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Zheng Y, Cong L, Zhao L, Wang P, Xing L, Liu J, Xu H, Li N, Zhao Y, Yuan L, Shi Q, Sun X, Liang Q, Wang Y. Lymphatic platelet thrombosis limits bone repair by precluding lymphatic transporting DAMPs. Nat Commun 2025; 16:829. [PMID: 39827193 PMCID: PMC11742876 DOI: 10.1038/s41467-025-56147-8] [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: 10/21/2023] [Accepted: 01/05/2025] [Indexed: 01/22/2025] Open
Abstract
In the musculoskeletal system, lymphatic vessels (LVs), which are interdigitated with blood vessels, travel and form an extensive transport network. Blood vessels in bone regulate osteogenesis and hematopoiesis, however, whether LVs in bone affect fracture healing is unclear. Here, we investigate the lymphatic draining function at the tibial fracture sites using near-infrared indocyanine green lymphatic imaging (NIR-ICG) and discover that lymphatic drainage insufficiency (LDI) starts on day one and persists for up to two weeks following the fracture in male mice. Sufficient lymphatic drainage facilitates fracture healing in male mice. Furthermore, we identify that lymphatic platelet thrombosis (LPT) blocks the draining lymphoid sinus and LVs, causes LDI, and inhibits fracture healing in male mice, which can be rescued by a blood thinner. Moreover, unblocked lymphatic drainage decreases neutrophils and increases M2-type macrophages of the hematoma niche to support osteoblast (OB) survival and bone marrow-derived mesenchymal stem cell (BMSC) proliferation via transporting damage-associated molecular patterns (DAMPs) in male rats. Lymphatic platelet thrombolysis also benefits senile fracture healing in female mice. These findings demonstrate that LPT limits bone regeneration by impeding lymphatic transporting DAMPs. Together, these findings represent a way forward in the treatment of bone repair.
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Affiliation(s)
- Yangkang Zheng
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, 201203, Shanghai, China
- Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, 227 Chongqing South Road, 200025, Shanghai, China
| | - Lin Cong
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, 201203, Shanghai, China
| | - Li Zhao
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, 201203, Shanghai, China
| | - Pengyu Wang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, 201203, Shanghai, China
| | - Lianping Xing
- Department of Pathology and Laboratory Medicine and Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY, 14642, USA
| | - Junling Liu
- Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, 227 Chongqing South Road, 200025, Shanghai, China
| | - Hao Xu
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, 201203, Shanghai, China
| | - Ning Li
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, 201203, Shanghai, China
| | - Yongjian Zhao
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, 201203, Shanghai, China
| | - Luying Yuan
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, 201203, Shanghai, China
| | - Qi Shi
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, 201203, Shanghai, China
| | - Xueqing Sun
- Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, 227 Chongqing South Road, 200025, Shanghai, China
| | - Qianqian Liang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China.
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China.
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, 201203, Shanghai, China.
| | - YongJun Wang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China.
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China.
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, 201203, Shanghai, China.
