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Hoveidaei AH, Sadat-Shojai M, Nabavizadeh SS, Niakan R, Shirinezhad A, MosalamiAghili S, Tabaie S. Clinical challenges in bone tissue engineering - A narrative review. Bone 2025; 192:117363. [PMID: 39638083 DOI: 10.1016/j.bone.2024.117363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 11/23/2024] [Accepted: 12/02/2024] [Indexed: 12/07/2024]
Abstract
Bone tissue engineering (BTE) has emerged as a promising approach to address large bone defects caused by trauma, infections, congenital malformations, and tumors. This review focuses on scaffold design, cell sources, growth factors, and vascularization strategies, highlighting their roles in developing effective treatments. We explore the complexities of balancing mechanical properties, porosity, and biocompatibility in scaffold materials, alongside optimizing mesenchymal stem cell delivery methods. The critical role of growth factors in bone regeneration and the need for controlled release systems are discussed. Vascularization remains a significant hurdle, with strategies such as angiogenic factors, co-culture systems, and bioprinting under investigation. Mechanical challenges, tissue responses, and inflammation management are examined, alongside gene therapy's potential for enhancing osteogenesis and angiogenesis via both viral and non-viral delivery methods. The review emphasizes the impact of patient-specific factors on bone healing outcomes and the importance of personalized approaches. Future directions are described, emphasizing the necessity of interdisciplinary cooperation to advance the field of BTE and convert laboratory results into clinically feasible solutions.
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Affiliation(s)
- Amir Human Hoveidaei
- International Center for Limb Lengthening, Rubin Institute for Advanced Orthopedics, Sinai Hospital of Baltimore, Baltimore, MD, USA.
| | - Mehdi Sadat-Shojai
- Department of Chemistry, College of Sciences, Shiraz University, Shiraz, Iran.
| | - Sara S Nabavizadeh
- Otolaryngology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Niakan
- Student Research Committee, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | | | - Sean Tabaie
- Department of Orthopaedic Surgery, Nationwide Children's Hospital, Columbus, OH, USA
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Xu X, Fu J, Yang G, Chen Z, Chen S, Yuan G. Dentin sialoprotein acts as an angiogenic factor through association with the membrane receptor endoglin. J Biol Chem 2025; 301:108279. [PMID: 39922489 PMCID: PMC11910139 DOI: 10.1016/j.jbc.2025.108279] [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: 08/04/2024] [Revised: 01/04/2025] [Accepted: 01/23/2025] [Indexed: 02/10/2025] Open
Abstract
Dentin sialophosphoprotein (DSPP) is highly expressed by odontoblasts, the cell type responsible for dentin formation. DSPP therefore has been extensively studied as a regulator of dentinogenesis. Besides defective dentinogenesis in teeth, Dspp-deficient mice also display reduced blood vessels in the transition zone of femurs. However, the exact role and underlying mechanisms of DSPP in the process of blood vessel formation remain enigmatic. Here, we show that dentin sialoprotein (DSP), the NH2-terminal cleavage product of DSPP, promotes the migration and capillary-like structure formation of human umbilical vein endothelial cells (HUVECs) as well as the migration and endothelial differentiation of human dental pulp stem cells (DPSCs). Further experiments demonstrate that endoglin (ENG), a membrane receptor associated with angiogenesis, can be co-immunoprecipitated by DSP. Flow cytometry assays show that HUVECs and DPSCs, two cell types with endogenous ENG expression, display obvious binding signals of supplemented DSP protein, but human embryonic kidney 293T (HEK293T) cells, a cell type without endogenous ENG expression, do not. Pretreatment with an anti-ENG antibody or knockdown of ENG inhibits the binding of DSP to DPSCs, while ENG overexpression enhances binding signals of DSP to HEK293T cells. Meanwhile, multiple experiments demonstrate that knockdown of ENG impairs DSP-induced migration and endothelial differentiation of DPSCs. Therefore, ENG is essential for the angiogenic effects of DSP. Moreover, Dspp-deficient mice exhibit defective capillary formation in molars, supporting the positive role of DSP in blood vessel development. Collectively, these findings identify that DSP acts as an angiogenic factor through association with ENG.
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Affiliation(s)
- Ximin Xu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, Hubei, China
| | - Jing Fu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, Hubei, China
| | - Guobin Yang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China
| | - Zhi Chen
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China
| | - Shuo Chen
- Department of Developmental Dentistry, School of Dentistry, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
| | - Guohua Yuan
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China; Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, Hubei, China.
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Guo Z, Jing X, Sun X, Sun S, Yang Y, Cao Y. Tumor angiogenesis and anti-angiogenic therapy. Chin Med J (Engl) 2024; 137:2043-2051. [PMID: 39051171 PMCID: PMC11374217 DOI: 10.1097/cm9.0000000000003231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Indexed: 07/27/2024] Open
Abstract
ABSTRACT Anti-angiogenic drugs (AADs), which mainly target the vascular endothelial growth factor-A signaling pathway, have become a therapeutic option for cancer patients for two decades. During this period, tremendous clinical experience of anti-angiogenic therapy has been acquired, new AADs have been developed, and the clinical indications for AAD treatment of various cancers have been expanded using monotherapy and combination therapy. However, improvements in the therapeutic outcomes of clinically available AADs and the development of more effective next-generation AADs are still urgently required. This review aims to provide historical and perspective views on tumor angiogenesis to allow readers to gain mechanistic insights and learn new therapeutic development. We revisit the history of concept initiation and AAD discovery, and summarize the up-to-date clinical translation of anti-angiogenic cancer therapy in this field.
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Affiliation(s)
- Ziheng Guo
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xu Jing
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm 17177, Sweden
| | - Xiaoting Sun
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm 17177, Sweden
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vison and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Shishuo Sun
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm 17177, Sweden
- Cancer Institute, the First Clinical Medical College, Xuzhou Medical University, Xuzhou, Jiangsu 221000, China
| | - Yunlong Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Yihai Cao
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm 17177, Sweden
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Zarei P, Ghasemi F. The Application of Artificial Intelligence and Drug Repositioning for the Identification of Fibroblast Growth Factor Receptor Inhibitors: A Review. Adv Biomed Res 2024; 13:9. [PMID: 38525398 PMCID: PMC10958741 DOI: 10.4103/abr.abr_170_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 08/24/2023] [Accepted: 09/03/2023] [Indexed: 03/26/2024] Open
Abstract
Artificial intelligence talks about modeling intelligent behavior through a computer with the least human involvement. Drug repositioning techniques based on artificial intelligence accelerate the research process and decrease the cost of experimental studies. Dysregulation of fibroblast growth factor (FGF) receptors as the tyrosine kinase family of receptors plays a vital role in a wide range of malignancies. Because of their functional significance, they were considered promising drug targets for the therapy of various cancers. This review has summarized small molecules capable of inhibiting FGF receptors that progressed using artificial intelligence and repositioning drugs examined in clinical trials associated with cancer therapy. This review is based on a literature search in PubMed, Web of Science, Scopus EMBASE, and Google Scholar databases to gather the necessary information in each chapter by employing keywords like artificial intelligence, computational drug design, drug repositioning, and FGF receptor inhibitors. To achieve this goal, a spacious literature review of human studies in these fields-published over the last 20 decades-was performed. According to published reports, nonselective FGF receptor inhibitors can be used for cancer management, and multitarget kinase inhibitors are the first drug class approved due to more advanced clinical studies. For example, AZD4547 and BGJ398 are gradually entering the consumption cycle and are good options as combined treatments. Artificial intelligence and drug repositioning methods can help preselect suitable drug targets more successfully for future inhibition of carcinogenicity.
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Affiliation(s)
- Parvin Zarei
- Department of Bioinformatics, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fahimeh Ghasemi
- Department of Bioinformatics, Isfahan University of Medical Sciences, Isfahan, Iran
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Georg Magalhães C, Ploeger Mansueli C, Manieri TM, Quintilio W, Garbuio A, de Jesus Marinho J, de Moraes JZ, Tsuruta LR, Moro AM. Impaired proliferation and migration of HUVEC and melanoma cells by human anti-FGF2 mAbs derived from a murine hybridoma by guided selection. Bioengineered 2023; 14:2252667. [PMID: 37661761 PMCID: PMC10478743 DOI: 10.1080/21655979.2023.2252667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 05/23/2023] [Accepted: 05/25/2023] [Indexed: 09/05/2023] Open
Abstract
Disadvantages of using murine monoclonal antibodies (mAb) in human therapy, such as immunogenicity response, led to the development of technologies to transform murine antibodies into human antibodies. The murine anti-FGF2 3F12E7 mAb was proposed as a promising agent to treat metastatic melanoma tumors; once it blocks the FGF2, responsible for playing a role in tumor growth, angiogenesis, and metastasis. Considering the therapeutic potential of anti-FGF2 3F12E7 mAb and its limited use in humans due to its origin, we used this antibody as the template for a guided selection humanization technique to obtain human anti-FGF2 mAbs. Three Fab libraries (murine, hybrid, and human) were constructed for humanization. The libraries were phage-displayed, and the panning was performed against recombinant human FGF2 (rFGF2). The selected human variable light and heavy chains were cloned into AbVec vectors for full-length IgG expression into HEK293-F cells. Surface plasmon resonance analyses showed binding to rFGF2 of seven mAbs out of 20 expressed. Assays performed with these mAbs resulted in two that showed proliferation reduction and cell migration attenuation of HUVEC and SK-Mel-28 melanoma cells. In-silico analyses predicted that these two human anti-FGF2 mAbs interact with FGF2 at a similar patch of residues than the chimeric anti-FGF2 antibody, comprehending a region within the heparin-binding domains of FGF2, essential for its function. These results are comparable to those achieved by the murine anti-FGF2 3F12E7 mAb and showed success in the humanization process and selection of two human mAbs with the potential to inhibit undesirable FGF2 roles.
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Affiliation(s)
| | | | | | - Wagner Quintilio
- Laboratory of Biopharmaceuticals, Butantan Institute, São Paulo, Brazil
| | - Angélica Garbuio
- Laboratory of Biopharmaceuticals, Butantan Institute, São Paulo, Brazil
| | | | - Jane Zveiter de Moraes
- Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | | | - Ana Maria Moro
- Laboratory of Biopharmaceuticals, Butantan Institute, São Paulo, Brazil
- CeRDI, Center for Research and Development in Immunobiologicals, Butantan Institute, São Paulo, Brazil
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Tan X, Tao Q, Yin S, Fu G, Wang C, Xiang F, Hu H, Zhang S, Wang Z, Li D. A single administration of FGF2 after renal ischemia-reperfusion injury alleviates post-injury interstitial fibrosis. Nephrol Dial Transplant 2023; 38:2537-2549. [PMID: 37243325 DOI: 10.1093/ndt/gfad114] [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: 10/04/2022] [Indexed: 05/28/2023] Open
Abstract
BACKGROUND Despite lack of clinical therapy in acute kidney injury (AKI) or its progression to chronic kidney disease (CKD), administration of growth factors shows great potential in the treatment of renal repair and further fibrosis. At an early phase of AKI, administration of exogenous fibroblast growth factor 2 (FGF2) protects against renal injury by inhibition of mitochondrial damage and inflammatory response. Here, we investigated whether this treatment attenuates the long-term renal interstitial fibrosis induced by ischemia-reperfusion (I/R) injury. METHODS Unilateral renal I/R with contralateral nephrectomy was utilized as an in vivo model for AKI and subsequent CKD. Rats were randomly divided into four groups: Sham-operation group, I/R group, I/R-FGF2 group and FGF2-3D group. These groups were monitored for up to 2 months. Serum creatinine, inflammatory response and renal histopathology changes were detected to evaluate the role of FGF2 in AKI and followed renal interstitial fibrosis. Moreover, the expression of vimentin, α-SMA, CD31 and CD34 were examined. RESULTS Two months after I/R injury, the severity of renal interstitial fibrosis was significantly attenuated in both of I/R-FGF2 group and FGF2-3D group, compared with the I/R group. The protective effects of FGF2 administration were associated with the reduction of high-mobility group box 1 (HMGB1)-mediated inflammatory response, the inhibition of transforming growth factor beta (TGF-β1)/Smads signaling-induced epithelial-mesenchymal transition and the maintenance of peritubular capillary structure. CONCLUSIONS A single dose of exogenous FGF2 administration 1 h or 3 days after reperfusion inhibited renal fibrogenesis and thus blocked the transition of AKI to CKD. Our findings provided novel insight into the role of FGF signaling in AKI-to-CKD progression and underscored the potential of FGF-based therapy for this devastating disease.
