability model and a cardiac ischemia:reperfusion model resulted in improved animal outcomes when compared with wild-type controls. CONCLUSIONS The results implicate PLCβ2 as a key positive regulator of VEGF-induced vascular permeability through regulation of both calcium flux and phosphatidylinositol 4,5-bisphosphate levels at the cellular level. Targeting of PLCβ2 in a therapeutic setting may provide a novel approach to regulating vascular permeability in patients.
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Affiliation(s)
- Kathryn N. Phoenix
- Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT
| | - Zhichao Yue
- Pat and Jim Calhoun Cardiology Center, University of Connecticut Health Center, Farmington, CT
| | - Lixia Yue
- Pat and Jim Calhoun Cardiology Center, University of Connecticut Health Center, Farmington, CT
| | - Chunxia G. Cronin
- Pat and Jim Calhoun Cardiology Center, University of Connecticut Health Center, Farmington, CT
| | - Bruce T. Liang
- Pat and Jim Calhoun Cardiology Center, University of Connecticut Health Center, Farmington, CT
| | - Luke H. Hoeppner
- The Hormel Institute, University of Minnesota, Austin, MN, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Kevin P. Claffey
- Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT
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28
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Rasel MSI, Mohona FA, Akter W, Kabir S, Chowdhury AA, Chowdhury JA, Hassan MA, Al Mamun A, Ghose DK, Ahmad Z, Khan FS, Bari MF, Rahman MS, Amran MS. Exploration of Site-Specific Drug Targeting-A Review on EPR-, Stimuli-, Chemical-, and Receptor-Based Approaches as Potential Drug Targeting Methods in Cancer Treatment. JOURNAL OF ONCOLOGY 2022; 2022:9396760. [PMID: 36284633 PMCID: PMC9588330 DOI: 10.1155/2022/9396760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 07/21/2022] [Indexed: 11/17/2022]
Abstract
Cancer has been one of the most dominant causes of mortality globally over the last few decades. In cancer treatment, the selective targeting of tumor cells is indispensable, making it a better replacement for conventional chemotherapies by diminishing their adverse side effects. While designing a drug to be delivered selectively in the target organ, the drug development scientists should focus on various factors such as the type of cancer they are dealing with according to which drug, targeting moieties, and pharmaceutical carriers should be targeted. All published articles have been collected regarding cancer and drug-targeting approaches from well reputed databases including MEDLINE, Embase, Cochrane Library, CENTRAL and ClinicalTrials.gov, Science Direct, PubMed, Scopus, Wiley, and Springer. The articles published between January 2010 and December 2020 were considered. Due to the existence of various mechanisms, it is challenging to choose which one is appropriate for a specific case. Moreover, a combination of more than one approach is often utilized to achieve optimal drug effects. In this review, we have summarized and highlighted central mechanisms of how the targeted drug delivery system works in the specific diseased microenvironment, along with the strategies to make an approach more effective. We have also included some pictorial illustrations to have a precise idea about different types of drug targeting. The core contribution of this work includes providing a cancer drug development scientist with a broad preliminary idea to choose the appropriate approach among the various targeted drug delivery mechanisms. Also, the study will contribute to improving anticancer treatment approaches by providing a pathway for lesser side effects observed in conventional chemotherapeutic techniques.
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Affiliation(s)
- Md. Shamiul Islam Rasel
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Shahbag, Dhaka 1000, Bangladesh
| | - Farhana Afrin Mohona
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Shahbag, Dhaka 1000, Bangladesh
| | - Wahida Akter
- College of Pharmacy, University of Houston, Houston, USA
| | - Shaila Kabir
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Dhaka, Shahbag, Dhaka 1000, Bangladesh
| | - Abu Asad Chowdhury
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Dhaka, Shahbag, Dhaka 1000, Bangladesh
| | - Jakir Ahmed Chowdhury
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Dhaka, Shahbag, Dhaka 1000, Bangladesh
| | - Md. Abul Hassan
- Department of Science & Technology, Tokushima University Graduate School, Tokushima, Japan
| | - Abdullah Al Mamun
- Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035 Zhejiang, China
| | - Dipayon Krisna Ghose
- Department of Biochemistry and Molecular Biology, Jagannath University, Dhaka 1100, Bangladesh
| | - Zubair Ahmad
- Unit of Bee Research and Honey Production, King Khalid University, Abha 61413, Saudi Arabia
- Department of Biology, College of Arts and Sciences, King Khalid University, Abha 61413, Saudi Arabia
| | - Farhat S. Khan
- Department of Biology, College of Arts and Sciences, King Khalid University, Abha 61413, Saudi Arabia
| | - Md. Fazlul Bari
- Department of Biochemistry and Molecular Biology, Trust University, Barishal, Ruiya, Nobogram Road, Barishal 8200, Bangladesh
| | - Md. Sohanur Rahman
- Department of Biochemistry and Molecular Biology, Trust University, Barishal, Ruiya, Nobogram Road, Barishal 8200, Bangladesh
| | - Md. Shah Amran
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Dhaka, Shahbag, Dhaka 1000, Bangladesh
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Sevastre AS, Manea EV, Popescu OS, Tache DE, Danoiu S, Sfredel V, Tataranu LG, Dricu A. Intracellular Pathways and Mechanisms of Colored Secondary Metabolites in Cancer Therapy. Int J Mol Sci 2022; 23:ijms23179943. [PMID: 36077338 PMCID: PMC9456420 DOI: 10.3390/ijms23179943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/27/2022] [Accepted: 08/29/2022] [Indexed: 12/03/2022] Open
Abstract
Despite the great advancements made in cancer treatment, there are still many unsatisfied aspects, such as the wide palette of side effects and the drug resistance. There is an obvious increasing scientific attention towards nature and what it can offer the human race. Natural products can be used to treat many diseases, of which some plant products are currently used to treat cancer. Plants produce secondary metabolites for their signaling mechanisms and natural defense. A variety of plant-derived products have shown promising anticancer properties in vitro and in vivo. Rather than recreating the natural production environment, ongoing studies are currently setting various strategies to significantly manipulate the quantity of anticancer molecules in plants. This review focuses on the recently studied secondary metabolite agents that have shown promising anticancer activity, outlining their potential mechanisms of action and pathways.