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Zhu J, Qiu X, Jin X, Nie X, Ou S, Wu G, Shen J, Zhang R. ZNF468-mediated epigenetic upregulation of VEGF-C facilitates lymphangiogenesis and lymphatic metastasis in ESCC via PI3K/Akt and ERK1/2 signaling pathways. Cell Oncol (Dordr) 2024; 47:1927-1942. [PMID: 39141315 DOI: 10.1007/s13402-024-00976-0] [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] [Accepted: 07/23/2024] [Indexed: 08/15/2024] Open
Abstract
PURPOSE Dysfunctional lymphangiogenesis is pivotal for various pathological processes including tumor lymph node metastasis which is a crucial cause of therapeutic failure for ESCC. In this study, we aim to elucidate the molecular mechanisms and clinical relevance of Zinc-finger protein ZNF468 in lymphangiogenesis and lymphatic metastasis in ESCC. METHODS Immunohistochemistry, Western blot, Kaplan-Meier plotter analysis and Gene Set Enrichment Analysis were preformed to detect the association of ZNF468 with lymphangiogenesis and poor prognosis in ESCC patients. Foot-pads lymph node metastasis model, tube formation assay, 3D-culture assay and invasion assay were preformed to verify the effect of ZNF468 on lymphangiogenesis and lymph node metastasis. CUT&Tag analysis, immunoprecipitation and mass spectrometry analysis and ChIP-PCR assay were preformed to study the molecular mechanisms of ZNF468 in lymphangiogenesis. RESULTS We found that ectopic expression of ZNF468 was correlated with higher microlymphatic vessel density in ESCC tissues, leading to poorer prognosis of ESCC patients. ZNF468 enhanced the capacity of lymphangiogenesis and promoted lymphatic metastasis in ESCC both in vitro and in vivo. However, silencing ZNF468 reversed these phenotypes in ESCC. Mechanically, we demonstrated that ZNF468 recruits the histone modification factors (PRMT1/HAT1) to increase the levels of H4R2me2a and H3K9ac, which then leads to the recruitment of the transcription initiation complex on the VEGF-C promoter, ultimately promoting the upregulation of VEGF-C transcription. Strikingly, the promoting effect of lymphatic metastasis induced by ZNF468 in ESCC was abrogated by targeting PRMT1 using Arginine methyltransferase inhibitor-1 or silencing VEGF-C. Furthermore, we found that the activation of PI3K/AKT and ERK1/2 signaling is required for ZNF468-medicated lymphatic metastasis in ESCC. Importantly, the clinical relevance between ZNF468 and VEGF-C were confirmed not only in ESCC samples and but also in multiple cancer types. CONCLUSION Our results identified a precise mechanism underlying ZNF468-induced epigenetic upregulation of VEGF-C in facilitating lymphangiogenesis and lymph node metastasis of ESCC, which might provide a novel prognostic biomarker and potential therapeutic for ESCC patients.
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Affiliation(s)
- Jinrong Zhu
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xiangyu Qiu
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xin Jin
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xiaoya Nie
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, China
| | - Shengming Ou
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, China
| | - Geyan Wu
- Biomedicine Research Centre, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provicial Clinical Research Center for Obsterics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China.
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
| | - Jianfei Shen
- Department of Cardiothoracic Surgery, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Taizhou, China.
| | - Rongxin Zhang
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, China.
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Navaneethabalakrishnan S, Goodlett B, Smith H, Montalvo R, Cardenas A, Mitchell B. Differential changes in end organ immune cells and inflammation in salt-sensitive hypertension: effects of increasing M2 macrophages. Clin Sci (Lond) 2024; 138:921-940. [PMID: 38949840 PMCID: PMC11250104 DOI: 10.1042/cs20240699] [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: 04/08/2024] [Revised: 06/18/2024] [Accepted: 07/01/2024] [Indexed: 07/02/2024]
Abstract
Salt-sensitive hypertension (SSHTN) is associated with M1 macrophage polarization and inflammatory responses, leading to inflammation-associated lymphangiogenesis and functional impairment across multiple organs, including kidneys and gonads. However, it remains unclear whether promoting M2 macrophage polarization can alleviate the hypertension, inflammation, and end organ damage in mice with salt sensitive hypertension (SSHTN). Male and female mice were made hypertensive by administering nitro-L-arginine methyl ester hydrochloride (L-NAME; 0.5 mg/ml) for 2 weeks in the drinking water, followed by a 2-week interval without any treatments, and a subsequent high salt diet for 3 weeks (SSHTN). AVE0991 (AVE) was intraperitoneally administered concurrently with the high salt diet. Control mice were provided standard diet and tap water. AVE treatment significantly attenuated BP and inflammation in mice with SSHTN. Notably, AVE promoted M2 macrophage polarization, decreased pro-inflammatory immune cell populations, and improved function in renal and gonadal tissues of mice with SSHTN. Additionally, AVE decreased lymphangiogenesis in the kidneys and testes of male SSHTN mice and the ovaries of female SSHTN mice. These findings highlight the effectiveness of AVE in mitigating SSHTN-induced elevated BP, inflammation, and end organ damage by promoting M2 macrophage polarization and suppressing pro-inflammatory immune responses. Targeting macrophage polarization emerges as a promising therapeutic approach for alleviating inflammation and organ damage in SSHTN. Further studies are warranted to elucidate the precise mechanisms underlying AVE-mediated effects and to assess its clinical potential in managing SSHTN.