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Affiliation(s)
- Xiaohua Tan
- Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Qianyu Tao
- Department of Pharmacy, Beilun District People's Hospital, Ningbo, Zhejiang, China
| | - Shulan Yin
- Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Guangming Fu
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Chengqin Wang
- Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Fenggang Xiang
- Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Haiqi Hu
- Department of Pharmacy, Jinhua Hospital of Zhejiang University, Jinhua, Zhejiang, China
| | - Sudan Zhang
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
| | - Zheng Wang
- Department of Genetics and Cell Biology, School of Basic Medicine, Qingdao University, Qingdao, Shandong, China
- Department of Reproductive Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Dequan Li
- Trauma Surgery & Emergency Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Intelligent Treatment and Life Support for Critical Diseases of Zhejiang Province, Wenzhou, Zhejiang, China
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Wu T, Jiang Y, Shi W, Wang Y, Li T. Endoplasmic reticulum stress: a novel targeted approach to repair bone defects by regulating osteogenesis and angiogenesis. J Transl Med 2023; 21:480. [PMID: 37464413 PMCID: PMC10353205 DOI: 10.1186/s12967-023-04328-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 07/06/2023] [Indexed: 07/20/2023] Open
Abstract
Bone regeneration therapy is clinically important, and targeted regulation of endoplasmic reticulum (ER) stress is important in regenerative medicine. The processing of proteins in the ER controls cell fate. The accumulation of misfolded and unfolded proteins occurs in pathological states, triggering ER stress. ER stress restores homeostasis through three main mechanisms, including protein kinase-R-like ER kinase (PERK), inositol-requiring enzyme 1ɑ (IRE1ɑ) and activating transcription factor 6 (ATF6), collectively known as the unfolded protein response (UPR). However, the UPR has both adaptive and apoptotic effects. Modulation of ER stress has therapeutic potential for numerous diseases. Repair of bone defects involves both angiogenesis and bone regeneration. Here, we review the effects of ER stress on osteogenesis and angiogenesis, with emphasis on ER stress under high glucose (HG) and inflammatory conditions, and the use of ER stress inducers or inhibitors to regulate osteogenesis and angiogenesis. In addition, we highlight the ability for exosomes to regulate ER stress. Recent advances in the regulation of ER stress mediated osteogenesis and angiogenesis suggest novel therapeutic options for bone defects.
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Affiliation(s)
- Tingyu Wu
- Department of Joint Surgery, The Affiliated Hospital of Qingdao University, No. 59, Haier Road, Qingdao, 266003, China
| | - Yaping Jiang
- Department of Oral Implantology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Weipeng Shi
- Department of Joint Surgery, The Affiliated Hospital of Qingdao University, No. 59, Haier Road, Qingdao, 266003, China
| | - Yingzhen Wang
- Department of Joint Surgery, The Affiliated Hospital of Qingdao University, No. 59, Haier Road, Qingdao, 266003, China
| | - Tao Li
- Department of Joint Surgery, The Affiliated Hospital of Qingdao University, No. 59, Haier Road, Qingdao, 266003, China.
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Romeo FJ, Mavropoulos SA, Ishikawa K. Progress in Clinical Gene Therapy for Cardiac Disorders. Mol Diagn Ther 2023; 27:179-191. [PMID: 36641770 PMCID: PMC10023344 DOI: 10.1007/s40291-022-00632-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/04/2022] [Indexed: 01/16/2023]
Abstract
Despite significant advances in novel treatments and approaches, cardiovascular disease remains the leading cause of death globally. Gene therapy is a promising option for many diseases, including cardiovascular diseases. In the last 30 years, gene therapy has slowly proceeded towards clinical translation and recently reached US Food and Drug Administration approval for several diseases such as Leber congenital amaurosis and spinal muscular atrophy, among others. Previous attempts at developing gene therapies for cardiovascular diseases have yielded promising results in preclinical studies and early-phase clinical trials. However, larger trials failed to demonstrate consistent benefits in patients with ischemic heart disease and heart failure. In this review, we summarize the history and current status of clinical cardiac gene therapy. Starting with angiogenic gene therapy, we also cover more recent gene therapy trials for heart failure and cardiomyopathies. New programs are actively vying to be the first to get Food and Drug Administration approval for a cardiac gene therapy product by taking advantage of novel techniques.
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Affiliation(s)
- Francisco J Romeo
- Icahn School of Medicine at Mount Sinai, Cardiovascular Research Institute, 1 Gustave L. Levy Place, Box 1014, New York, NY, 10029, USA
| | - Spyros A Mavropoulos
- Icahn School of Medicine at Mount Sinai, Cardiovascular Research Institute, 1 Gustave L. Levy Place, Box 1014, New York, NY, 10029, USA
| | - Kiyotake Ishikawa
- Icahn School of Medicine at Mount Sinai, Cardiovascular Research Institute, 1 Gustave L. Levy Place, Box 1014, New York, NY, 10029, USA.
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Lyttle BD, Vaughn AE, Bardill JR, Apte A, Gallagher LT, Zgheib C, Liechty KW. Effects of microRNAs on angiogenesis in diabetic wounds. Front Med (Lausanne) 2023; 10:1140979. [PMID: 37020673 PMCID: PMC10067680 DOI: 10.3389/fmed.2023.1140979] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 02/27/2023] [Indexed: 04/07/2023] Open
Abstract
Diabetes mellitus is a morbid condition affecting a growing number of the world population, and approximately one third of diabetic patients are afflicted with diabetic foot ulcers (DFU), which are chronic non-healing wounds that frequently progress to require amputation. The treatments currently used for DFU focus on reducing pressure on the wound, staving off infection, and maintaining a moist environment, but the impaired wound healing that occurs in diabetes is a constant obstacle that must be faced. Aberrant angiogenesis is a major contributor to poor wound healing in diabetes and surgical intervention is often necessary to establish peripheral blood flow necessary for healing wounds. Over recent years, microRNAs (miRNAs) have been implicated in the dysregulation of angiogenesis in multiple pathologies including diabetes. This review explores the pathways of angiogenesis that become dysregulated in diabetes, focusing on miRNAs that have been identified and the mechanisms by which they affect angiogenesis.
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Affiliation(s)
- Bailey D. Lyttle
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, School of Medicine, University of Colorado Denver—Anschutz Medical Campus, Aurora, CO, United States
- *Correspondence: Bailey D. Lyttle,
| | - Alyssa E. Vaughn
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, School of Medicine, University of Colorado Denver—Anschutz Medical Campus, Aurora, CO, United States
| | - James R. Bardill
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, School of Medicine, University of Colorado Denver—Anschutz Medical Campus, Aurora, CO, United States
| | - Anisha Apte
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, College of Medicine, University of Arizona Health Sciences College of Medicine—Tucson, Tucson, AZ, United States
| | - Lauren T. Gallagher
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, School of Medicine, University of Colorado Denver—Anschutz Medical Campus, Aurora, CO, United States
| | - Carlos Zgheib
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, College of Medicine, University of Arizona Health Sciences College of Medicine—Tucson, Tucson, AZ, United States
| | - Kenneth W. Liechty
- Laboratory for Fetal and Regenerative Biology, Department of Surgery, College of Medicine, University of Arizona Health Sciences College of Medicine—Tucson, Tucson, AZ, United States
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10
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Zhang Z, Warner KA, Mantesso A, Nör JE. PDGF-BB signaling via PDGFR-β regulates the maturation of blood vessels generated upon vasculogenic differentiation of dental pulp stem cells. Front Cell Dev Biol 2022; 10:977725. [PMID: 36340037 PMCID: PMC9627550 DOI: 10.3389/fcell.2022.977725] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 09/29/2022] [Indexed: 11/13/2022] Open
Abstract
A functional vascular network requires that blood vessels are invested by mural cells. We have shown that dental pulp stem cells (DPSC) can undergo vasculogenic differentiation, and that the resulting vessels anastomize with the host vasculature and become functional (blood carrying) vessels. However, the mechanisms underlying the maturation of DPSC-derived blood vessels remains unclear. Here, we performed a series of studies to understand the process of mural cell investment of blood vessels generated upon vasculogenic differentiation of dental pulp stem cells. Primary human DPSC were co-cultured with primary human umbilical artery smooth muscle cells (HUASMC) in 3D gels in presence of vasculogenic differentiation medium. We observed DPSC capillary sprout formation and SMC recruitment, alignment and remodeling that resulted in complex vascular networks. While HUASMC enhanced the number of capillary sprouts and stabilized the capillary network when co-cultured with DPSC, HUASMC by themselves were unable to form capillary sprouts. In vivo, GFP transduced human DPSC seeded in biodegradable scaffolds and transplanted into immunodeficient mice generated functional human blood vessels invested with murine smooth muscle actin (SMA)-positive, GFP-negative cells. Inhibition of PDGFR-β signaling prevented the SMC investment of DPSC-derived capillary sprouts in vitro and of DPSC-derived blood vessels in vivo. In contrast, inhibition of Tie-2 signaling did not have a significant effect on the SMC recruitment in DPSC-derived vascular structures. Collectively, these results demonstrate that PDGF-BB signaling via PDGFR-β regulates the process of maturation (mural investment) of blood vessels generated upon vasculogenic differentiation of human dental pulp stem cells.
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Affiliation(s)
- Zhaocheng Zhang
- Angiogenesis Research Laboratory, Department of Cariology, Restorative Sciences and Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, United States
| | - Kristy A. Warner
- Angiogenesis Research Laboratory, Department of Cariology, Restorative Sciences and Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, United States
| | - Andrea Mantesso
- Angiogenesis Research Laboratory, Department of Cariology, Restorative Sciences and Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, United States
| | - Jacques E. Nör
- Angiogenesis Research Laboratory, Department of Cariology, Restorative Sciences and Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, United States
- Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, United States
- Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, MI, United States
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Hayashida K, Aquino RS, Park PW. Coreceptor Functions of Cell Surface Heparan Sulfate Proteoglycans. Am J Physiol Cell Physiol 2022; 322:C896-C912. [PMID: 35319900 PMCID: PMC9109798 DOI: 10.1152/ajpcell.00050.2022] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Receptor-ligand interactions play an important role in many biological processes by triggering specific cellular responses. These interactions are frequently regulated by coreceptors that facilitate, alter, or inhibit signaling. Coreceptors work in parallel with other specific and accessory molecules to coordinate receptor-ligand interactions. Cell surface heparan sulfate proteoglycans (HSPGs) function as unique coreceptors because they can bind to many ligands and receptors through their HS and core protein motifs. Cell surface HSPGs are typically expressed in abundance of the signaling receptors and, thus, are capable of mediating the initial binding of ligands to the cell surface. HSPG coreceptors do not possess kinase domains or intrinsic enzyme activities and, for the most part, binding to cell surface HSPGs does not directly stimulate intracellular signaling. Because of these features, cell surface HSPGs primarily function as coreceptors for many receptor-ligand interactions. Given that cell surface HSPGs are widely conserved, they likely serve fundamental functions to preserve basic physiological processes. Indeed, cell surface HSPGs can support specific cellular interactions with growth factors, morphogens, chemokines, extracellular matrix (ECM) components, and microbial pathogens and their secreted virulence factors. Through these interactions, HSPG coreceptors regulate cell adhesion, proliferation, migration and differentiation, and impact the onset, progression, and outcome of pathophysiological processes, such as development, tissue repair, inflammation, infection, and tumorigenesis. This review seeks to provide an overview of the various mechanisms of how cell surface HSPGs function as coreceptors.