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Affiliation(s)
- Ani-Simona Sevastre
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 200349 Craiova, Romania
| | - Elena Victoria Manea
- Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 200349 Craiova, Romania
| | - Oana Stefana Popescu
- Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 200349 Craiova, Romania
| | - Daniela Elise Tache
- Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 200349 Craiova, Romania
| | - Suzana Danoiu
- Department of Pathophysiology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 200349 Craiova, Romania
| | - Veronica Sfredel
- Department of Physiology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 200349 Craiova, Romania
| | - Ligia Gabriela Tataranu
- Neurosurgical Department, Clinical Hospital “Bagdasar-Arseni”, 041915 Bucharest, Romania
- Correspondence: ; Tel.: +40-21-334-30-25
| | - Anica Dricu
- Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Str. Petru Rares nr. 2-4, 200349 Craiova, Romania
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30
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He J, Liu Z, Zhu X, Xia H, Gao H, Lu J. Ultrasonic Microbubble Cavitation Enhanced Tissue Permeability and Drug Diffusion in Solid Tumor Therapy. Pharmaceutics 2022; 14:1642. [PMID: 36015267 PMCID: PMC9414228 DOI: 10.3390/pharmaceutics14081642] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 07/31/2022] [Accepted: 08/04/2022] [Indexed: 01/21/2023] Open
Abstract
Chemotherapy has an essential role not only in advanced solid tumor therapy intervention but also in society's health at large. Chemoresistance, however, seriously restricts the efficiency and sensitivity of chemotherapeutic agents, representing a significant threat to patients' quality of life and life expectancy. How to reverse chemoresistance, improve efficacy sensitization response, and reduce adverse side effects need to be tackled urgently. Recently, studies on the effect of ultrasonic microbubble cavitation on enhanced tissue permeability and retention (EPR) have attracted the attention of researchers. Compared with the traditional targeted drug delivery regimen, the microbubble cavitation effect, which can be used to enhance the EPR effect, has the advantages of less trauma, low cost, and good sensitization effect, and has significant application prospects. This article reviews the research progress of ultrasound-mediated microbubble cavitation in the treatment of solid tumors and discusses its mechanism of action to provide new ideas for better treatment strategies.
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Affiliation(s)
- Jide He
- Department of Urology, Peking University Third Hospital, Beijing 100191, China
| | - Zenan Liu
- Department of Urology, Peking University Third Hospital, Beijing 100191, China
| | - Xuehua Zhu
- Department of Urology, Peking University Third Hospital, Beijing 100191, China
| | - Haizhui Xia
- Department of Urology, Peking University Third Hospital, Beijing 100191, China
| | - Huile Gao
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, China
| | - Jian Lu
- Department of Urology, Peking University Third Hospital, Beijing 100191, China
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31
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Gurgul I, Mazuryk O, Stachyra K, Olszanecki R, Lekka M, Łomzik M, Suzenet F, Gros PC, Brindell M. Impact of Polypyridyl Ru Complexes on Angiogenesis-Contribution to Their Antimetastatic Activity. Int J Mol Sci 2022; 23:7708. [PMID: 35887054 PMCID: PMC9323615 DOI: 10.3390/ijms23147708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/08/2022] [Accepted: 07/08/2022] [Indexed: 12/10/2022] Open
Abstract
The use of polypyridyl Ru complexes to inhibit metastasis is a novel approach, and recent studies have shown promising results. We have reported recently that Ru (II) complexes gathering two 4,7-diphenyl-1,10-phenanthroline (dip) ligands and the one being 2,2'-bipyridine (bpy) or its derivative with a 4-[3-(2-nitro-1H-imidazol-1-yl)propyl (bpy-NitroIm) or 5-(4-{4'-methyl-[2,2'-bipyridine]-4-yl}but-1-yn-1-yl)pyridine-2-carbaldehyde semicarbazone (bpy-SC) moieties can alter the metastatic cascade, among others, by modulating cell adhesion properties. In this work, we show further studies of this group of complexes by evaluating their effect on HMEC-1 endothelial cells. While all the tested complexes significantly inhibited the endothelial cell migration, Ru-bpy additionally interrupted the pseudovessels formation. Functional changes in endothelial cells might arise from the impact of the studied compounds on cell elasticity and expression of proteins (vinculin and paxillin) involved in focal adhesions. Furthermore, molecular studies showed that complexes modulate the expression of cell adhesion molecules, which has been suggested to be one of the factors that mediate the activation of angiogenesis. Based on the performed studies, we can conclude that the investigated polypyridyl Ru (II) complexes can deregulate the functionality of endothelial cells which may lead to the inhibition of angiogenesis.
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Affiliation(s)
- Ilona Gurgul
- Faculty of Chemistry, Jagiellonian University in Krakow, Gronostajowa 2, 30-387 Krakow, Poland; (I.G.); (M.Ł.)
| | - Olga Mazuryk
- Faculty of Chemistry, Jagiellonian University in Krakow, Gronostajowa 2, 30-387 Krakow, Poland; (I.G.); (M.Ł.)
| | - Kamila Stachyra
- Chair of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, Grzegorzecka 16, 31-531 Krakow, Poland; (K.S.); (R.O.)
| | - Rafał Olszanecki
- Chair of Pharmacology, Faculty of Medicine, Jagiellonian University Medical College, Grzegorzecka 16, 31-531 Krakow, Poland; (K.S.); (R.O.)
| | - Małgorzata Lekka
- Department of Biophysical Microstructures, Institute of Nuclear Physics, Polish Academy of Sciences, PL-31342 Krakow, Poland;
| | - Michał Łomzik
- Faculty of Chemistry, Jagiellonian University in Krakow, Gronostajowa 2, 30-387 Krakow, Poland; (I.G.); (M.Ł.)
- Department of Organic Chemistry, Faculty of Chemistry, University of Łódź, ul. Tamka 12, 91-403 Łódź, Poland
| | - Franck Suzenet
- Institute of Organic and Analytical Chemistry, University of Orléans, UMR-CNRS 7311, rue de Chartres, BP 6759, CEDEX 2, 45067 Orléans, France;
| | | | - Małgorzata Brindell
- Faculty of Chemistry, Jagiellonian University in Krakow, Gronostajowa 2, 30-387 Krakow, Poland; (I.G.); (M.Ł.)
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An Insight into Anticancer Effect of Propolis and Its Constituents: A Review of Molecular Mechanisms. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:5901191. [PMID: 35754701 PMCID: PMC9232326 DOI: 10.1155/2022/5901191] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 05/30/2022] [Indexed: 12/29/2022]
Abstract
Propolis is a natural compound collected by honeybees from different parts of plants. Honeybees produce a sticky component besides honey by mixing the tree resin and other botanical sources with saliva called propolis or bee glue. Propolis was traditionally used as a wound healing substance, cosmetic, medicine, and many other conditions. Till now, there is no definite curable treatment for most cancers and chemotherapeutic drugs and drugs used for targeted therapies have serious side effects. According to a recent research, natural products are becoming increasingly essential in cancer prevention. Natural products are a great source of potential therapeutic agents, especially in the treatment of cancer. Previous studies have reported that the presence of caffeic acid phenethyl ester (CAPE), artepillin C, and chrysin is responsible for the anticancer potential of propolis. Most of the previous studies suggested that propolis and its active compounds inhibit cancer progression by targeting multiple signaling pathways including phosphoinositide 3-kinases (PI3K)/Akt and mitogen-activated protein kinase (MAPK) signaling molecules, and induce cell cycle arrest. Induction of apoptosis by propolis is mediated through extrinsic and intrinsic apoptotic pathways. The aim of this review is to highlight and summarize the molecular targets and anticancer potential of propolis and its active compounds on cell survival, proliferation, metastasis, and apoptosis in cancer cells.