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Affiliation(s)
| | - Bethany L. Goodlett
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX, U.S.A
| | - Hannah L. Smith
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX, U.S.A
| | - Robert A. Montalvo
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX, U.S.A
| | - Alyssa Cardenas
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX, U.S.A
| | - Brett M. Mitchell
- Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX, U.S.A
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Chen T, Ruan Y, Ji L, Cai J, Tong M, Xue Y, Zhao H, Cai X, Xu J. S100A6 drives lymphatic metastasis of liver cancer via activation of the RAGE/NF-kB/VEGF-D pathway. Cancer Lett 2024; 587:216709. [PMID: 38350547 DOI: 10.1016/j.canlet.2024.216709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 02/02/2024] [Accepted: 02/06/2024] [Indexed: 02/15/2024]
Abstract
Patients diagnosed with lymph node (LN) metastatic liver cancer face an exceedingly grim prognosis. In-depth analysis of LN metastatic patients' characteristics and tumor cells' interactions with human lymphatic endothelial cells (HLECs), can provide important biological and therapeutic insights. Here we identify at the single-cell level that S100A6 expression differs between primary tumor and their LN metastasis. Of particular significance, we uncovered the disparity in S100A6 expression between tumors and normal tissues is greater in intrahepatic cholangiocarcinoma (ICC) patients, frequently accompanied by LN metastases, than that in hepatocellular carcinoma (HCC), with rare occurrence of LN metastasis. Furthermore, in the infrequent instances of LN metastasis in HCC, heightened S100A6 expression was observed, suggesting a critical role of S100A6 in the process of LN metastasis. Subsequent experiments further uncovered that S100A6 secreted from tumor cells promotes lymphangiogenesis by upregulating the expression and secretion of vascular endothelial growth factor-D (VEGF-D) in HLECs through the RAGE/NF-kB/VEGF-D pathway while overexpression of S100A6 in tumor cells also augmented their migration and invasion. Taken together, these data reveal the dual effects of S100A6 in promoting LN metastasis in liver cancer, thus highlighting its potential as a promising therapeutic target.
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Affiliation(s)
- TianYi Chen
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, China
| | - YeLing Ruan
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, China
| | - Lin Ji
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, China
| | - JingWei Cai
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, China
| | - Meng Tong
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, China
| | - YangTao Xue
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, China
| | - Hu Zhao
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, China
| | - XiuJun Cai
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, China; Zhejiang University Cancer Center, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China.
| | - JunJie Xu
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, China; Zhejiang University Cancer Center, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China.
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Zheng Y, Wang P, Zhao L, Xing L, Xu H, Li N, Zhao Y, Shi Q, Liang Q, Wang Y. A novel therapy for fracture healing by increasing lymphatic drainage. J Orthop Translat 2024; 45:66-74. [PMID: 38511124 PMCID: PMC10950565 DOI: 10.1016/j.jot.2024.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 01/03/2024] [Accepted: 02/06/2024] [Indexed: 03/22/2024] Open
Abstract
Background The musculoskeletal system contains an extensive network of lymphatic vessels. Decreased lymph flow of the draining collecting lymphatics usually occurs in clinic after traumatic fractures. However, whether defects in lymphatic drainage can affect fracture healing is unclear. Methods To investigate the effect of lymphatic dysfunction on fracture healing, we used a selective VEGFR3 tyrosine kinase inhibitor to treat tibial fractured mice for 5 weeks versus a vehicle-treated control. To ensure successfully establishing deceased lymphatic drainage model for fractured mice, we measured lymphatic clearance by near infrared indocyanine green lymphatic imaging (NIR-ICG) and the volume of the draining popliteal lymph nodes (PLNs) by ultrasound at the whole phases of fracture healing. In addition, hindlimb edema from day 0 to day 7 post-fracture, pain sensation by Hargreaves test at day 1 post-fracture, bone histomorphometry by micro-CT