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Affiliation(s)
- Kazutaka Hayashida
- Department of Medicine, Boston Children's Hospital, Boston, MA, United States
| | - Rafael S Aquino
- Department of Medicine, Boston Children's Hospital, Boston, MA, United States
| | - Pyong Woo Park
- Department of Medicine, Boston Children's Hospital, Boston, MA, United States.,Department of Pediatrics, Harvard Medical School, Boston, MA, United States
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12
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Nguyen NT, Bui QA, Nguyen HHN, Nguyen TT, Ly KL, Tran HLB, Doan VN, Nhi TTY, Nguyen NH, Nguyen NH, Tran NQ, Nguyen DT. Curcuminoid Co-Loading Platinum Heparin-Poloxamer P403 Nanogel Increasing Effectiveness in Antitumor Activity. Gels 2022; 8:59. [PMID: 35049594 PMCID: PMC8774475 DOI: 10.3390/gels8010059] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/06/2022] [Accepted: 01/10/2022] [Indexed: 01/27/2023] Open
Abstract
Nanosized multi-drug delivery systems provide synergistic effects between drugs and bioactive compounds, resulting in increased overall efficiency and restricted side effects compared to conventional single-drug chemotherapy. In this study, we develop an amphiphilic heparin-poloxamer P403 (HP403) nanogel that could effectively co-load curcuminoid (Cur) and cisplatin hydrate (CisOH) (HP403@CisOH@Cur) via two loading mechanisms. The HP403 nanogels and HP403@CisOH@Cur nanogels were closely analyzed with 1H-NMR spectroscopy, FT-IR spectroscopy, TEM, and DLS, exhibiting high stability in spherical forms. In drug release profiles, accelerated behavior of Cur and CisOH at pH 5.5 compared with neutral pH was observed, suggesting effective delivery of the compounds in tumor sites. In vitro studies showed high antitumor activity of HP403@CisOH@Cur nanogels, while in vivo assays showed that the dual-drug platform prolonged the survival time of mice and prevented tail necrosis. In summary, HP403@CisOH@Cur offers an intriguing strategy to achieve the cisplatin and curcumin synergistic effect in a well-designed delivery platform that increases antitumor effectiveness and overcomes undesired consequences caused by cisplatin in breast cancer treatment.
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Affiliation(s)
- Ngoc The Nguyen
- Faculty of Medicine-Pharmacy, Tra Vinh University, Tra Vinh City 87000, Vietnam; (T.T.N.); (K.L.L.)
| | - Quynh Anh Bui
- Institute of Applied Materials Science, Vietnam Academy of Science and Technology, Ho Chi Minh City 71500, Vietnam; (Q.A.B.); (N.H.N.); (N.Q.T.)
| | - Hoang Huong Nhu Nguyen
- Faculty of Biology and Biotechnology, University of Science—Vietnam National University, Ho Chi Minh City 72700, Vietnam; (H.H.N.N.); (H.L.B.T.); (V.N.D.)
| | - Tien Thanh Nguyen
- Faculty of Medicine-Pharmacy, Tra Vinh University, Tra Vinh City 87000, Vietnam; (T.T.N.); (K.L.L.)
| | - Khanh Linh Ly
- Faculty of Medicine-Pharmacy, Tra Vinh University, Tra Vinh City 87000, Vietnam; (T.T.N.); (K.L.L.)
| | - Ha Le Bao Tran
- Faculty of Biology and Biotechnology, University of Science—Vietnam National University, Ho Chi Minh City 72700, Vietnam; (H.H.N.N.); (H.L.B.T.); (V.N.D.)
| | - Vu Nguyen Doan
- Faculty of Biology and Biotechnology, University of Science—Vietnam National University, Ho Chi Minh City 72700, Vietnam; (H.H.N.N.); (H.L.B.T.); (V.N.D.)
| | - Tran Thi Yen Nhi
- Graduate University of Science and Technology, Vietnam Academy of Science and Technology, Ho Chi Minh City 71500, Vietnam;
- Institute of Environmental Technology and Sustainable Development, Nguyen Tat Thanh University, Ho Chi Minh City 72800, Vietnam
| | - Ngoc Hoa Nguyen
- German Vietnamese Technology Center, HCMC University of Food Industry, Ho Chi Minh City 72000, Vietnam;
| | - Ngoc Hao Nguyen
- Institute of Applied Materials Science, Vietnam Academy of Science and Technology, Ho Chi Minh City 71500, Vietnam; (Q.A.B.); (N.H.N.); (N.Q.T.)
| | - Ngoc Quyen Tran
- Institute of Applied Materials Science, Vietnam Academy of Science and Technology, Ho Chi Minh City 71500, Vietnam; (Q.A.B.); (N.H.N.); (N.Q.T.)
- Graduate University of Science and Technology, Vietnam Academy of Science and Technology, Ho Chi Minh City 71500, Vietnam;
| | - Dinh Trung Nguyen
- Institute of Applied Materials Science, Vietnam Academy of Science and Technology, Ho Chi Minh City 71500, Vietnam; (Q.A.B.); (N.H.N.); (N.Q.T.)
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13
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Li P, Li Q, Biswas N, Xin H, Diemer T, Liu L, Perez Gutierrez L, Paternostro G, Piermarocchi C, Domanskyi S, Wang RK, Ferrara N. LIF, a mitogen for choroidal endothelial cells, protects the choriocapillaris: implications for prevention of geographic atrophy. EMBO Mol Med 2022; 14:e14511. [PMID: 34779136 PMCID: PMC8749470 DOI: 10.15252/emmm.202114511] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 10/21/2021] [Accepted: 10/25/2021] [Indexed: 12/18/2022] Open
Abstract
In the course of our studies aiming to discover vascular bed-specific endothelial cell (EC) mitogens, we identified leukemia inhibitory factor (LIF) as a mitogen for bovine choroidal EC (BCE), although LIF has been mainly characterized as an EC growth inhibitor and an anti-angiogenic molecule. LIF stimulated growth of BCE while it inhibited, as previously reported, bovine aortic EC (BAE) growth. The JAK-STAT3 pathway mediated LIF actions in both BCE and BAE cells, but a caspase-independent proapoptotic signal mediated by cathepsins was triggered in BAE but not in BCE. LIF administration directly promoted activation of STAT3 and increased blood vessel density in mouse eyes. LIF also had protective effects on the choriocapillaris in a model of oxidative retinal injury. Analysis of available single-cell transcriptomic datasets shows strong expression of the specific LIF receptor in mouse and human choroidal EC. Our data suggest that LIF administration may be an innovative approach to prevent atrophy associated with AMD, through protection of the choriocapillaris.
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Affiliation(s)
- Pin Li
- Department of PathologyUniversity of California San DiegoLa JollaCAUSA
| | - Qin Li
- Department of OphthalmologyUniversity of California San DiegoLa JollaCAUSA
| | - Nilima Biswas
- Department of PathologyUniversity of California San DiegoLa JollaCAUSA
| | - Hong Xin
- Department of PathologyUniversity of California San DiegoLa JollaCAUSA
| | - Tanja Diemer
- Department of PathologyUniversity of California San DiegoLa JollaCAUSA
| | - Lixian Liu
- Department of PathologyUniversity of California San DiegoLa JollaCAUSA
| | | | | | - Carlo Piermarocchi
- Department of Physics and AstronomyMichigan State UniversityEast LansingMIUSA
| | - Sergii Domanskyi
- Department of Physics and AstronomyMichigan State UniversityEast LansingMIUSA
| | - Ruikang K Wang
- Department of BioengineeringUniversity of WashingtonSeattleWAUSA
| | - Napoleone Ferrara
- Department of PathologyUniversity of California San DiegoLa JollaCAUSA
- Department of OphthalmologyUniversity of California San DiegoLa JollaCAUSA
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14
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Liu Y, Liu Y, Deng J, Li W, Nie X. Fibroblast Growth Factor in Diabetic Foot Ulcer: Progress and Therapeutic Prospects. Front Endocrinol (Lausanne) 2021; 12:744868. [PMID: 34721299 PMCID: PMC8551859 DOI: 10.3389/fendo.2021.744868] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 09/29/2021] [Indexed: 12/24/2022] Open
Abstract
Diabetic foot ulcer (DFU) is a combination of neuropathy and various degrees of peripheral vasculopathy in diabetic patients resulting in lower extremity infection, ulcer formation, and deep-tissue necrosis. The difficulty of wound healing in diabetic patients is caused by a high glucose environment and various biological factors in the patient. The patients' skin local microenvironment changes and immune chemotactic response dysfunction. Wounds are easy to be damaged and ulcerated repeatedly, but difficult to heal, and eventually develop into chronic ulcers. DFU is a complex biological process in which many cells interact with each other. A variety of growth factors released from wounds are necessary for coordination and promotion of healing. Fibroblast growth factor (FGF) is a family of cell signaling proteins, which can mediate various processes such as angiogenesis, wound healing, metabolic regulation and embryonic development through its specific receptors. FGF can stimulate angiogenesis and proliferation of fibroblasts, and it is a powerful angiogenesis factor. Twenty-three subtypes have been identified and divided into seven subfamilies. Traditional treatments for DFU can only remove necrotic tissue, delay disease progression, and have a limited ability to repair wounds. In recent years, with the increasing understanding of the function of FGF, more and more researchers have been applying FGF-1, FGF-2, FGF-4, FGF-7, FGF-21 and FGF-23 topically to DFU with good therapeutic effects. This review elaborates on the recently developed FGF family members, outlining their mechanisms of action, and describing their potential therapeutics in DFU.
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Affiliation(s)
- Ye Liu
- College of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Yiqiu Liu
- College of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Junyu Deng
- College of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Wei Li
- College of Pharmacy, Zunyi Medical University, Zunyi, China
- Joint International Research Laboratory of Ethnomedicine of Chinese Ministry of Education, Zunyi Medical University, Zunyi, China
| | - Xuqiang Nie
- College of Pharmacy, Zunyi Medical University, Zunyi, China
- Joint International Research Laboratory of Ethnomedicine of Chinese Ministry of Education, Zunyi Medical University, Zunyi, China
- Key Lab of the Basic Pharmacology of the Ministry of Education, Zunyi Medical University, Zunyi, China
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15
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Endoglin deficiency impairs VEGFR2 but not FGFR1 or TIE2 activation and alters VEGF-mediated cellular responses in human primary endothelial cells. Transl Res 2021; 235:129-143. [PMID: 33894400 PMCID: PMC8328903 DOI: 10.1016/j.trsl.2021.04.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 03/29/2021] [Accepted: 04/14/2021] [Indexed: 01/23/2023]
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease characterized by vascular dysplasia. Mutations of the endoglin (ENG) gene that encodes a co-receptor of the transforming growth factor β1 signaling pathway cause type I HHT. ENG is primarily expressed in endothelial cells (ECs), but its interaction with other key angiogenic pathways to control angiogenesis has not been well addressed. The aim of this study is to investigate ENG interplay with VEGFR2, FGFR1 and TIE2 in primary human ECs. ENG was knocked-down with siRNA in human umbilical vein ECs (HUVECs) and human lung microvascular ECs (HMVEC-L). Gene expression was measured by RT-qPCR and Western blotting. Cell signaling pathway activation was analyzed by detecting phosphor-ERK and phosphor-AKT levels. Cell migration and apoptosis were assessed using the Boyden chamber assay and the CCK-8 Kit, respectively. Loss of ENG in HUVECs led to significantly reduced expression of VEGFR2 but not TIE2 or FGFR1, which was also confirmed in HMVEC-L. HUVECs lacking ENG had significantly lower levels of active Rac1 and a substantial reduction of the transcription factor Sp1, an activator of VEGFR2 transcription, in nuclei. Furthermore, VEGF- but not bFGF- or angiopoietin-1-induced phosphor-ERK and phosphor-AKT were suppressed in ENG deficient HUVECs. Functional analysis revealed that ENG knockdown inhibited cell migratory but enhanced anti-apoptotic activity induced by VEGF. In contrast, bFGF, angiopoietin-1 and -2 induced HUVEC migration and anti-apoptotic activities were not affected by ENG knockdown. In conclusion, ENG deficiency alters the VEGF/VEGFR2 pathway, which may play a role in HHT pathogenesis.