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Nafissi N, Mohammadlou M, Akbari ME, Mahdavi SR, Sheikh M, Borji M, Babaee E, Baharlou R. The impact of intraoperative radiotherapy on breast cancer: focus on the levels of angiogenic factors. World J Surg Oncol 2022; 20:191. [PMID: 35681234 PMCID: PMC9178821 DOI: 10.1186/s12957-022-02653-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 05/26/2022] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE Angiogenesis is one of the hallmarks of cancers that is involved in tumor progression. Angiogenic factors induce the formation of new blood vessels and tumor extension, and finally reduce the survival of patients. Intraoperative radiotherapy (IORT), in which radiation is delivered to the tumor bed can kill cells and change tumor microenvironment. Here, we compared the impact of IORT on the levels of angiogenic factors in the blood and surgical wound fluids (SWF) of the breast cancer patients. PATIENTS AND METHODS Three hundred sixty patients, who had undergone breast-conserving surgery between 2013 and 2018, were enrolled in IORT and non-IORT groups non-randomly. Blood and drained wound fluid (WF) samples were collected from the patients before and after surgery, followed by quantification of the amounts of TGF-β, EGF, FGF, VEGF, and DLL4 in the patients using ELISA. RESULTS Our results were indicative of significant differences between the pre-surgery and post-surgery serum levels of EGF, DLL4, and VEGF. Furthermore, ROC analyses showed that TGF-β and DLL4 can differentiate of the early-stage from late-stage of the disease. Interestingly, the rate of the death and recurrence was reduced in IORT group. CONCLUSIONS In summary, IORT is a safe and effective treatment that can affect angiogenic factors and improve the overall- and recurrence-free survival of breast cancer patients.
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Affiliation(s)
- Nahid Nafissi
- Department of Breast, Rasoul Akram Hospital Clinical Research Development Center (RCRDC), Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Mohammadlou
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | | | - Seyed Rabie Mahdavi
- Department of Medical Physics, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Sheikh
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
| | - Mohammad Borji
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ebrahim Babaee
- Preventive Medicine and Public Health Research Center, Psychosocial Health Research Institute, Department of Community and Family Medicine, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Rasoul Baharlou
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran.
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran.
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34
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Horst B, Pradhan S, Chaudhary R, Listik E, Quintero-Macias L, Choi AS, Southard M, Liu Y, Whitaker R, Hempel N, Berchuck A, Nixon AB, Lee NY, Henis YI, Mythreye K. Hypoxia-induced inhibin promotes tumor growth and vascular permeability in ovarian cancers. Commun Biol 2022; 5:536. [PMID: 35654828 PMCID: PMC9163327 DOI: 10.1038/s42003-022-03495-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 05/17/2022] [Indexed: 12/21/2022] Open
Abstract
Hypoxia, a driver of tumor growth and metastasis, regulates angiogenic pathways that are targets for vessel normalization and ovarian cancer management. However, toxicities and resistance to anti-angiogenics can limit their use making identification of new targets vital. Inhibin, a heteromeric TGFβ ligand, is a contextual regulator of tumor progression acting as an early tumor suppressor, yet also an established biomarker for ovarian cancers. Here, we find that hypoxia increases inhibin levels in ovarian cancer cell lines, xenograft tumors, and patients. Inhibin is regulated primarily through HIF-1, shifting the balance under hypoxia from activins to inhibins. Hypoxia regulated inhibin promotes tumor growth, endothelial cell invasion and permeability. Targeting inhibin in vivo through knockdown and anti-inhibin strategies robustly reduces permeability in vivo and alters the balance of pro and anti-angiogenic mechanisms resulting in vascular normalization. Mechanistically, inhibin regulates permeability by increasing VE-cadherin internalization via ACVRL1 and CD105, a receptor complex that we find to be stabilized directly by inhibin. Our findings demonstrate direct roles for inhibins in vascular normalization via TGF-β receptors providing new insights into the therapeutic significance of inhibins as a strategy to normalize the tumor vasculature in ovarian cancer. Hypoxia increases levels of the heteromeric TGFβ ligand inhibin in ovarian cancer and inhibin promotes tumor growth, endothelial cell invasion and permeability.
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35
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Sima LE, Matei D, Condello S. The Outside-In Journey of Tissue Transglutaminase in Cancer. Cells 2022; 11:cells11111779. [PMID: 35681474 PMCID: PMC9179582 DOI: 10.3390/cells11111779] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/20/2022] [Accepted: 05/25/2022] [Indexed: 02/04/2023] Open
Abstract
Tissue transglutaminase (TG2) is a member of the transglutaminase family that catalyzes Ca2+-dependent protein crosslinks and hydrolyzes guanosine 5′-triphosphate (GTP). The conformation and functions of TG2 are regulated by Ca2+ and GTP levels; the TG2 enzymatically active open conformation is modulated by high Ca2+ concentrations, while high intracellular GTP promotes the closed conformation, with inhibition of the TG-ase activity. TG2’s unique characteristics and its ubiquitous distribution in the intracellular compartment, coupled with its secretion in the extracellular matrix, contribute to modulate the functions of the protein. Its aberrant expression has been observed in several cancer types where it was linked to metastatic progression, resistance to chemotherapy, stemness, and worse clinical outcomes. The N-terminal domain of TG2 binds to the 42 kDa gelatin-binding domain of fibronectin with high affinity, facilitating the formation of a complex with β-integrins, essential for cellular adhesion to the matrix. This mechanism allows TG2 to interact with key matrix proteins and to regulate epithelial to mesenchymal transition and stemness. Here, we highlight the current knowledge on TG2 involvement in cancer, focusing on its roles translating extracellular cues into activation of oncogenic programs. Improved understanding of these mechanisms could lead to new therapeutic strategies targeting this multi-functional protein.