and callus composition by Alcian Blue-Hematoxylin/Orange G staining at day 14 post-fracture, and bone quality by biomechanical testing at day 35 post-fracture were applied to evaluate fracture healing. To promote fracture healing via increasing lymphatic drainage, we then treated fractured mice with anti-mouse podoplanin (PDPN) neutralizing antibody or isotype IgG antibody for 1 week to observe lymphatic drainage function and assess bone repair as methods described above. Results Compared to vehicle-treated group, SAR-treatment group significantly decreased lymphatic clearance and the volume of draining PLNs. SAR-treatment group significantly increased soft tissue swelling, and reduced bone volume (BV)/tissue volume (TV), trabecular number (Tb.N), woven bone and biomechanical properties of fracture callus. In addition, anti-PDPN treated group significantly reduced the number of CD41+ platelets in PLNs and increased the number of pulsatile lymphatic vessels, lymphatic clearance and the volume of PLNs. Moreover, anti-PDPN treated group significantly reduced hindlimb edema and pain sensation and increased BV/TV, trabecular number (Tb.Th), woven bone and biomechanical properties of fracture callus. Conclusions Inhibition of proper lymphatic drainage function delayed fracture healing. Use of a anti-PDPN neutralizing antibody reduced lymphatic platelet thrombosis (LPT), increased lymphatic drainage and improved fracture healing. The translational potential of this article (1) We demonstrated lymphatic drainage function is crucial for fracture healing. (2) To unblock the lymphatic drainage and prevent the risk of bleeding and mortality by blood thinner, we demonstrated PDPN neutralizing antibody is a novel and safe way forward in the treatment of bone fracture healing by eliminating LPT and increasing lymphatic drainage.
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Affiliation(s)
- Yangkang Zheng
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, 201203, Shanghai, China
| | - Pengyu Wang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, 201203, Shanghai, China
| | - Li Zhao
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, 201203, Shanghai, China
| | - Lianping Xing
- Department of Pathology and Laboratory Medicine and Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY, 14642, USA
| | - Hao Xu
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, 201203, Shanghai, China
| | - Ning Li
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, 201203, Shanghai, China
| | - Yongjian Zhao
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, 201203, Shanghai, China
| | - Qi Shi
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, 201203, Shanghai, China
| | - Qianqian Liang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, 201203, Shanghai, China
| | - YongJun Wang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 Wan-Ping South Road, 200032, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, 201203, Shanghai, China
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Wang YJ, Zheng Y, Cong L, Wang P, Zhao L, Xing L, Liu J, Xu H, Li N, Zhao Y, Shi Q, Liang Q. Lymphatic platelet thrombosis limits bone repair by precluding lymphatic transporting DAMPs. RESEARCH SQUARE 2023:rs.3.rs-3474507. [PMID: 38014223 PMCID: PMC10680927 DOI: 10.21203/rs.3.rs-3474507/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
Lymphatic vessels (LVs) interdigitated with blood vessels, travel and form an extensive transport network in the musculoskeletal system. Blood vessels in bone regulate osteogenesis and hematopoiesis, however, whether LVs in bone affect fracture healing is unclear. Here, by near infrared indocyanine green lymphatic imaging (NIR-ICG), we examined lymphatic draining function at the tibial fracture sites and found lymphatic drainage insufficiency (LDI) occurred as early as two weeks after fracture. Sufficient lymphatic drainage facilitates fracture healing. In addition, we identified that lymphatic platelet thrombosis (LPT) blocks the draining lymphoid sinus and LVs, caused LDI and then inhibited fracture healing, which can be rescued by a pharmacological approach. Moreover, unblocked lymphatic drainage decreased neutrophils and increased M2-like macrophages of hematoma niche to support osteoblast (OB) survival and bone marrow-derived mesenchymal stem cell (BMSC) proliferation via transporting damage-associated molecular patterns (DAMPs). These findings demonstrate that LPT limits bone regeneration by blocking lymphatic drainage from transporting DAMPs. Together, these findings represent a novel way forward in the treatment of bone repair.