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16
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Keridou I, Franco L, Martínez JC, Turon P, Del Valle LJ, Puiggalí J. Electrospun scaffolds for wound healing applications from poly(4‐hydroxybutyrate): A biobased and biodegradable linear polymer with high elastomeric properties. J Appl Polym Sci 2021. [DOI: 10.1002/app.51447] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Ina Keridou
- Departament d'Enginyeria Química Universitat Politècnica de Catalunya, Escola d'Enginyeria de Barcelona Est‐EEBE Barcelona Spain
| | - Lourdes Franco
- Departament d'Enginyeria Química Universitat Politècnica de Catalunya, Escola d'Enginyeria de Barcelona Est‐EEBE Barcelona Spain
- Barcelona Research Center for Multiscale Science and Engineering Universitat Politècnica de Catalunya, Escola d'Enginyeria de Barcelona Est‐EEBE Barcelona Spain
| | | | - Pau Turon
- B. Braun Surgical, S.A.U. Barcelona Spain
| | - Luis J. Del Valle
- Departament d'Enginyeria Química Universitat Politècnica de Catalunya, Escola d'Enginyeria de Barcelona Est‐EEBE Barcelona Spain
- Barcelona Research Center for Multiscale Science and Engineering Universitat Politècnica de Catalunya, Escola d'Enginyeria de Barcelona Est‐EEBE Barcelona Spain
| | - Jordi Puiggalí
- Departament d'Enginyeria Química Universitat Politècnica de Catalunya, Escola d'Enginyeria de Barcelona Est‐EEBE Barcelona Spain
- Barcelona Research Center for Multiscale Science and Engineering Universitat Politècnica de Catalunya, Escola d'Enginyeria de Barcelona Est‐EEBE Barcelona Spain
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17
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Vascularization Strategies in Bone Tissue Engineering. Cells 2021; 10:cells10071749. [PMID: 34359919 PMCID: PMC8306064 DOI: 10.3390/cells10071749] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/05/2021] [Accepted: 07/06/2021] [Indexed: 12/12/2022] Open
Abstract
Bone is a highly vascularized tissue, and its development, maturation, remodeling, and regeneration are dependent on a tight regulation of blood vessel supply. This condition also has to be taken into consideration in the context of the development of artificial tissue substitutes. In classic tissue engineering, bone-forming cells such as primary osteoblasts or mesenchymal stem cells are introduced into suitable scaffolds and implanted in order to treat critical-size bone defects. However, such tissue substitutes are initially avascular. Because of the occurrence of hypoxic conditions, especially in larger tissue substitutes, this leads to the death of the implanted cells. Therefore, it is necessary to devise vascularization strategies aiming at fast and efficient vascularization of implanted artificial tissues. In this review article, we present and discuss the current vascularization strategies in bone tissue engineering. These are based on the use of angiogenic growth factors, the co-implantation of blood vessel forming cells, the ex vivo microfabrication of blood vessels by means of bioprinting, and surgical methods for creating surgically transferable composite tissues.
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18
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Libby P. Inflammation in Atherosclerosis-No Longer a Theory. Clin Chem 2021; 67:131-142. [PMID: 33393629 DOI: 10.1093/clinchem/hvaa275] [Citation(s) in RCA: 184] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 10/23/2020] [Indexed: 12/30/2022]
Abstract
BACKGROUND Inflammation links to atherosclerosis and its complications in various experimental investigations. Animal studies have implicated numerous inflammatory mediators in the initiation and complication of atherosclerosis. Numerous studies in humans have shown associations of biomarkers of inflammation with cardiovascular events provoked by atheromata. Inflammatory status, determined by the biomarker C-reactive protein, can guide the allocation of statin therapy to individuals without elevated low-density lipoprotein (LDL) concentrations to prevent first ever adverse cardiovascular events. CONTENT Until recently, no direct evidence has shown that an intervention that selectively limits inflammation can improve outcomes in patients with atherosclerosis. A recent study, based on decades of preclinical investigation, treated patients who had sustained a myocardial infarction and whose LDL was well-controlled on statin treatment with an antibody that neutralizes interleukin-1 beta. This trial, conducted in over 10 000 individuals, showed a reduction in major adverse cardiac events, establishing for the first time the clinical efficacy of an anti-inflammatory intervention in atherosclerosis. Two large subsequent studies have shown that colchicine treatment can also prevent recurrent events in patients recovering from an acute coronary syndrome or in the stable phase of coronary artery disease. These clinical trials have transformed inflammation in atherosclerosis from theory to practice. SUMMARY Much work remains to optimize further anti-inflammatory interventions, minimize unwanted actions, and refine patient selection. This long road from discovery in the laboratory to successful clinical trials represents a victory for medical science, and opens a new avenue to reducing the risk that remains despite current treatments for atherosclerosis.
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Affiliation(s)
- Peter Libby
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
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19
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Chu PY, Koh APF, Antony J, Huang RYJ. Applications of the Chick Chorioallantoic Membrane as an Alternative Model for Cancer Studies. Cells Tissues Organs 2021; 211:222-237. [PMID: 33780951 DOI: 10.1159/000513039] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 11/13/2020] [Indexed: 11/19/2022] Open
Abstract
A variety of in vivo experimental models have been established for the studies of human cancer using both cancer cell lines and patient-derived xenografts (PDXs). In order to meet the aspiration of precision medicine, the in vivomurine models have been widely adopted. However, common constraints such as high cost, long duration of experiments, and low engraftment efficiency remained to be resolved. The chick embryo chorioallantoic membrane (CAM) is an alternative model to overcome some of these limitations. Here, we provide an overview of the applications of the chick CAM model in the study of oncology. The CAM model has shown significant retention of tumor heterogeneity alongside increased xenograft take rates in several PDX studies. Various imaging techniques and data analysis have been applied to study tumor metastasis, angiogenesis, and therapeutic response to novel agents. Lastly, to practically illustrate the feasibility of utilizing the CAM model, we summarize the general protocol used in a case study utilizing an ovarian cancer PDX.
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Affiliation(s)
- Pei-Yu Chu
- Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Angele Pei-Fern Koh
- Cancer Science Institute of Singapore, Center for Translational Medicine, National University of Singapore, Singapore, Singapore
| | - Jane Antony
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford, California, USA
| | - Ruby Yun-Ju Huang
- School of Medicine and Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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20
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Zahra FT, Sajib MS, Mikelis CM. Role of bFGF in Acquired Resistance upon Anti-VEGF Therapy in Cancer. Cancers (Basel) 2021; 13:1422. [PMID: 33804681 PMCID: PMC8003808 DOI: 10.3390/cancers13061422] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 03/15/2021] [Accepted: 03/17/2021] [Indexed: 12/13/2022] Open
Abstract
Anti-angiogenic approaches targeting the vascular endothelial growth factor (VEGF) signaling pathway have been a significant research focus during the past decades and are well established in clinical practice. Despite the expectations, their benefit is ephemeral in several diseases, including specific cancers. One of the most prominent side effects of the current, VEGF-based, anti-angiogenic treatments remains the development of resistance, mostly due to the upregulation and compensatory mechanisms of other growth factors, with the basic fibroblast growth factor (bFGF) being at the top of the list. Over the past decade, several anti-angiogenic approaches targeting simultaneously different growth factors and their signaling pathways have been developed and some have reached the clinical practice. In the present review, we summarize the knowledge regarding resistance mechanisms upon anti-angiogenic treatment, mainly focusing on bFGF. We discuss its role in acquired resistance upon prolonged anti-angiogenic treatment in different tumor settings, outline the reported resistance mechanisms leading to bFGF upregulation, and summarize the efforts and outcome of combined anti-angiogenic approaches to date.
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Affiliation(s)
| | | | - Constantinos M. Mikelis
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; (F.T.Z.); (M.S.S.)
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21
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Ribatti D, Pezzella F. Overview on the Different Patterns of Tumor Vascularization. Cells 2021; 10:cells10030639. [PMID: 33805699 PMCID: PMC8000806 DOI: 10.3390/cells10030639] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/08/2021] [Accepted: 03/10/2021] [Indexed: 12/13/2022] Open
Abstract
Angiogenesis is a crucial event in the physiological processes of embryogenesis and wound healing. During malignant transformation, dysregulation of angiogenesis leads to the formation of a vascular network of tumor-associated capillaries promoting survival and proliferation of the tumor cells. Starting with the hypothesis formulated by Judah Folkman that tumor growth is angiogenesis-dependent, this area of research has a solid scientific foundation and inhibition of angiogenesis is a major area of therapeutic development for the treatment of cancer. Over this period numerous authors published data of vascularization of tumors, which attributed the cause of neo-vascularization to various factors including inflammation, release of angiogenic cytokines, vasodilatation, and increased tumor metabolism. More recently, it has been demonstrated that tumor vasculature is not necessarily derived by endothelial cell proliferation and sprouting of new capillaries, but alternative vascularization mechanisms have been described, namely vascular co-option and vasculogenic mimicry. In this article, we have analyzed the mechanisms involved in tumor vascularization in association with classical angiogenesis, including post-natal vasculogenesis, intussusceptive microvascular growth, vascular co-option, and vasculogenic mimicry. We have also discussed the role of these alternative mechanism in resistance to anti-angiogenic therapy and potential therapeutic approaches to overcome resistance.
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Affiliation(s)
- Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, 70124 Bari, Italy
- Correspondence: (D.R.); (F.P.)
| | - Francesco Pezzella
- Nuffield Division of Laboratory Science, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX39DU, UK
- Correspondence: (D.R.); (F.P.)
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22
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Gómez Toledo A, Sorrentino JT, Sandoval DR, Malmström J, Lewis NE, Esko JD. A Systems View of the Heparan Sulfate Interactome. J Histochem Cytochem 2021; 69:105-119. [PMID: 33494649 PMCID: PMC7841697 DOI: 10.1369/0022155420988661] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 12/23/2020] [Indexed: 12/28/2022] Open
Abstract
Heparan sulfate proteoglycans consist of a small family of proteins decorated with one or more covalently attached heparan sulfate glycosaminoglycan chains. These chains have intricate structural patterns based on the position of sulfate groups and uronic acid epimers, which dictate their ability to engage a large repertoire of heparan sulfate-binding proteins, including extracellular matrix proteins, growth factors and morphogens, cytokines and chemokines, apolipoproteins and lipases, adhesion and growth factor receptors, and components of the complement and coagulation system. This review highlights recent progress in the characterization of the so-called "heparan sulfate interactome," with a major focus on systems-wide strategies as a tool for discovery and characterization of this subproteome. In addition, we compiled all heparan sulfate-binding proteins reported in the literature to date and grouped them into a few major functional classes by applying a networking approach.
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Affiliation(s)
- Alejandro Gómez Toledo
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California
- Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California
- Department of Clinical Sciences, Lund, Division of Infection Medicine, Lund University, Lund, Sweden
| | - James T Sorrentino
- Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, California
- Department of Bioengineering, University of California, San Diego, La Jolla, California
| | - Daniel R Sandoval
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California
- Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California
| | - Johan Malmström
- Department of Clinical Sciences, Lund, Division of Infection Medicine, Lund University, Lund, Sweden
| | - Nathan E Lewis
- Department of Bioengineering, University of California, San Diego, La Jolla, California
- Department of Pediatrics, University of California, San Diego, La Jolla, California
| | - Jeffrey D Esko
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California
- Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California
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23
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Abstract
Microvasculature functions at the tissue and cell level, regulating local mass exchange of oxygen and nutrient-rich blood. While there has been considerable success in the biofabrication of large- and small-vessel replacements, functional microvasculature has been particularly challenging to engineer due to its size and complexity. Recently, three-dimensional bioprinting has expanded the possibilities of fabricating sophisticated microvascular systems by enabling precise spatiotemporal placement of cells and biomaterials based on computer-aided design. However, there are still significant challenges facing the development of printable biomaterials that promote robust formation and controlled 3D organization of microvascular networks. This review provides a thorough examination and critical evaluation of contemporary biomaterials and their specific roles in bioprinting microvasculature. We first provide an overview of bioprinting methods and techniques that enable the fabrication of microvessels. We then offer an in-depth critical analysis on the use of hydrogel bioinks for printing microvascularized constructs within the framework of current bioprinting modalities. We end with a review of recent applications of bioprinted microvasculature for disease modeling, drug testing, and tissue engineering, and conclude with an outlook on the challenges facing the evolution of biomaterials design for bioprinting microvasculature with physiological complexity.