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Affiliation(s)
- Livia Elena Sima
- Department of Molecular Cell Biology, Institute of Biochemistry of the Romanian Academy, 060031 Bucharest, Romania;
| | - Daniela Matei
- Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
- Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA
| | - Salvatore Condello
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Correspondence:
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36
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Chu LY, Huang BL, Huang XC, Peng YH, Xie JJ, Xu YW. EFNA1 in gastrointestinal cancer: Expression, regulation and clinical significance. World J Gastrointest Oncol 2022; 14:973-988. [PMID: 35646281 PMCID: PMC9124989 DOI: 10.4251/wjgo.v14.i5.973] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 09/17/2021] [Accepted: 04/04/2022] [Indexed: 02/06/2023] Open
Abstract
Ephrin-A1 is a protein that in humans is encoded by the EFNA1 gene. The ephrins and EPH-related receptors comprise the largest subfamily of receptor protein-tyrosine kinases which play an indispensable role in normal growth and development or in the pathophysiology of various tumors. The role of EFNA1 in tumorigenesis and development is complex and depends on the cell type and microenvironment which in turn affect the expression of EFNA1. This article reviews the expression, prognostic value, regulation and clinical significance of EFNA1 in gastrointestinal tumors.
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Affiliation(s)
- Ling-Yu Chu
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Bin-Liang Huang
- Department of Clinical Laboratory Medicine, The Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Xu-Chun Huang
- Department of Clinical Laboratory Medicine, The Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yu-Hui Peng
- Department of Clinical Laboratory Medicine, The Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Guangdong Esophageal Cancer Research Institute, The Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jian-Jun Xie
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yi-Wei Xu
- Department of Clinical Laboratory Medicine, The Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Guangdong Esophageal Cancer Research Institute, The Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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37
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Bouzari B, Mohammadi S, Bokov DO, Krasnyuk II, Hosseini-Fard SR, Hajibaba M, Mirzaei R, Karampoor S. Angioregulatory role of miRNAs and exosomal miRNAs in glioblastoma pathogenesis. Biomed Pharmacother 2022; 148:112760. [PMID: 35228062 DOI: 10.1016/j.biopha.2022.112760] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 02/23/2022] [Accepted: 02/23/2022] [Indexed: 11/19/2022] Open
Abstract
Glioblastoma (GB) is a highly aggressive cancer of the central nervous system, occurring in the brain or spinal cord. Many factors such as angiogenesis are associated with GB development. Angiogenesis is a procedure by which the pre-existing blood vessels create new vessels that play an essential role in health and disease, including tumors. Also, angiogenesis is one of the significant factors thought to be responsible for treatment resistance in many tumors, including GB. Hence, an improved understanding of the molecular processes underlying GB angiogenesis will pave the way for developing potential new treatments. Recently, it has been found that microRNAs (miRNAs) and exosomal miRNAs have a crucial role in inducing or inhibiting the angiogenesis process in GB development. A better knowledge of the miRNA's regulation pathway in the angiogenesis process in cancer offers unique mechanistic insight into the mechanism of tumor-associated neovascularization. Because of advancements in miRNA characterization and delivery methods, miRNAs can also be employed in clinical settings as potential biomarkers for anti-angiogenic treatment response as well as therapies targeting tumor angiogenesis. The recent finding and insights about miRNAs' angioregulatory role and exosomal miRNAs in GB are provided throughout the review. Also, we discuss the new concept of miRNAs-based therapies for GB in the future.
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Affiliation(s)
- Behnaz Bouzari
- Department of Pathology, Firouzgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Shabahang Mohammadi
- ENT and Head and Neck Research Center and Department, Firoozgar General Hospital, The Five Senses Health Institute, Iran
| | - Dmitry Olegovich Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, 8 Trubetskaya St., bldg. 2, Moscow 119991, Russian Federation; Laboratory of Food Chemistry, Federal Research Center of Nutrition, Biotechnology and Food Safety, 2/14 Ustyinsky pr., Moscow 109240, Russian Federation
| | - Ivan Ivanovich Krasnyuk
- Institute of Pharmacy, Sechenov First Moscow State Medical University, 8 Trubetskaya St., bldg. 2, Moscow 119991, Russian Federation
| | - Seyed Reza Hosseini-Fard
- Department of Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Marzieh Hajibaba
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Rasoul Mirzaei
- Department of Microbiology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran; Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran.
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38
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Zhu Z, Teng KY, Zhou J, Xu Y, Zhang L, Zhao H, Zhang X, Tian L, Li Z, Lu T, Ma S, Li Z, Dai Z, Wang J, Chen X, Wu X, Pan Y, Shi W, You Z, Chen H, Chung V, Yu J, He S, Zhao X, Cao L, Li D. B7H6 Serves as a Negative Prognostic Marker and an Immune Modulator in Human Pancreatic Cancer. Front Oncol 2022; 12:814312. [PMID: 35311080 PMCID: PMC8929685 DOI: 10.3389/fonc.2022.814312] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 02/07/2022] [Indexed: 12/30/2022] Open
Abstract
Pancreatic cancer (PC), the third leading cause of cancer-related death in the U.S., is frequently found too late to be cured by traditional chemotherapy. Expression of B7 homolog 6 (B7H6), a member of the B7 family of immunoreceptors, has been found in PC and several other cancers. B7H6 is a ligand for cytotoxicity triggering receptor 3 (NKp30), which is expressed on NK cells. Here, we demonstrate that B7H6 can be detected in PC tissues but not normal organs. Its expression in patients associated significantly with tumor differentiation grade and lymphatic metastasis. The soluble form of B7H6 was detected in the PC patients’ sera, and its concentration associated with tumor differentiation grade and tumor, node, metastasis (TNM) stages. Also, higher levels of B7H6 in PC patients’ malignant tissues or serum correlated with shorter overall survival. In vitro, downregulation of B7H6 by CRISPR/Cas9 or siRNA technology had no significant impact on the viability or mobility of PC cells. Instead, knocking out B7H6 sensitized PC cells to NK-mediated cytotoxicity and cytokine production. These results indicate that B7H6 not only serves as a negative prognostic marker but also acts as an immune modulator in PC.