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Affiliation(s)
- Yong-Jun Wang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yangkang Zheng
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lin Cong
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Pengyu Wang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Li Zhao
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | | | - Junling Liu
- Shanghai Jiao Tong University School of Medcine
| | - Hao Xu
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine
| | - Ning Li
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine
| | - Yongjian Zhao
- Longhua Hospital Shanghai University of Traditional Chinese Medicine
| | - Qi Shi
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qianqian Liang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine
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Saygili Demir C, Sabine A, Gong M, Dormond O, Petrova TV. Mechanosensitive mTORC1 signaling maintains lymphatic valves. J Cell Biol 2023; 222:e202207049. [PMID: 37036444 PMCID: PMC10097975 DOI: 10.1083/jcb.202207049] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 01/26/2023] [Accepted: 03/23/2023] [Indexed: 04/11/2023] Open
Abstract
Homeostatic maintenance and repair of lymphatic vessels are essential for health. We investigated the dynamics and the molecular mechanisms of lymphatic endothelial cell (LEC) renewal in adult mesenteric quiescent lymphatic vasculature using label-retention, lineage tracing, and cell ablation strategies. Unlike during development, adult LEC turnover and proliferation was confined to the valve regions of collecting vessels, with valve cells displaying the shortest lifespan. Proliferating valve sinus LECs were the main source for maintenance and repair of lymphatic valves. We identified mechanistic target of rapamycin complex 1 (mTORC1) as a mechanoresponsive pathway activated by fluid shear stress in LECs. Depending on the shear stress level, mTORC1 activity drives division of valve cells or dictates their mechanic resilience through increased protein synthesis. Overactivation of lymphatic mTORC1 in vivo promoted supernumerary valve formation. Our work provides insights into the molecular mechanisms of maintenance of healthy lymphatic vascular system.
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Affiliation(s)
- Cansaran Saygili Demir
- Department of Oncology, Lausanne University Hospital-University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland
| | - Amélie Sabine
- Department of Oncology, Lausanne University Hospital-University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland
| | - Muyun Gong
- Department of Oncology, Lausanne University Hospital-University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland
| | - Olivier Dormond
- Department of Visceral Surgery, Lausanne University Hospital, Lausanne, Switzerland
| | - Tatiana V. Petrova
- Department of Oncology, Lausanne University Hospital-University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research Lausanne, Lausanne, Switzerland
- Swiss Institute for Experimental Cancer Research, École polytechnique fédérale de Lausanne, Lausanne, Switzerland
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8
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Brown S, Campbell AC, Kuonqui K, Sarker A, Park HJ, Shin J, Kataru RP, Coriddi M, Dayan JH, Mehrara BJ. The Future of Lymphedema: Potential Therapeutic Targets for Treatment. CURRENT BREAST CANCER REPORTS 2023; 15:1-9. [PMID: 37359311 PMCID: PMC10233555 DOI: 10.1007/s12609-023-00491-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/03/2023] [Indexed: 06/28/2023]
Abstract
Purpose of Review This review aims to summarize the current knowledge regarding the pharmacological interventions studied in both experimental and clinical trials for secondary lymphedema. Recent Findings Lymphedema is a progressive disease that results in tissue swelling, pain, and functional disability. The most common cause of secondary lymphedema in developed countries is an iatrogenic injury to the lymphatic system during cancer treatment. Despite its high incidence and severe sequelae, lymphedema is usually treated with palliative options such as compression and physical therapy. However, recent studies on the pathophysiology of lymphedema have explored pharmacological treatments in preclinical and early phase clinical trials. Summary Many potential treatment options for lymphedema have been explored throughout the past two decades including systemic agents and topical approaches to decrease the potential toxicity of systemic treatment. Treatment strategies including lymphangiogenic factors, anti-inflammatory agents, and anti-fibrotic therapies may be used independently or in conjunction with surgical approaches.