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Affiliation(s)
- Ryan W. Barrs
- Bioengineering Department, Clemson University, Clemson, SC 29634, USA
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Jia Jia
- Bioengineering Department, Clemson University, Clemson, SC 29634, USA
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Sophia E. Silver
- Bioengineering Department, Clemson University, Clemson, SC 29634, USA
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Michael Yost
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Ying Mei
- Bioengineering Department, Clemson University, Clemson, SC 29634, USA
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
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24
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Therapeutic paradigm of dual targeting VEGF and PDGF for effectively treating FGF-2 off-target tumors. Nat Commun 2020; 11:3704. [PMID: 32709869 PMCID: PMC7382445 DOI: 10.1038/s41467-020-17525-6] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 07/01/2020] [Indexed: 12/12/2022] Open
Abstract
FGF-2 displays multifarious functions in regulation of angiogenesis and vascular remodeling. However, effective drugs for treating FGF-2+ tumors are unavailable. Here we show that FGF-2 modulates tumor vessels by recruiting NG2+ pricytes onto tumor microvessels through a PDGFRβ-dependent mechanism. FGF-2+ tumors are intrinsically resistant to clinically available drugs targeting VEGF and PDGF. Surprisingly, dual targeting the VEGF and PDGF signaling produces a superior antitumor effect in FGF-2+ breast cancer and fibrosarcoma models. Mechanistically, inhibition of PDGFRβ ablates FGF-2-recruited perivascular coverage, exposing anti-VEGF agents to inhibit vascular sprouting. These findings show that the off-target FGF-2 is a resistant biomarker for anti-VEGF and anti-PDGF monotherapy, but a highly beneficial marker for combination therapy. Our data shed light on mechanistic interactions between various angiogenic and remodeling factors in tumor neovascularization. Optimization of antiangiogenic drugs with different principles could produce therapeutic benefits for treating their resistant off-target cancers. Anti-VEGF therapy has many limitations that might be resolved by using combination treatment approaches. Here, the authors demonstrate that the dual-targeting of VEGF and PDGF is required for targeting resistant FGF2+ tumors which depend on the recruitment of pericytes on tumor microvessels.
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Hwang J, Sullivan MO, Kiick KL. Targeted Drug Delivery via the Use of ECM-Mimetic Materials. Front Bioeng Biotechnol 2020; 8:69. [PMID: 32133350 PMCID: PMC7040483 DOI: 10.3389/fbioe.2020.00069] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 01/27/2020] [Indexed: 12/14/2022] Open
Abstract
The use of drug delivery vehicles to improve the efficacy of drugs and to target their action at effective concentrations over desired periods of time has been an active topic of research and clinical investigation for decades. Both synthetic and natural drug delivery materials have facilitated locally controlled as well as targeted drug delivery. Extracellular matrix (ECM) molecules have generated widespread interest as drug delivery materials owing to the various biological functions of ECM. Hydrogels created using ECM molecules can provide not only biochemical and structural support to cells, but also spatial and temporal control over the release of therapeutic agents, including small molecules, biomacromolecules, and cells. In addition, the modification of drug delivery carriers with ECM fragments used as cell-binding ligands has facilitated cell-targeted delivery and improved the therapeutic efficiency of drugs through interaction with highly expressed cellular receptors for ECM. The combination of ECM-derived hydrogels and ECM-derived ligand approaches shows synergistic effects, leading to a great promise for the delivery of intracellular drugs, which require specific endocytic pathways for maximal effectiveness. In this review, we provide an overview of cellular receptors that interact with ECM molecules and discuss examples of selected ECM components that have been applied for drug delivery in both local and systemic platforms. Finally, we highlight the potential impacts of utilizing the interaction between ECM components and cellular receptors for intracellular delivery, particularly in tissue regeneration applications.
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Affiliation(s)
- Jeongmin Hwang
- Department of Biomedical Engineering, University of Delaware, Newark, DE, United States
| | - Millicent O. Sullivan
- Department of Biomedical Engineering, University of Delaware, Newark, DE, United States
- Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE, United States
| | - Kristi L. Kiick
- Department of Materials Science and Engineering, University of Delaware, Newark, DE, United States
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Jana P, Acharya K. Mushroom: A New Resource for Anti-Angiogenic Therapeutics. FOOD REVIEWS INTERNATIONAL 2020. [DOI: 10.1080/87559129.2020.1721529] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Pradipta Jana
- Molecular and Applied Mycology and Pathology Laboratory, Department of Botany, University of Calcutta, Calcutta, India
| | - Krishnendu Acharya
- Molecular and Applied Mycology and Pathology Laboratory, Department of Botany, University of Calcutta, Calcutta, India
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Sandoval DR, Gomez Toledo A, Painter CD, Tota EM, Sheikh MO, West AMV, Frank MM, Wells L, Xu D, Bicknell R, Corbett KD, Esko JD. Proteomics-based screening of the endothelial heparan sulfate interactome reveals that C-type lectin 14a (CLEC14A) is a heparin-binding protein. J Biol Chem 2020; 295:2804-2821. [PMID: 31964714 DOI: 10.1074/jbc.ra119.011639] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 01/10/2020] [Indexed: 12/21/2022] Open
Abstract
Animal cells express heparan sulfate proteoglycans that perform many important cellular functions by way of heparan sulfate-protein interactions. The identification of membrane heparan sulfate-binding proteins is challenging because of their low abundance and the need for extensive enrichment. Here, we report a proteomics workflow for the identification and characterization of membrane-anchored and extracellular proteins that bind heparan sulfate. The technique is based on limited proteolysis of live cells in the absence of denaturation and fixation, heparin-affinity chromatography, and high-resolution LC-MS/MS, and we designate it LPHAMS. Application of LPHAMS to U937 monocytic and primary murine and human endothelial cells identified 55 plasma membrane, extracellular matrix, and soluble secreted proteins, including many previously unidentified heparin-binding proteins. The method also facilitated the mapping of the heparin-binding domains, making it possible to predict the location of the heparin-binding site. To validate the discovery feature of LPHAMS, we characterized one of the newly-discovered heparin-binding proteins, C-type lectin 14a (CLEC14A), a member of the C-type lectin family that modulates angiogenesis. We found that the C-type lectin domain of CLEC14A binds one-to-one to heparin with nanomolar affinity, and using molecular modeling and mutagenesis, we mapped its heparin-binding site. CLEC14A physically interacted with other glycosaminoglycans, including endothelial heparan sulfate and chondroitin sulfate E, but not with neutral or sialylated oligosaccharides. The LPHAMS technique should be applicable to other cells and glycans and provides a way to expand the repertoire of glycan-binding proteins for further study.
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Affiliation(s)
- Daniel R Sandoval
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093; Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, California 92093
| | - Alejandro Gomez Toledo
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093
| | - Chelsea D Painter
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093; Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, California 92093
| | - Ember M Tota
- Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093
| | - M Osman Sheikh
- Department of Biochemistry and Molecular Biology, Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602
| | - Alan M V West
- Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, California 92093
| | | | - Lance Wells
- Department of Biochemistry and Molecular Biology, Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602
| | - Ding Xu
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, New York 14214
| | - Roy Bicknell
- College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Kevin D Corbett
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093
| | - Jeffrey D Esko
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093.
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Age- and BMI-Associated Expression of Angiogenic Factors in White Adipose Tissue of Children. Int J Mol Sci 2019; 20:ijms20205204. [PMID: 31640116 PMCID: PMC6829445 DOI: 10.3390/ijms20205204] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Revised: 10/04/2019] [Accepted: 10/16/2019] [Indexed: 12/15/2022] Open
Abstract
The growth of adipose tissue and its vasculature are tightly associated. Angiogenic factors have been linked to obesity, yet little is known about their expression during early childhood. To identify associations of angiogenic factors with characteristics on individual and tissue level, subcutaneous white adipose tissue samples were taken from 45 children aged 0-9 years undergoing elective surgery. We measured the expression of vascular endothelial growth factor A (VEFGA), fibroblast growth factor 1 and 2 (FGF1, FGF2), angiopoietin 1 and 2 (ANGPT1, ANGPT2), TEK receptor tyrosine kinase (TEK), and von Willebrand factor (VWF). In addition, we determined the mean adipocyte size in histologic tissue sections. We found positive correlations of age with FGF1 and FGF2 and a negative correlation with ANGPT2, with pronounced differences in the first two years of life. FGF1, FGF2, and ANGPT1 correlated positively with adipocyte size. Furthermore, we identified a correlation of ANGPT1 and TEK with body mass index-standard deviation score (BMI-SDS), a measure to define childhood obesity. Except for ANGPT2, all angiogenic factors correlated positively with the endothelial marker VWF. In sum, our findings suggest that differences related to BMI-SDS begin early in childhood, and the analyzed angiogenic factors possess distinct roles in adipose tissue biology.
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Abstract
AbstractThe ability to control the movement of molecules is both fascinating scientifically as well as being critically important to the well-being of our planet and its people. In particular, the sustained release of molecules over prolonged periods at controlled rates has had and will continue to have enormous implications for the delivery of substances in medicine, agriculture, the environment, nutrition, aquaculture, household consumer products, and numerous other areas. This field is advancing at a rapidly accelerating pace. In this article, I largely discuss our own work, starting 45 years ago, in enabling the controlled release of macromolecules from biocompatible polymers. I also discuss the synthesis of novel materials to affect molecular movement and I then examine external approaches for controlling the movement of molecules through materials, using forces such as electric, acoustic, and magnetic fields. I further discuss approaches for controlling molecular movement through physiologic barriers, such as the skin, lung, and intestine. Finally, I outline several future areas of this field, including how it can affect the developing world, the ability to control the movement of molecules into mammalian cells, and the design of intelligent approaches to control molecular delivery.
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Kefalakes E, Sarikidi A, Bursch F, Ettcheto M, Schmuck M, Rumpel R, Grothe C, Petri S. Isoform-selective as opposed to complete depletion of fibroblast growth factor 2 (FGF-2) has no major impact on survival and gene expression in SOD1 G93A amyotrophic lateral sclerosis mice. Eur J Neurosci 2019; 50:3028-3045. [PMID: 30883949 DOI: 10.1111/ejn.14405] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 01/29/2019] [Accepted: 03/05/2019] [Indexed: 12/27/2022]
Abstract
We have previously shown that total knockout of fibroblast growth factor-2 (FGF-2) results in prolonged survival and improved motor performance in superoxide dismutase 1 (SOD1G93A ) mutant mice, the most widely used animal model of the fatal adult onset motor neuron disease amyotrophic lateral sclerosis (ALS). Moreover, we found differential expression of growth factors in SOD1G93A mice, with distinct regulation patterns of FGF-2 in spinal cord and muscle tissue. Within the present study we aimed to characterize FGF-2-isoform specific effects on survival, motor performance as well as gene expression patterns predominantly in muscle tissue by generating double mutant SOD1G93A FGF-2 high molecular weight- and SOD1G93A FGF-2 low molecular weight-knockout mice. While isoform specific depletion was not beneficial regarding survival or motor performance of double mutant mice, we found isoform-dependent differential gene expression of epidermal growth factor (EGF) in the muscle of SOD1G93A FGF-2 low molecular weight knockout mice compared to single mutant SOD1G93A mice. This significant downregulation of EGF in the muscle tissue of double mutant SOD1G93A FGF-2 low molecular weight knockout mice implies that FGF-2 low molecular weight knockout (or the presence of the FGF-2 high molecular weight isoform) selectively impacts EGF gene expression in ALS muscle tissue.