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Affiliation(s)
- Zheng Zhu
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.,Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, United States.,Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Kun-Yu Teng
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, United States
| | - Jian Zhou
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yunyun Xu
- Pediatric Clinical Research Institute, Children's Hospital Affiliated to Soochow University, Suzhou, China
| | - Lifeng Zhang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Hua Zhao
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xueguang Zhang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Lei Tian
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, United States
| | - Zhiyao Li
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, United States
| | - Ting Lu
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, United States
| | - Shoubao Ma
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, United States
| | - Zhenlong Li
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, United States
| | - Zhenyu Dai
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, United States
| | - Jing Wang
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, United States
| | - Xingyu Chen
- Department of General Surgery, Taizhou Fourth People's Hospital, Taizhou, China
| | - Xing Wu
- Department of General Surgery, The First People's Hospital of Huzhou, Huzhou, China
| | - Yihan Pan
- College of Liberal Arts, University of Minnesota Twin Cities, Minneapolis, MN, United States
| | - Weiqiang Shi
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhiqun You
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Hanyu Chen
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, United States
| | - Vincent Chung
- Department of Medical Oncology, City of Hope National Medical Center, Los Angeles, CA, United States
| | - Jianhua Yu
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, United States
| | - Songbing He
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xin Zhao
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Lei Cao
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China.,Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Dechun Li
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
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Li S, Nguyen TT, Ung TT, Sah DK, Park SY, Lakshmanan VK, Jung YD. Piperine Attenuates Lithocholic Acid-Stimulated Interleukin-8 by Suppressing Src/EGFR and Reactive Oxygen Species in Human Colorectal Cancer Cells. Antioxidants (Basel) 2022; 11:530. [PMID: 35326180 PMCID: PMC8944659 DOI: 10.3390/antiox11030530] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 03/06/2022] [Accepted: 03/08/2022] [Indexed: 02/04/2023] Open
Abstract
Piperine, a natural alkaloidal pungent product present in pepper plants, possesses the properties of anti-inflammatory and anti-metastasis. Lithocholic acid is a monohydroxy-5beta-cholanic acid with an alpha-hydroxy substituent at position 3; it is a secondary bile acid that plays a pivotal role in fat absorption, and has been discovered to mediate colorectal cancer (CRC) cell invasion and migration. However, the effect of piperine on angiogenesis has been poorly investigated. In the current study, we examined the role of piperine on LCA-stimulated angiogenesis by measuring interleukin-8 (IL-8) expression; moreover, we revealed the potential molecular mechanisms in CRC cells. Here, we showed that piperine inhibited LCA-stimulated endothelial EA.hy926 cell angiogenesis in a conditioned medium obtained from colorectal HCT-116 cells. Experiments with an IL-8 neutralizer showed that IL-8 present in the conditioned medium was the major angiogenic factor. Piperine inhibited LCA-stimulated ERK1/2 and AKT via the Src/EGFR-driven ROS signaling pathway in the colorectal cell line (HCT-116). Through mutagenesis and inhibitory studies, we revealed that ERK1/2 acted as an upstream signaling molecule in AP-1 activation, and AKT acted as an upstream signaling molecule in NF-κB activation, which in turn attenuated IL-8 expression. Taken together, we demonstrated that piperine blocked LCA-stimulated IL-8 expression by suppressing Src and EGFR in human CRC HCT-116 cells, thus remarkably attenuating endothelial EA.hy926 cell tube formation.
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Affiliation(s)
- Shinan Li
- Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Korea; (S.L.); (T.T.N.); (T.T.U.); (D.K.S.); (S.Y.P.)
| | - Thi Thinh Nguyen
- Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Korea; (S.L.); (T.T.N.); (T.T.U.); (D.K.S.); (S.Y.P.)
- Nanogen Pharmaceutical Biotechnology Joint Stock Company, Ho Chi Minh City 70000, Vietnam
| | - Trong Thuan Ung
- Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Korea; (S.L.); (T.T.N.); (T.T.U.); (D.K.S.); (S.Y.P.)
- Nanogen Pharmaceutical Biotechnology Joint Stock Company, Ho Chi Minh City 70000, Vietnam
| | - Dhiraj Kumar Sah
- Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Korea; (S.L.); (T.T.N.); (T.T.U.); (D.K.S.); (S.Y.P.)
| | - Seon Young Park
- Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Korea; (S.L.); (T.T.N.); (T.T.U.); (D.K.S.); (S.Y.P.)
| | - Vinoth-Kumar Lakshmanan
- Faculty of Clinical Research, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, Tamil Nadu 600 116, India
| | - Young Do Jung
- Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Korea; (S.L.); (T.T.N.); (T.T.U.); (D.K.S.); (S.Y.P.)
- Department of Biochemistry, Chonnam National University Medical School, Seoyang Ro 264, Hwasun 58128, Korea
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Kumar VS, Anjali K. Tumour generated exosomal miRNAs: A major player in tumour angiogenesis. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166383. [DOI: 10.1016/j.bbadis.2022.166383] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 02/18/2022] [Accepted: 03/07/2022] [Indexed: 12/12/2022]
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Huttala O, Loreth D, Staff S, Tanner M, Wikman H, Ylikomi T. Decellularized In Vitro Capillaries for Studies of Metastatic Tendency and Selection of Treatment. Biomedicines 2022; 10:biomedicines10020271. [PMID: 35203480 PMCID: PMC8869401 DOI: 10.3390/biomedicines10020271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/21/2022] [Accepted: 01/22/2022] [Indexed: 11/19/2022] Open
Abstract
Vascularization plays an important role in the microenvironment of the tumor. Therefore, it should be a key element to be considered in the development of in vitro cancer assays. In this study, we decellularized in vitro capillaries to remove genetic material and optimized the medium used to increase the robustness and versatility of applications. The growth pattern and drug responses of cancer cell lines and patient-derived primary cells were studied on decellularized capillaries. Interestingly, two distinct growth patterns were seen when cancer cells were grown on decellularized capillaries: “network” and “cluster”. Network formation correlated with the metastatic properties of the cells and cluster formation was observed in non-metastatic cells. Drug responses of patient-derived cells correlated better with clinical findings when cells were cultured on decellularized capillaries compared with those cultured on plastic. Decellularized capillaries provide a novel method for cancer cell culture applications. It bridges the gap between complex 3D culture methods and traditional 2D culture methods by providing the ease and robustness of 2D culture as well as an in vivo-like microenvironment and scaffolding for 3D cultures.
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Affiliation(s)
- Outi Huttala
- Cell Biology, Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland;
- Tays Cancer Center, Tampere University Hospital, 33520 Tampere, Finland; (S.S.); (M.T.)
- Correspondence: ; Tel.: +358-401909721
| | - Desiree Loreth
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (D.L.); (H.W.)
| | - Synnöve Staff
- Tays Cancer Center, Tampere University Hospital, 33520 Tampere, Finland; (S.S.); (M.T.)
- Department of Obstetrics and Gynecology, Tampere University Hospital, 33520 Tampere, Finland
| | - Minna Tanner
- Tays Cancer Center, Tampere University Hospital, 33520 Tampere, Finland; (S.S.); (M.T.)