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Affiliation(s)
- Stav Brown
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 USA
| | - Adana C. Campbell
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 USA
| | - Kevin Kuonqui
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 USA
| | - Ananta Sarker
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 USA
| | - Hyeung Ju Park
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 USA
| | - Jinyeon Shin
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 USA
| | - Raghu P. Kataru
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 USA
| | - Michelle Coriddi
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 USA
| | - Joseph H. Dayan
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 USA
| | - Babak J. Mehrara
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 USA
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9
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Li Z, Antila S, Nurmi H, Chilov D, Korhonen EA, Fang S, Karaman S, Engelhardt B, Alitalo K. Blockade of VEGFR3 signaling leads to functional impairment of dural lymphatic vessels without affecting autoimmune neuroinflammation. Sci Immunol 2023; 8:eabq0375. [PMID: 37058549 DOI: 10.1126/sciimmunol.abq0375] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2023]
Abstract
The recent discovery of lymphatic vessels (LVs) in the dura mater, the outermost layer of meninges around the central nervous system (CNS), has opened a possibility for the development of alternative therapeutics for CNS disorders. The vascular endothelial growth factor C (VEGF-C)/VEGF receptor 3 (VEGFR3) signaling pathway is essential for the development and maintenance of dural LVs. However, its significance in mediating dural lymphatic function in CNS autoimmunity is unclear. We show that inhibition of the VEGF-C/VEGFR3 signaling pathway using a monoclonal VEGFR3-blocking antibody, a soluble VEGF-C/D trap, or deletion of the Vegfr3 gene in adult lymphatic endothelium causes notable regression and functional impairment of dural LVs but has no effect on the development of CNS autoimmunity in mice. During autoimmune neuroinflammation, the dura mater was only minimally affected, and neuroinflammation-induced helper T (TH) cell recruitment, activation, and polarization were significantly less pronounced in the dura mater than in the CNS. In support of this notion, during autoimmune neuroinflammation, blood vascular endothelial cells in the cranial and spinal dura expressed lower levels of cell adhesion molecules and chemokines, and antigen-presenting cells (i.e., macrophages and dendritic cells) had lower expression of chemokines, MHC class II-associated molecules, and costimulatory molecules than their counterparts in the brain and spinal cord, respectively. The significantly weaker TH cell responses in the dura mater may explain why dural LVs do not contribute directly to CNS autoimmunity.
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Affiliation(s)
- Zhilin Li
- Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Salli Antila
- Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Wihuri Research Institute, Helsinki, Finland
| | - Harri Nurmi
- Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Wihuri Research Institute, Helsinki, Finland
| | - Dmitri Chilov
- Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Emilia A Korhonen
- Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Wihuri Research Institute, Helsinki, Finland
| | - Shentong Fang
- Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Wihuri Research Institute, Helsinki, Finland
| | - Sinem Karaman
- Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Wihuri Research Institute, Helsinki, Finland
| | | | - Kari Alitalo
- Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Wihuri Research Institute, Helsinki, Finland
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10
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Promotion of Lymphangiogenesis by Targeted Delivery of VEGF-C Improves Diabetic Wound Healing. Cells 2023; 12:cells12030472. [PMID: 36766814 PMCID: PMC9913977 DOI: 10.3390/cells12030472] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 01/20/2023] [Accepted: 01/30/2023] [Indexed: 02/04/2023] Open
Abstract
Chronic wounds represent a major therapeutic challenge. Lymphatic vessel function is impaired in chronic ulcers but the role of lymphangiogenesis in wound healing has remained unclear. We found that lymphatic vessels are largely absent from chronic human wounds as evaluated in patient biopsies. Excisional wound healing studies were conducted using transgenic mice with or without an increased number of cutaneous lymphatic vessels, as well as antibody-mediated inhibition of lymphangiogenesis. We found that a lack of lymphatic vessels mediated a proinflammatory wound microenvironment and delayed wound closure, and that the VEGF-C/VEGFR3 signaling axis is required for wound lymphangiogenesis. Treatment of diabetic mice (db/db mice) with the F8-VEGF-C fusion protein that targets the alternatively spliced extra domain A (EDA) of fibronectin, expressed in remodeling tissue, promoted wound healing, and potently induced wound lymphangiogenesis. The treatment also reduced tissue inflammation and exerted beneficial effects on the wound microenvironment, including myofibroblast density and collagen deposition. These findings indicate that activating the lymphatic vasculature might represent a new therapeutic strategy for treating chronic non-healing wounds.