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Affiliation(s)
- Ekaterini Kefalakes
- Department of Neurology, Hannover Medical School, Hannover, Germany.,Center for Systems Neuroscience (ZSN), Hannover, Germany
| | | | - Franziska Bursch
- Department of Neurology, Hannover Medical School, Hannover, Germany.,Center for Systems Neuroscience (ZSN), Hannover, Germany
| | - Miren Ettcheto
- Department of Pharmacology, Toxicology and Therapeutical Chemistry, Faculty of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain.,Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.,Institute of Neuroscience, University of Barcelona, Barcelona, Spain.,Department of Biochemistry, Faculty of Medicine and Life Science, University of Rovira i Virgili, Reus, Spain
| | - Martin Schmuck
- University of California, DAVIS School of Veterinary Medicine, Davis, CA
| | - Regina Rumpel
- Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hannover, Germany
| | - Claudia Grothe
- Center for Systems Neuroscience (ZSN), Hannover, Germany.,Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hannover, Germany
| | - Susanne Petri
- Department of Neurology, Hannover Medical School, Hannover, Germany.,Center for Systems Neuroscience (ZSN), Hannover, Germany
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Jaud M, Philippe C, Van Den Berghe L, Ségura C, Mazzolini L, Pyronnet S, Laurell H, Touriol C. The PERK Branch of the Unfolded Protein Response Promotes DLL4 Expression by Activating an Alternative Translation Mechanism. Cancers (Basel) 2019; 11:cancers11020142. [PMID: 30691003 PMCID: PMC6406545 DOI: 10.3390/cancers11020142] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 01/15/2019] [Accepted: 01/22/2019] [Indexed: 12/23/2022] Open
Abstract
Delta-like 4 (DLL4) is a pivotal endothelium specific Notch ligand that has been shown to function as a regulating factor during physiological and pathological angiogenesis. DLL4 functions as a negative regulator of angiogenic branching and sprouting. Interestingly, Dll4 is with Vegf-a one of the few examples of haplo-insufficiency, resulting in obvious vascular abnormalities and in embryonic lethality. These striking phenotypes are a proof of concept of the crucial role played by the bioavailability of VEGF and DLL4 during vessel patterning and that there must be a very fine-tuning of DLL4 expression level. However, to date the expression regulation of this factor was poorly studied. In this study, we showed that the DLL4 5′-UTR harbors an Internal Ribosomal Entry Site (IRES) that, in contrast to cap-dependent translation, was efficiently utilized in cells subjected to several stresses including hypoxia and endoplasmic reticulum stress (ER stress). We identified PERK, a kinase activated by ER stress, as the driver of DLL4 IRES-mediated translation, and hnRNP-A1 as an IRES-Trans-Acting Factor (ITAF) participating in the IRES-dependent translation of DLL4 during endoplasmic reticulum stress. The presence of a stress responsive internal ribosome entry site in the DLL4 msRNA suggests that the process of alternative translation initiation, by controlling the expression of this factor, could have a crucial role in the control of endothelial tip cell function.
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Affiliation(s)
- Manon Jaud
- Inserm UMR1037, CRCT (Cancer Research Center of Toulouse), CNRS ERL5294, Université Toulouse III Paul-Sabatier, F-31037 Toulouse, France.
| | - Céline Philippe
- Inserm UMR1037, CRCT (Cancer Research Center of Toulouse), CNRS ERL5294, Université Toulouse III Paul-Sabatier, F-31037 Toulouse, France.
| | - Loic Van Den Berghe
- Inserm UMR1037, CRCT (Cancer Research Center of Toulouse), CNRS ERL5294, Université Toulouse III Paul-Sabatier, F-31037 Toulouse, France.
- Vectorology Plateform, Technological pole CRCT, F-31037 Toulouse, France.
| | - Christèle Ségura
- Inserm UMR1037, CRCT (Cancer Research Center of Toulouse), CNRS ERL5294, Université Toulouse III Paul-Sabatier, F-31037 Toulouse, France.
- Vectorology Plateform, Technological pole CRCT, F-31037 Toulouse, France.
| | - Laurent Mazzolini
- Inserm UMR1037, CRCT (Cancer Research Center of Toulouse), CNRS ERL5294, Université Toulouse III Paul-Sabatier, F-31037 Toulouse, France.
| | - Stéphane Pyronnet
- Inserm UMR1037, CRCT (Cancer Research Center of Toulouse), CNRS ERL5294, Université Toulouse III Paul-Sabatier, F-31037 Toulouse, France.
| | - Henrik Laurell
- Inserm UMR1048, I2MC (Institut des Maladies Métaboliques et Cardiovasculaires), Toulouse, France.
| | - Christian Touriol
- Inserm UMR1037, CRCT (Cancer Research Center of Toulouse), CNRS ERL5294, Université Toulouse III Paul-Sabatier, F-31037 Toulouse, France.
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32
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The Tubulin Detyrosination Cycle: Function and Enzymes. Trends Cell Biol 2019; 29:80-92. [DOI: 10.1016/j.tcb.2018.08.003] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 08/14/2018] [Accepted: 08/15/2018] [Indexed: 12/24/2022]
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Presta M, Foglio E, Churruca Schuind A, Ronca R. Long Pentraxin-3 Modulates the Angiogenic Activity of Fibroblast Growth Factor-2. Front Immunol 2018; 9:2327. [PMID: 30349543 PMCID: PMC6187966 DOI: 10.3389/fimmu.2018.02327] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 09/19/2018] [Indexed: 12/15/2022] Open
Abstract
Angiogenesis, the process of new blood vessel formation from pre-existing ones, plays a key role in various physiological and pathological conditions. Alteration of the angiogenic balance, consequent to the deranged production of angiogenic growth factors and/or natural angiogenic inhibitors, is responsible for angiogenesis-dependent diseases, including cancer. Fibroblast growth factor-2 (FGF2) represents the prototypic member of the FGF family, able to induce a complex “angiogenic phenotype” in endothelial cells in vitro and a potent neovascular response in vivo as the consequence of a tight cross talk between pro-inflammatory and angiogenic signals. The soluble pattern recognition receptor long pentraxin-3 (PTX3) is a member of the pentraxin family produced locally in response to inflammatory stimuli. Besides binding features related to its role in innate immunity, PTX3 interacts with FGF2 and other members of the FGF family via its N-terminal extension, thus inhibiting FGF-mediated angiogenic responses in vitro and in vivo. Accordingly, PTX3 inhibits the growth and vascularization of FGF-dependent tumors and FGF2-mediated smooth muscle cell proliferation and artery restenosis. Recently, the characterization of the molecular bases of FGF2/PTX3 interaction has allowed the identification of NSC12, the first low molecular weight pan-FGF trap able to inhibit FGF-dependent tumor growth and neovascularization. The aim of this review is to provide an overview of the impact of PTX3 and PTX3-derived molecules on the angiogenic, inflammatory, and tumorigenic activity of FGF2 and their potential implications for the development of more efficacious anti-FGF therapeutic agents to be used in those clinical settings in which FGFs play a pathogenic role.
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Affiliation(s)
- Marco Presta
- Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Brescia, Italy
| | - Eleonora Foglio
- Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Brescia, Italy
| | - Ander Churruca Schuind
- Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Brescia, Italy
| | - Roberto Ronca
- Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Brescia, Italy
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34
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Coffin JD, Homer-Bouthiette C, Hurley MM. Fibroblast Growth Factor 2 and Its Receptors in Bone Biology and Disease. J Endocr Soc 2018; 2:657-671. [PMID: 29942929 PMCID: PMC6009610 DOI: 10.1210/js.2018-00105] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 05/23/2018] [Indexed: 01/24/2023] Open
Abstract
The fibroblast growth factor (FGF) regulatory axis is phylogenetically ancient, evolving into a large mammalian/human gene family of 22 ligands that bind to four receptor tyrosine kinases for a complex physiologic system controlling cell growth, differentiation, and metabolism. The tissue targets for the primary FGF function are mainly in cartilage and in bone for morphogenesis, mineralization, and metabolism. A multitude of complexities in the FGF ligand-receptor signaling pathways have made translation into therapies for FGF-related bone disorders such as osteomalacia, osteoarthritis, and osteoporosis difficult but not impossible.
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Affiliation(s)
| | | | - Marja Marie Hurley
- Department of Medicine, University of Connecticut School of Medicine, UCONN Health, Farmington, Connecticut
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Eguchi K, Shindo T, Ito K, Ogata T, Kurosawa R, Kagaya Y, Monma Y, Ichijo S, Kasukabe S, Miyata S, Yoshikawa T, Yanai K, Taki H, Kanai H, Osumi N, Shimokawa H. Whole-brain low-intensity pulsed ultrasound therapy markedly improves cognitive dysfunctions in mouse models of dementia - Crucial roles of endothelial nitric oxide synthase. Brain Stimul 2018; 11:959-973. [PMID: 29857968 DOI: 10.1016/j.brs.2018.05.012] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 05/01/2018] [Accepted: 05/20/2018] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Therapeutic focused-ultrasound to the hippocampus has been reported to exert neuroprotective effects on dementia. In the present study, we examined whether the whole-brain LIPUS (low-intensity pulsed ultrasound) therapy is effective and safe in 2 mouse models of dementia (vascular dementia, VaD and Alzheimer's disease, AD), and if so, to elucidate the common underlying mechanism(s) involved. METHODS We used bilateral carotid artery stenosis (BCAS) model with micro-coils in male C57BL/6 mice as a VaD model and 5XFAD transgenic mice as an AD model. We applied the LIPUS therapy (1.875 MHz, 6.0 kHz, 32cycles) to the whole brain. RESULTS In both models, the LIPUS therapy markedly ameliorated cognitive impairments (Y-maze test and/or passive avoidance test) associated with improved cerebral blood flow (CBF). Mechanistically, the LIPUS therapy significantly increased CD31-positive endothelial cells and Olig2-positive oligodendrocyte precursor cells (OPCs) in the VaD model, while it reduced Iba-1-positive microglias and amyloid-β (Aβ) plaque in the AD model. In both models, endothelium-related genes were significantly upregulated in RNA-sequencing, and expressions of endothelial nitric oxide synthase (eNOS) and neurotrophins were upregulated in Western blotting. Interestingly, the increases in glia cells and neurotrophin expressions showed significant correlations with eNOS expression. Importantly, these beneficial effects of LIPUS were absent in eNOS-knockout mice. CONCLUSIONS These results indicate that the whole-brain LIPUS is an effective and non-invasive therapy for dementia by activating specific cells corresponding to each pathology, for which eNOS activation plays an important role as a common mechanism.