- Department of Oncology, Tampere University Hospital, 33520 Tampere, Finland
- Department of Oncology, Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland
| | - Harriet Wikman
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (D.L.); (H.W.)
| | - Timo Ylikomi
- Cell Biology, Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland;
- Tays Cancer Center, Tampere University Hospital, 33520 Tampere, Finland; (S.S.); (M.T.)
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Mahhengam N, Kazemnezhad K, Setia Budi H, Ansari MJ, Olegovich Bokov D, Suksatan W, Thangavelu L, Siahmansouri H. Targeted therapy of tumor microenvironment by gold nanoparticles as a new therapeutic approach. J Drug Target 2022; 30:494-510. [DOI: 10.1080/1061186x.2022.2032095] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Negah Mahhengam
- Faculty of General Medicine, Belarusian State Medical University, Minsk, Belarus.
| | - Kimia Kazemnezhad
- Faculty of General Medicine, Belarusian State Medical University, Minsk, Belarus.
| | - Hendrik Setia Budi
- Department of Oral Biology, Faculty of Dental Medicine, Universitas Airlangga, Surabaya 60132, Indonesia.
| | - Mohammad Javed Ansari
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University,Al-kharj, Saudi Arabia.
| | - Dmitry Olegovich Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, 8 Trubetskaya St., bldg. 2, Moscow, 119991, Russian Federation.
| | - Wanich Suksatan
- Faculty of Nursing, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, Thailand.
| | - Lakshmi Thangavelu
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Saveetha University, Chennai, India.
| | - Homayoon Siahmansouri
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Álvarez-Torres MDM, Fuster-García E, Juan-Albarracín J, Reynés G, Aparici-Robles F, Ferrer-Lozano J, García-Gómez JM. Local detection of microvessels in IDH-wildtype glioblastoma using relative cerebral blood volume: an imaging marker useful for astrocytoma grade 4 classification. BMC Cancer 2022; 22:40. [PMID: 34991512 PMCID: PMC8734263 DOI: 10.1186/s12885-021-09117-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 12/15/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The microvessels area (MVA), derived from microvascular proliferation, is a biomarker useful for high-grade glioma classification. Nevertheless, its measurement is costly, labor-intense, and invasive. Finding radiologic correlations with MVA could provide a complementary non-invasive approach without an extra cost and labor intensity and from the first stage. This study aims to correlate imaging markers, such as relative cerebral blood volume (rCBV), and local MVA in IDH-wildtype glioblastoma, and to propose this imaging marker as useful for astrocytoma grade 4 classification. METHODS Data from 73 tissue blocks belonging to 17 IDH-wildtype glioblastomas and 7 blocks from 2 IDH-mutant astrocytomas were compiled from the Ivy GAP database. MRI processing and rCBV quantification were carried out using ONCOhabitats methodology. Histologic and MRI co-registration was done manually with experts' supervision, achieving an accuracy of 88.8% of overlay. Spearman's correlation was used to analyze the association between rCBV and microvessel area. Mann-Whitney test was used to study differences of rCBV between blocks with presence or absence of microvessels in IDH-wildtype glioblastoma, as well as to find differences with IDH-mutant astrocytoma samples. RESULTS Significant positive correlations were found between rCBV and microvessel area in the IDH-wildtype blocks (p < 0.001), as well as significant differences in rCBV were found between blocks with microvascular proliferation and blocks without it (p < 0.0001). In addition, significant differences in rCBV were found between IDH-wildtype glioblastoma and IDH-mutant astrocytoma samples, being 2-2.5 times higher rCBV values in IDH-wildtype glioblastoma samples. CONCLUSIONS The proposed rCBV marker, calculated from diagnostic MRIs, can detect in IDH-wildtype glioblastoma those regions with microvessels from those without it, and it is significantly correlated with local microvessels area. In addition, the proposed rCBV marker can differentiate the IDH mutation status, providing a complementary non-invasive method for high-grade glioma classification.
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Affiliation(s)
| | - Elies Fuster-García
- Oslo University Hospital, Department of Diagnostic Physics, 0424, Oslo, Norway
| | - Javier Juan-Albarracín
- Universitat Politècnica de València, Biomedical Data Science Laboratory, ITACA, 46022, Valencia, Spain
| | - Gaspar Reynés
- Health Research Institute Hospital La Fe, Department of Medical Oncology, Cancer Research Group, 46026, Valencia, Spain
| | - Fernando Aparici-Robles
- Health Research Institute Hospital La Fe, Department of Medical Imaging, 46026, Valencia, Spain
| | - Jaime Ferrer-Lozano
- Health Research Institute Hospital La Fe, Department of Pathology, 46026, Valencia, Spain
| | - Juan Miguel García-Gómez
- Universitat Politècnica de València, Biomedical Data Science Laboratory, ITACA, 46022, Valencia, Spain
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Simanullang RH, Situmorang PC, Ginting L, Tarigan ER, Syahputra RA, Chairunisa C, Maliki MF. PDGF-β and IL-18 Expressions on Carcinoma Cervical by Rhodomyrtus tomentosa. Pak J Biol Sci 2022; 25:986-992. [PMID: 36591929 DOI: 10.3923/pjbs.2022.986.992] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
<b>Background and Objective:</b> Cervical cancer, along with lung and breast cancer, is one of Indonesia's most aggressive gynaecological diseases. <i>Rhodomyrtus tomentosa</i> has antioxidant and antiproliferative properties that could be developed into herbal medicines for molecular therapy. The IL-18 and PDGF-β are tumour-promoting agent proteins that may be therapeutic targets for a variety of cancers that were investigated in this study. <b>Materials and Methods:</b> Rats were classified into five groups: Group C- is the control group, Group C+ is the cancer model group and Group RHO200 is the <i>Rhodomyrtus tomentosa</i> 100 mg<sup>1</sup> b.wt., rat group, Group RHO400 is the <i>Rhodomyrtus tomentosa</i> 200 mg<sup>1</sup> b.wt., rat group and Group RHO400 is the <i>Rhodomyrtus tomentosa</i> 400 mg<sup>1</sup> b.wt., rat group. The rats were dissected 30 days after receiving <i>Rhodomyrtus tomentosa</i>. Immunohistochemistry is used to stain cervical tissues. <b>Results:</b> The expression of IL-18 and PDGF-β was significantly different (p<0.01). The IL-18 and PDGF-β were most abundant at the lowest <i>Rhodomyrtus tomentosa</i> doses (100-200 mg kg<sup>1</sup> b.wt.), while they were least abundant at the 400 mg kg<sup>1</sup> b.wt., doses. Histological analysis revealed that the highest dose of IL-18 and PDGF-β expression reduced abnormal tissue and the space between tumours, followed by several carcinoma cells that stopped growing. <b>Conclusion:</b> <i>Rhodomyrtus tomentosa</i> can be used as a herbal therapy to reduce the expression of PDGF-β and IL-18 (two cancer marker agents).