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Affiliation(s)
- Kumiko Eguchi
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomohiko Shindo
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kenta Ito
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tsuyoshi Ogata
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Ryo Kurosawa
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yuta Kagaya
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yuto Monma
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Sadamitsu Ichijo
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Sachie Kasukabe
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Satoshi Miyata
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takeo Yoshikawa
- Department of Pharmacology, Tohoku University School of Medicine Sendai, Japan
| | - Kazuhiko Yanai
- Department of Pharmacology, Tohoku University School of Medicine Sendai, Japan
| | - Hirofumi Taki
- Biomedical Engineering for Health and Welfare, Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan
| | - Hiroshi Kanai
- Department of Electronic Engineering, Tohoku University Graduate School of Engineering, Sendai, Japan
| | - Noriko Osumi
- Department of Developmental Neuroscience, Tohoku University, Sendai, Japan
| | - Hiroaki Shimokawa
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
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Delayed recognition of Judah Folkman’s hypothesis on tumor angiogenesis: when a Prince awakens a Sleeping Beauty by self-citation. Scientometrics 2018. [DOI: 10.1007/s11192-018-2752-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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De Sanctis F, Ugel S, Facciponte J, Facciabene A. The dark side of tumor-associated endothelial cells. Semin Immunol 2018; 35:35-47. [PMID: 29490888 DOI: 10.1016/j.smim.2018.02.002] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 02/02/2018] [Indexed: 12/29/2022]
Abstract
Angiogenesis is a hallmark of cancer and a requisite that tumors must achieve to fulfill their metabolic needs of nutrients and oxygen. As a critical step in cancer progression, the 'angiogenic switch' allows tumor cells to survive and grow, and provides them access to vasculature resulting in metastatic progression and dissemination. Tumor-dependent triggering of the angiogenic switch has critical consequences on tumor progression which extends from an increased nutrient supply and relies instead on the ability of the tumor to hijack the host immune response for the generation of a local immunoprivileged microenvironment. Tumor angiogenic-mediated establishment of endothelial anergy is responsible for this process. However, tumor endothelium can also promote immune tolerance by unbalanced expression of co-stimulatory and co-inhibitory molecules and by releasing soluble factors that restrain T cell function and induce apoptosis. In this review, we discuss the molecular properties of the tumor endothelial barrier and endothelial anergy and discuss the main immunosuppressive mechanisms triggered by the tumor endothelium. Lastly, we describe the current anti-angiogenic therapeutic landscape and how targeting tumor angiogenesis can contribute to improve clinical benefits for patients.
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Affiliation(s)
- Francesco De Sanctis
- Immunology Section, Department of Medicine, University of Verona, 37134, Verona, Italy
| | - Stefano Ugel
- Immunology Section, Department of Medicine, University of Verona, 37134, Verona, Italy
| | - John Facciponte
- Ovarian Cancer Research Center (OCRC), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Andrea Facciabene
- Ovarian Cancer Research Center (OCRC), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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Duran CL, Abbey CA, Bayless KJ. Establishment of a three-dimensional model to study human uterine angiogenesis. Mol Hum Reprod 2018; 24:74-93. [PMID: 29329415 PMCID: PMC6454809 DOI: 10.1093/molehr/gax064] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 10/25/2017] [Accepted: 12/19/2017] [Indexed: 01/29/2023] Open
Abstract
STUDY QUESTION Can primary human uterine microvascular endothelial cells (UtMVECs) be used as a model to study uterine angiogenic responses in vitro that are relevant in pregnancy? SUMMARY ANSWER UtMVECs demonstrated angiogenic responses when stimulated with proangiogenic factors, including sphingosine 1-phosphate (S1P), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), physiological levels of wall shear stress (WSS), human chorionic gonadotropin (hCG) and various combinations of estrogen and progesterone. WHAT IS KNOWN ALREADY During sprouting angiogenesis, signaling from growth factors and cytokines induces a monolayer of quiescent endothelial cells (ECs) lining the vasculature to degrade the extracellular matrix and invade the surrounding tissue to form new capillaries. During pregnancy and the female reproductive cycle, the uterine endothelium becomes activated and undergoes sprouting angiogenesis to increase the size and number of blood vessels in the endometrium. STUDY DESIGN, SIZE, DURATION The study was designed to examine the angiogenic potential of primary human UtMVECs using the well-characterized human umbilical vein EC (HUVEC) line as a control to compare angiogenic potential. ECs were seeded onto three-dimensional (3D) collagen matrices, supplemented with known proangiogenic stimuli relevant to pregnancy and allowed to invade for 24 h. Sprouting responses were analyzed using manual and automated methods for quantification. PARTICIPANTS/MATERIALS, SETTING, METHODS RT-PCR, Western blot analysis and immunostaining were used to characterize UtMVECs. Angiogenic responses were examined using 3D invasion assays. Western blotting was used to confirm signaling responses after proangiogenic lipid, pharmacological inhibitor, and recombinant lentiviral treatments. All experiments were repeated at least three times. MAIN RESULTS AND THE ROLE OF CHANCE After ensuring that UtMVECs expressed the proper endothelial markers, we found that UtMVECs invade 3D collagen matrices dose-dependently in response to known proangiogenic stimuli (e.g. S1P, VEGF, bFGF, hCG, estrogen, progesterone and WSS) present during early pregnancy. Invasion responses were positively correlated with phosphorylation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) and p42/p44 mitogen-activated protein kinase (ERK). Inhibition of these second messengers significantly impaired sprouting (P < 0.01). Gene silencing of membrane type 1-matrix metalloproteinase using multiple approaches completely abrogated sprouting (P < 0.001). Finally, UtMVECs displayed a unique ability to undergo sprouting in response to hCG, and combined estrogen and progesterone treatment. LARGE SCALE DATA Not applicable. LIMITATIONS, REASONS FOR CAUTION The study of uterine angiogenesis in vitro has limitations and any findings many not fully represent the in vivo state. However, these experiments do provide evidence for the ability of UtMVECs to be used in functional sprouting assays in a 3D environment, stimulated by physiological factors that are produced locally within the uterus during early pregnancy. WIDER IMPLICATIONS OF THE FINDINGS We show that UtMVECs can be used reliably to investigate how growth factors, hormones, lipids and other factors, such as flow, affect angiogenesis in the uterus. STUDY FUNDING/COMPETING INTERESTS This work was supported by NIH award HL095786 to K.J.B. The authors have no conflicts of interest.
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Affiliation(s)
- Camille L Duran
- Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, 440 Reynolds Medical Building, College Station, TX 77843-1114, USA
- Interdisciplinary Program in Genetics, Texas A&M University, Mail Stop 2128, College Station, TX 77843, USA
| | - Colette A Abbey
- Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, 440 Reynolds Medical Building, College Station, TX 77843-1114, USA
| | - Kayla J Bayless
- Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, 440 Reynolds Medical Building, College Station, TX 77843-1114, USA
- Interdisciplinary Program in Genetics, Texas A&M University, Mail Stop 2128, College Station, TX 77843, USA
- Interdisciplinary Faculty of Reproductive Biology, Texas A&M University, Mail Stop 2471, College Station, TX 77843, USA
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Dual roles of endothelial FGF-2-FGFR1-PDGF-BB and perivascular FGF-2-FGFR2-PDGFRβ signaling pathways in tumor vascular remodeling. Cell Discov 2018; 4:3. [PMID: 29423271 PMCID: PMC5798893 DOI: 10.1038/s41421-017-0002-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 11/08/2017] [Accepted: 11/09/2017] [Indexed: 02/07/2023] Open
Abstract
Perivascular cells are important cellular components in the tumor microenvironment (TME) and they modulate vascular integrity, remodeling, stability, and functions. Here we show using mice models that FGF-2 is a potent pericyte-stimulating factor in tumors. Mechanistically, FGF-2 binds to FGFR2 to stimulate pericyte proliferation and orchestrates the PDGFRβ signaling for vascular recruitment. FGF-2 sensitizes the PDGFRβ signaling through increasing PDGFRβ levels in pericytes. To ensure activation of PDGFRβ, the FGF-2-FGFR1-siganling induces PDGF-BB and PDGF-DD, two ligands for PDGFRβ, in angiogenic endothelial cells. Thus, FGF-2 directly and indirectly stimulates pericyte proliferation and recruitment by modulating the PDGF-PDGFRβ signaling. Our study identifies a novel mechanism by which the FGF-2 and PDGF-BB collaboratively modulate perivascular cell coverage in tumor vessels, thus providing mechanistic insights of pericyte-endothelial cell interactions in TME and conceptual implications for treatment of cancers and other diseases by targeting the FGF-2-FGFR-pericyte axis.
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40
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Gambogic acid ameliorates diabetes-induced proliferative retinopathy through inhibition of the HIF-1α/VEGF expression via targeting PI3K/AKT pathway. Life Sci 2018; 192:293-303. [DOI: 10.1016/j.lfs.2017.11.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 10/23/2017] [Accepted: 11/07/2017] [Indexed: 01/07/2023]
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41
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Ng CF, Frieboes HB. Model of vascular desmoplastic multispecies tumor growth. J Theor Biol 2017; 430:245-282. [PMID: 28529153 PMCID: PMC5614902 DOI: 10.1016/j.jtbi.2017.05.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2016] [Revised: 03/07/2017] [Accepted: 05/09/2017] [Indexed: 12/21/2022]
Abstract
We present a three-dimensional nonlinear tumor growth model composed of heterogeneous cell types in a multicomponent-multispecies system, including viable, dead, healthy host, and extra-cellular matrix (ECM) tissue species. The model includes the capability for abnormal ECM dynamics noted in tumor development, as exemplified by pancreatic ductal adenocarcinoma, including dense desmoplasia typically characterized by a significant increase of interstitial connective tissue. An elastic energy is implemented to provide elasticity to the connective tissue. Cancer-associated fibroblasts (myofibroblasts) are modeled as key contributors to this ECM remodeling. The tumor growth is driven by growth factors released by these stromal cells as well as by oxygen and glucose provided by blood vasculature which along with lymphatics are stimulated to proliferate in and around the tumor based on pro-angiogenic factors released by hypoxic tissue regions. Cellular metabolic processes are simulated, including respiration and glycolysis with lactate fermentation. The bicarbonate buffering system is included for cellular pH regulation. This model system may be of use to simulate the complex interactions between tumor and stromal cells as well as the associated ECM and vascular remodeling that typically characterize malignant cancers notorious for poor therapeutic response.
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Affiliation(s)
- Chin F Ng
- Department of Bioengineering, University of Louisville, Lutz Hall 419, KY 40208, USA
| | - Hermann B Frieboes
- Department of Bioengineering, University of Louisville, Lutz Hall 419, KY 40208, USA; James Graham Brown Cancer Center, University of Louisville, KY, USA.
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42
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Matkar PN, Ariyagunarajah R, Leong-Poi H, Singh KK. Friends Turned Foes: Angiogenic Growth Factors beyond Angiogenesis. Biomolecules 2017; 7:biom7040074. [PMID: 28974056 PMCID: PMC5745456 DOI: 10.3390/biom7040074] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 09/15/2017] [Accepted: 09/22/2017] [Indexed: 12/13/2022] Open
Abstract
Angiogenesis, the formation of new blood vessels from pre-existing ones is a biological process that ensures an adequate blood flow is maintained to provide the cells with a sufficient supply of nutrients and oxygen within the body. Numerous soluble growth factors and inhibitors, cytokines, proteases as well as extracellular matrix proteins and adhesion molecules stringently regulate the multi-factorial process of angiogenesis. The properties and interactions of key angiogenic molecules such as vascular endothelial growth factors (VEGFs), fibroblast growth factors (FGFs) and angiopoietins have been investigated in great detail with respect to their molecular impact on angiogenesis. Since the discovery of angiogenic growth factors, much research has been focused on their biological actions and their potential use as therapeutic targets for angiogenic or anti-angiogenic strategies in a context-dependent manner depending on the pathologies. It is generally accepted that these factors play an indispensable role in angiogenesis. However, it is becoming increasingly evident that this is not their only role and it is likely that the angiogenic factors have important functions in a wider range of biological and pathological processes. The additional roles played by these molecules in numerous pathologies and biological processes beyond angiogenesis are discussed in this review.
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Affiliation(s)
- Pratiek N Matkar
- Division of Cardiology, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada.
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
| | | | - Howard Leong-Poi
- Division of Cardiology, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada.
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
| | - Krishna K Singh
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
- Division of Vascular Surgery, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada.
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada.
- Department of Surgery, University of Toronto, Toronto, ON M5S 1A8, Canada.
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43
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History and conceptual developments in vascular biology and angiogenesis research: a personal view. Angiogenesis 2017; 20:463-478. [DOI: 10.1007/s10456-017-9569-2] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 07/18/2017] [Indexed: 01/05/2023]
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44
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Al-Abd AM, Alamoudi AJ, Abdel-Naim AB, Neamatallah TA, Ashour OM. Anti-angiogenic agents for the treatment of solid tumors: Potential pathways, therapy and current strategies - A review. J Adv Res 2017; 8:591-605. [PMID: 28808589 PMCID: PMC5544473 DOI: 10.1016/j.jare.2017.06.006] [Citation(s) in RCA: 146] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 06/20/2017] [Accepted: 06/26/2017] [Indexed: 02/08/2023] Open
Abstract
Recent strategies for the treatment of cancer, other than just tumor cell killing have been under intensive development, such as anti-angiogenic therapeutic approach. Angiogenesis inhibition is an important strategy for the treatment of solid tumors, which basically depends on cutting off the blood supply to tumor micro-regions, resulting in pan-hypoxia and pan-necrosis within solid tumor tissues. The differential activation of angiogenesis between normal and tumor tissues makes this process an attractive strategic target for anti-tumor drug discovery. The principles of anti-angiogenic treatment for solid tumors were originally proposed in 1972, and ever since, it has become a putative target for therapies directed against solid tumors. In the early twenty first century, the FDA approved anti-angiogenic drugs, such as bevacizumab and sorafenib for the treatment of several solid tumors. Over the past two decades, researches have continued to improve the performance of anti-angiogenic drugs, describe their drug interaction potential, and uncover possible reasons for potential treatment resistance. Herein, we present an update to the pre-clinical and clinical situations of anti-angiogenic agents and discuss the most recent trends in this field.
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Affiliation(s)
- Ahmed M Al-Abd
- Pharmacology Department, Medical Division, National Research Centre, Dokki, Giza, Egypt.,Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.,Biomedical Research Section, Nawah Scientific, Mokkatam, Cairo, Egypt
| | - Abdulmohsin J Alamoudi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ashraf B Abdel-Naim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.,Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Thikryat A Neamatallah
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Osama M Ashour
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.,Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia 61519, Egypt
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45
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Lakshmanan R, Ukani G, Rishi MT, Maulik N. Trimodal rescue of hind limb ischemia with growth factors, cells, and nanocarriers: fundamentals to clinical trials. Can J Physiol Pharmacol 2017; 95:1125-1140. [PMID: 28407473 DOI: 10.1139/cjpp-2016-0713] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Peripheral artery disease is a severe medical condition commonly characterized by critical or acute limb ischemia. Gradual accumulation of thrombotic plaques in peripheral arteries of the lower limb may lead to intermittent claudication or ischemia in muscle tissue. Ischemic muscle tissue with lesions may become infected, resulting in a non-healing wound. Stable progression of the non-healing wound associated with severe ischemia might lead to functional deterioration of the limb, which, depending on the severity, can result in amputation. Immediate rescue of ischemic muscles through revascularization strategies is considered the gold standard to treat critical limb ischemia. Growth factors offer multiple levels of protection in revascularization of ischemic tissue. In this review, the basic mechanism through which growth factors exert their beneficial properties to rescue the ischemic limb is extensively discussed. Moreover, clinical trials based on growth factor and stem cell therapy to treat critical limb ischemia are considered. The clinical utility of stem cell therapy for the treatment of limb ischemia is explained and recent advances in nanocarrier technology for selective growth factor and stem cell supplementation are summarized.
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Affiliation(s)
- Rajesh Lakshmanan
- Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, Farmington, CT 06030, USA.,Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, Farmington, CT 06030, USA
| | - Gopi Ukani
- Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, Farmington, CT 06030, USA.,Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, Farmington, CT 06030, USA
| | - Muhammad Tipu Rishi
- Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, Farmington, CT 06030, USA.,Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, Farmington, CT 06030, USA
| | - Nilanjana Maulik
- Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, Farmington, CT 06030, USA.,Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, University of Connecticut School of Medicine, Farmington, CT 06030, USA
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46
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Yang WH, Xu J, Mu JB, Xie J. Revision of the concept of anti-angiogenesis and its applications in tumor treatment. Chronic Dis Transl Med 2017; 3:33-40. [PMID: 29063054 PMCID: PMC5627689 DOI: 10.1016/j.cdtm.2017.01.002] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Indexed: 12/16/2022] Open
Abstract
Anti-angiogenesis therapy, by blocking formation of new blood vessels in tumors, is the standard-of-care therapy for various cancer types. The classic concept of anti-angiogenesis is expected to turn a tumor into a "dormant" disease. However, the combination of anti-angiogenesis agents with conventional therapeutics has generally produced only modest survival benefits for cancer patients in clinical trials. Therefore, the concept and applications of anti-angiogenesis have evolved dramatically along with lessons learned from recent clinical experience. In this article, we will discuss the revised concept of anti-angiogenesis therapy and the applications of anti-angiogenesis drugs, and focus particularly on how to utilize current anti-angiogenesis agents and develop new approaches to provide more benefits to patients with cancer.
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Affiliation(s)
- Wen-Hui Yang
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi 030001, China
- Tumor Hospital of Shanxi Province, Taiyuan, Shanxi 030013, China
| | - Jun Xu
- Tumor Hospital of Shanxi Province, Taiyuan, Shanxi 030013, China
| | - Jian-Bing Mu
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Jun Xie
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, Shanxi 030001, China
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47
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The Pleiotropic Role of L1CAM in Tumor Vasculature. Int J Mol Sci 2017; 18:ijms18020254. [PMID: 28134764 PMCID: PMC5343790 DOI: 10.3390/ijms18020254] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Revised: 01/19/2017] [Accepted: 01/23/2017] [Indexed: 02/06/2023] Open
Abstract
Angiogenesis, the formation of new vessels, is a key step in the development, invasion, and dissemination of solid tumors and, therefore, represents a viable target in the context of antitumor therapy. Indeed, antiangiogenic approaches have given promising results in preclinical models and entered the clinical practice. However, in patients, the results obtained so far with antiangiogenic drugs have not completely fulfilled expectations, especially because their effect has been transient with tumors developing resistance and evasion mechanisms. A better understanding of the mechanisms that underlie tumor vascularization and the functional regulation of cancer vessels is a prerequisite for the development of novel and alternative antiangiogenic treatments. The L1 cell adhesion molecule (L1CAM), a cell surface glycoprotein previously implicated in the development and plasticity of the nervous system, is aberrantly expressed in the vasculature of various cancer types. L1CAM plays multiple pro-angiogenic roles in the endothelial cells of tumor-associated vessels, thus emerging as a potential therapeutic target. In addition, L1CAM prevents the maturation of cancer vasculature and its inhibition promotes vessel normalization, a process that is thought to improve the therapeutic response of tumors to cytotoxic drugs. We here provide an overview on tumor angiogenesis and antiangiogenic therapies and summarize the current knowledge on the biological role of L1CAM in cancer vasculature. Finally, we highlight the clinical implications of targeting L1CAM as a novel antiangiogenic and vessel-normalizing approach.
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48
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Disrupting Tumor Angiogenesis and "the Hunger Games" for Breast Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1026:171-195. [PMID: 29282684 DOI: 10.1007/978-981-10-6020-5_8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Angiogenesis, one of the hallmarks of cancers, has become an attractive target for cancer therapy since decades ago. It is broadly thought that upregulation of angiogenesis is involved in tumor progression and metastasis. Though tumor vessels are tortuous, disorganized, and leaky, they deliver oxygen and nutrients for tumor development. Based on this knowledge, many kinds of drugs targeting angiogenesis pathways have been developed, such as bevacizumab. However, the clinical outcomes of anti-angiogenesis therapies are moderate in metastatic breast cancer as well as in metastatic colorectal cancer and non-small cell lung cancer, even combined with traditional chemotherapy. In this chapter, the morphologic angiogenesis patterns and the key molecular pathways regulating angiogenesis are elaborated. The FDA-approved anti-angiogenesis drugs and current challenges of anti-angiogenesis therapy are described. The strategies to overcome the barriers will also be elucidated.
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49
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Kareva I, Abou-Slaybi A, Dodd O, Dashevsky O, Klement GL. Normal Wound Healing and Tumor Angiogenesis as a Game of Competitive Inhibition. PLoS One 2016; 11:e0166655. [PMID: 27935954 PMCID: PMC5147849 DOI: 10.1371/journal.pone.0166655] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 11/01/2016] [Indexed: 12/20/2022] Open
Abstract
Both normal wound healing and tumor angiogenesis are mitigated by the sequential, carefully orchestrated release of growth stimulators and inhibitors. These regulators are released from platelet clots formed at the sites of activated endothelium in a temporally and spatially controlled manner, and the order of their release depends on their affinity to glycosaminoglycans (GAG) such as heparan sulfate (HS) within the extracellular matrix, and platelet open canallicular system. The formation of vessel sprouts, triggered by angiogenesis regulating factors with lowest affinities for heparan sulfate (e.g. VEGF), is followed by vessel-stabilizing PDGF-B or bFGF with medium affinity for HS, and by inhibitors such as PF-4 and TSP-1 with the highest affinities for HS. The invasive wound-like edge of growing tumors has an overabundance of angiogenesis stimulators, and we propose that their abundance out-competes angiogenesis inhibitors, effectively preventing inhibition of angiogenesis and vessel maturation. We evaluate this hypothesis using an experimentally motivated agent-based model, and propose a general theoretical framework for understanding mechanistic similarities and differences between the processes of normal wound healing and pathological angiogenesis from the point of view of competitive inhibition.
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Affiliation(s)
- Irina Kareva
- Floating Hospital for Children at Tufts Medical Center, Boston, Massachusetts, United States of America
- Mathematical, Computational and Modeling Sciences Center, Arizona State Univ, Tempe, Arizona, United States of America
| | - Abdo Abou-Slaybi
- Floating Hospital for Children at Tufts Medical Center, Boston, Massachusetts, United States of America
| | - Oliver Dodd
- Floating Hospital for Children at Tufts Medical Center, Boston, Massachusetts, United States of America
- Massachusetts Institute of Technology, Boston, Massachusetts, United States of America
| | - Olga Dashevsky
- Floating Hospital for Children at Tufts Medical Center, Boston, Massachusetts, United States of America
- Dept. of Medical Oncology, Dana−Farber Cancer Institute, Dept. of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Giannoula Lakka Klement
- Floating Hospital for Children at Tufts Medical Center, Boston, Massachusetts, United States of America
- Pediatric Hematology Oncology, Floating Hospital for Children at Tufts Medical Center, Boston, Massachusetts, United States of America
- Sackler School of Graduate Biomedical Sciences at Tufts University, Boston, Massachusetts, United States of America
- * E-mail: ,
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50
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Falcon BL, Chintharlapalli S, Uhlik MT, Pytowski B. Antagonist antibodies to vascular endothelial growth factor receptor 2 (VEGFR-2) as anti-angiogenic agents. Pharmacol Ther 2016; 164:204-25. [PMID: 27288725 DOI: 10.1016/j.pharmthera.2016.06.001] [Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Interaction of numerous signaling pathways in endothelial and mesangial cells results in exquisite control of the process of physiological angiogenesis, with a central role played by vascular endothelial growth factor receptor 2 (VEGFR-2) and its cognate ligands. However, deregulated angiogenesis participates in numerous pathological processes. Excessive activation of VEGFR-2 has been found to mediate tissue-damaging vascular changes as well as the induction of blood vessel expansion to support the growth of solid tumors. Consequently, therapeutic intervention aimed at inhibiting the VEGFR-2 pathway has become a mainstay of treatment in cancer and retinal diseases. In this review, we introduce the concepts of physiological and pathological angiogenesis, the crucial role played by the VEGFR-2 pathway in these processes, and the various inhibitors of its activity that have entered the clinical practice. We primarily focus on the development of ramucirumab, the antagonist monoclonal antibody (mAb) that inhibits VEGFR-2 and has recently been approved for use in patients with gastric, colorectal, and lung cancers. We examine in-depth the pre-clinical studies using DC101, the mAb to mouse VEGFR-2, which provided a conceptual foundation for the role of VEGFR-2 in physiological and pathological angiogenesis. Finally, we discuss further clinical development of ramucirumab and the future of targeting the VEGF pathway for the treatment of cancer.
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