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Constantin AM, Mihu CM, Boşca AB, Melincovici CS, Mărginean MV, Jianu EM, Ştefan RA, Alexandru BC, Moldovan IM, Şovrea AS, Sufleţel RT. Short histological kaleidoscope - recent findings in histology. Part I. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY = REVUE ROUMAINE DE MORPHOLOGIE ET EMBRYOLOGIE 2022; 63:7-29. [PMID: 36074664 PMCID: PMC9593135 DOI: 10.47162/rjme.63.1.01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 09/05/2022] [Indexed: 06/15/2023]
Abstract
This article is a review of new advances in histology, concerning either classification or structure of different tissular elements (basement membrane, hemidesmosomes, urothelium, glandular epithelia, adipose tissue, astrocytes), and various organs' constituents (blood-brain barrier, human dental cementum, tubarial salivary glands, hepatic stellate cells, pineal gland, fibroblasts of renal interstitium, Leydig testicular cells, ovarian hilar cells), as well as novel biotechnological techniques (tissue engineering in angiogenesis), recently introduced.
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Affiliation(s)
- Anne Marie Constantin
- Discipline of Histology, Department of Morphological Sciences, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania;
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Ismail AA, Shaker BT, Bajou K. The Plasminogen-Activator Plasmin System in Physiological and Pathophysiological Angiogenesis. Int J Mol Sci 2021; 23:ijms23010337. [PMID: 35008762 PMCID: PMC8745544 DOI: 10.3390/ijms23010337] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/20/2021] [Accepted: 12/23/2021] [Indexed: 12/20/2022] Open
Abstract
Angiogenesis is a process associated with the migration and proliferation of endothelial cells (EC) to form new blood vessels. It is involved in various physiological and pathophysiological conditions and is controlled by a wide range of proangiogenic and antiangiogenic molecules. The plasminogen activator–plasmin system plays a major role in the extracellular matrix remodeling process necessary for angiogenesis. Urokinase/tissue-type plasminogen activators (uPA/tPA) convert plasminogen into the active enzyme plasmin, which in turn activates matrix metalloproteinases and degrades the extracellular matrix releasing growth factors and proangiogenic molecules such as the vascular endothelial growth factor (VEGF-A). The plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of uPA and tPA, thereby an inhibitor of pericellular proteolysis and intravascular fibrinolysis, respectively. Paradoxically, PAI-1, which is expressed by EC during angiogenesis, is elevated in several cancers and is found to promote angiogenesis by regulating plasmin-mediated proteolysis and by promoting cellular migration through vitronectin. The urokinase-type plasminogen activator receptor (uPAR) also induces EC cellular migration during angiogenesis via interacting with signaling partners. Understanding the molecular functions of the plasminogen activator plasmin system and targeting angiogenesis via blocking serine proteases or their interactions with other molecules is one of the major therapeutic strategies scientists have been attracted to in controlling tumor growth and other pathological conditions characterized by neovascularization.
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Affiliation(s)
- Asmaa Anwar Ismail
- Department of Applied Biology, College of Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; (A.A.I.); (B.T.S.)
- Human Genetics & Stem Cells Research Group, Research Institute of Sciences & Engineering, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Baraah Tariq Shaker
- Department of Applied Biology, College of Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; (A.A.I.); (B.T.S.)
- Human Genetics & Stem Cells Research Group, Research Institute of Sciences & Engineering, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Khalid Bajou
- Department of Applied Biology, College of Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; (A.A.I.); (B.T.S.)
- Human Genetics & Stem Cells Research Group, Research Institute of Sciences & Engineering, University of Sharjah, Sharjah 27272, United Arab Emirates
- Correspondence:
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Akgol S, Kalkan BM, Yucel D, Kocabas F. SC1 limits tube formation, branching, migration, expansion and induce apoptosis of endothelial cells. Vascul Pharmacol 2021; 141:106903. [PMID: 34481979 DOI: 10.1016/j.vph.2021.106903] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 07/02/2021] [Accepted: 08/27/2021] [Indexed: 11/30/2022]
Abstract
Endothelial cells (ECs) are essential in the growth and progression of the tumor cells by supplying nutrition and angiogenesis factors. Targeting ECs emerged as a major strategy to prevent the growth of tumors. Studies suggest that ERK1/2 signaling is important for endothelial cells, which could be specifically targeted by small molecule SC1. We aimed to study the effects of SC1 treatments on endothelial cell proliferation, angiogenesis, and death. To this end, we performed viability, apoptosis, cell cycle, gene expression, wound closure, tube formation, and western blot analysis in endothelial cells post SC1 treatments. Intriguingly, we found that SC1 has an antiangiogenic effect on endothelial cells, which limits the endothelial cell expansion, tube formation, branching, and migration. The proliferation is especially limited in dose dependent manner by SC1. In addition, we found that SC1 elevates the apoptosis of endothelial cells and associated pathways including BAK1, Stat1, Sox4, and Caspase1. We believe that these findings could contribute to the development of improved therapies based on the SC1 as an attractive candidate for anticancer clinical studies targeted to tumor angiogenesis.
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Affiliation(s)
- Sezer Akgol
- Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, Istanbul, Turkey
| | | | - Dogacan Yucel
- Department of Medicine, University of Minnesota, USA
| | - Fatih Kocabas
- Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, Istanbul, Turkey.
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Franchini M, Tufano A, Casoria A, Coppola A. Arterial Thrombosis in Cancer Patients: An Update. Semin Thromb Hemost 2021; 47:942-949. [PMID: 34464985 DOI: 10.1055/s-0041-1733927] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Cancer is associated with an increased incidence of both venous thromboembolism (VTE) and arterial thrombosis (cardiovascular events and ischemic stroke). Cancer-associated arterial thrombotic events are less well studied than VTE, but increasingly recognized, particularly in specific malignancies and in association with specific anticancer therapies. The pathogenesis of arterial thrombotic events in cancer is complex and involves generation of tumor-associated procoagulant factors and a variety of alterations in platelet function as well as in the coagulation and fibrinolytic systems, and endothelial injury and dysfunction, that combine to produce hypercoagulability. The multifactorial interaction between this prothrombotic state, the individual cardiovascular risk, advanced age and presence of comorbidities, and the specific neoplasm characteristics and therapy, may induce the vascular events. Recent studies based on population databases and prospective or retrospective analyses with prolonged follow-up highlight that cancer patients experience an increased (approximately 1.5-2-fold) risk of both cerebrovascular and cardiovascular events compared with noncancer individuals, which peaks in the time period of the diagnosis of cancer but may persist for years. Beyond the type of cancer, the risk reflects the tumor burden, being higher in advanced stages and metastatic cancers. The occurrence of arterial thromboembolic events is also associated with increased overall mortality. We here present an update of the pathophysiology, risk factors, clinical evidence, and treatment considerations on cancer-associated arterial thrombosis, in the light of the need for specific multidisciplinary prevention and surveillance strategies in this setting, in the frame of cardio-oncology approaches.
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Affiliation(s)
- Massimo Franchini
- Department of Haematology and Transfusion Medicine, Carlo Poma Hospital, Mantova, Italy
| | - Antonella Tufano
- Department of Clinical Medicine and Surgery, Federico II University Hospital, Naples, Italy
| | - Aniello Casoria
- Department of Clinical Medicine and Surgery, Federico II University Hospital, Naples, Italy
| | - Antonio Coppola
- Department of General and Specialist Medicine, Hub Center for Inherited Bleeding Disorders, University Hospital, Parma, Italy
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Khoobchandani M, Khan A, Katti KK, Thipe VC, Al-Yasiri AY, MohanDoss DKD, Nicholl MB, Lugão AB, Hans CP, Katti KV. Green nanotechnology of MGF-AuNPs for immunomodulatory intervention in prostate cancer therapy. Sci Rep 2021; 11:16797. [PMID: 34408231 PMCID: PMC8373987 DOI: 10.1038/s41598-021-96224-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 08/05/2021] [Indexed: 02/07/2023] Open
Abstract
Men with castration-resistant prostate cancer (CRPC) face poor prognosis and increased risk of treatment-incurred adverse effects resulting in one of the highest mortalities among patient population globally. Immune cells act as double-edged sword depending on the tumor microenvironment, which leads to increased infiltration of pro-tumor (M2) macrophages. Development of new immunomodulatory therapeutic agents capable of targeting the tumor microenvironment, and hence orchestrating the transformation of pro-tumor M2 macrophages to anti-tumor M1, would substantially improve treatment outcomes of CRPC patients. We report, herein, Mangiferin functionalized gold nanoparticulate agent (MGF-AuNPs) and its immunomodulatory characteristics in treating prostate cancer. We provide evidence of immunomodulatory intervention of MGF-AuNPs in prostate cancers through observations of enhanced levels of anti-tumor cytokines (IL-12 and TNF-α) with concomitant reductions in the levels of pro-tumor cytokines (IL-10 and IL-6). In the MGF-AuNPs treated groups, IL-12 was elevated to ten-fold while TNF-α was elevated to about 50-fold, while IL-10 and IL-6 were reduced by two-fold. Ability of MGF-AuNPs to target splenic macrophages is invoked via targeting of NF-kB signaling pathway. Finally, therapeutic efficacy of MGF-AuNPs, in treating prostate cancer in vivo in tumor bearing mice, is described taking into consideration various immunomodulatory interventions triggered by this green nanotechnology-based nanomedicine agent.
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Affiliation(s)
- Menka Khoobchandani
- Department of Radiology, Institute of Green Nanotechnology, University of Missouri, Columbia, MO, 65212, USA
- Department of Radiation Oncology, Washington University School of Medicine, 4511 Forest Park Ave, St. Louis, MO, 63108, USA
| | - Aslam Khan
- Department of Biochemistry, University of Missouri, Columbia, MO, 65212, USA
| | - Kavita K Katti
- Department of Radiology, Institute of Green Nanotechnology, University of Missouri, Columbia, MO, 65212, USA
| | - Velaphi C Thipe
- Laboratório de Ecotoxicologia, Centro de Química e Meio Ambiente, Instituto de Pesquisas Energéticas e Nucleares (IPEN), Comissão Nacional de Energia Nuclear, IPEN/CNEN-SP, Butantã, São Paulo, SP, Brasil
| | - Amal Y Al-Yasiri
- Nuclear Science and Engineering Institute (NSEI), University of Missouri, Columbia, MO, 65211, USA
- College of Dentistry, University of Baghdad, Baghdad, Iraq
| | - Darsha K D MohanDoss
- Dhanvantari Nano Ayushadi Pvt Ltd, No. 8/34, Neelakanta Mehta Street, T. Nagar, Chennai, 600017, India
| | | | - Ademar B Lugão
- Laboratório de Ecotoxicologia, Centro de Química e Meio Ambiente, Instituto de Pesquisas Energéticas e Nucleares (IPEN), Comissão Nacional de Energia Nuclear, IPEN/CNEN-SP, Butantã, São Paulo, SP, Brasil
| | - Chetan P Hans
- Department of Medicine-Cardiology, University of Missouri, Columbia, MO, 65212, USA
| | - Kattesh V Katti
- Department of Radiology, Institute of Green Nanotechnology, University of Missouri, Columbia, MO, 65212, USA.
- Department of Physics, University of Missouri, Columbia, MO, 65212, USA.
- University of Missouri Research Reactor (MURR), University of Missouri, Columbia, MO, 65212, USA.
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Three-Dimensional Vascularized Lung Cancer-on-a-Chip with Lung Extracellular Matrix Hydrogels for In Vitro Screening. Cancers (Basel) 2021; 13:cancers13163930. [PMID: 34439103 PMCID: PMC8393390 DOI: 10.3390/cancers13163930] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 08/02/2021] [Accepted: 08/02/2021] [Indexed: 12/13/2022] Open
Abstract
Recent advances in immunotherapies and molecularly targeted therapies have led to an increased interest in exploring the field of in vitro tumor mimetic platforms. An increasing need to understand the mechanisms of anti-cancer therapies has led to the development of natural tumor tissue-like in vitro platforms capable of simulating the tumor microenvironment. The incorporation of vascular structures into the in vitro platforms could be a crucial factor for functional investigation of most anti-cancer therapies, including immunotherapies, which are closely related to the circulatory system. Decellularized lung extracellular matrix (ldECM), comprised of ECM components and pro-angiogenic factors, can initiate vascularization and is ideal for mimicking the natural microenvironment. In this study, we used a ldECM-based hydrogel to develop a 3D vascularized lung cancer-on-a-chip (VLCC). We specifically encapsulated tri-cellular spheroids made from A549 cells, HUVECs, and human lung fibroblasts, for simulating solid type lung cancer. Additionally, two channels were incorporated in the hydrogel construct to mimic perfusable vessel structures that resemble arterioles or venules. Our study highlights how a more effective dose-dependent action of the anti-cancer drug Doxorubicin was observed using a VLCC over 2D screening. This observation confirmed the potential of the VLCC as a 3D in vitro drug screening tool.
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