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11
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Li Y, Amaladas N, O’Mahony M, Manro JR, Inigo I, Li Q, Rasmussen ER, Brahmachary M, Doman TN, Hall G, Kalos M, Novosiadly R, Puig O, Pytowski B, Schaer DA. Treatment with a VEGFR-2 antibody results in intra-tumor immune modulation and enhances anti-tumor efficacy of PD-L1 blockade in syngeneic murine tumor models. PLoS One 2022; 17:e0268244. [PMID: 35849586 PMCID: PMC9292077 DOI: 10.1371/journal.pone.0268244] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 04/26/2022] [Indexed: 12/02/2022] Open
Abstract
Prolonged activation of vascular endothelial growth factor receptor-2 (VEGFR-2) due to mis-regulation of the VEGF pathway induces aberrant blood vessel expansion, which supports growth and survival of solid tumors. Therapeutic interventions that inhibit the VEGFR-2 pathway have therefore become a mainstay of cancer treatment. Non-clinical studies have recently revealed that blockade of angiogenesis can modulate the tumor microenvironment and enhance the efficacy of concurrent immune therapies. Ramucirumab is an FDA-approved anti-angiogenic antibody that inhibits VEGFR-2 and is currently being evaluated in clinical studies in combination with anti-programmed cell death (PD-1) axis checkpoint inhibitors (pembrolizumab, durvalumab, or sintilimab) across several cancer types. The purpose of this study is to establish a mechanistic basis for the enhanced activity observed in the combined blockade of VEGFR-2 and PD-1-axis pathways. Pre-clinical studies were conducted in murine tumor models known to be responsive to anti-PD-1 axis therapy, using monoclonal antibodies that block mouse VEGFR-2 and programmed death-ligand 1 (PD-L1). Combination therapy resulted in enhanced anti-tumor activity compared to anti-PD-L1 monotherapy. VEGFR-2 blockade at early timepoints post-anti-PD-L1 therapy resulted in a dose-dependent and transient enhanced infiltration of T cells, and establishment of immunological memory. VEGFR-2 blockade at later timepoints resulted in enhancement of anti-PD-L1-driven immune cell infiltration. VEGFR-2 and PD-L1 monotherapies induced both unique and overlapping patterns of immune gene expression, and combination therapy resulted in an enhanced immune activation signature. Collectively, these results provide new and actionable insights into the mechanisms by which concurrent VEGFR-2 and PD-L1 antibody therapy leads to enhanced anti-tumor efficacy.
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Affiliation(s)
- Yanxia Li
- Loxo Oncology at Lilly, Eli Lilly and Company, New York City, New York, United States of America
| | - Nelusha Amaladas
- Loxo Oncology at Lilly, Eli Lilly and Company, New York City, New York, United States of America
| | - Marguerita O’Mahony
- Loxo Oncology at Lilly, Eli Lilly and Company, New York City, New York, United States of America
| | - Jason R. Manro
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America
| | - Ivan Inigo
- Loxo Oncology at Lilly, Eli Lilly and Company, New York City, New York, United States of America
| | - Qi Li
- Loxo Oncology at Lilly, Eli Lilly and Company, New York City, New York, United States of America
| | - Erik R. Rasmussen
- Lilly Research Laboratories, Eli Lilly and Company, New York City, New York, United States of America
| | - Manisha Brahmachary
- Lilly Research Laboratories, Eli Lilly and Company, New York City, New York, United States of America
| | - Thompson N. Doman
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America
| | - Gerald Hall
- Loxo Oncology at Lilly, Eli Lilly and Company, New York City, New York, United States of America
| | - Michael Kalos
- Lilly Research Laboratories, Eli Lilly and Company, New York City, New York, United States of America
| | - Ruslan Novosiadly
- Lilly Research Laboratories, Eli Lilly and Company, New York City, New York, United States of America
| | - Oscar Puig
- Lilly Oncology, Alexandria Center for Life Sciences, New York City, New York, United States of America
- * E-mail:
| | - Bronislaw Pytowski
- Loxo Oncology at Lilly, Eli Lilly and Company, New York City, New York, United States of America
| | - David A. Schaer
- Loxo Oncology at Lilly, Eli Lilly and Company, New York City, New York, United States of America
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12
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Brown S, Dayan JH, Coriddi M, Campbell A, Kuonqui K, Shin J, Park HJ, Mehrara BJ, Kataru RP. Pharmacological Treatment of Secondary Lymphedema. Front Pharmacol 2022; 13:828513. [PMID: 35145417 PMCID: PMC8822213 DOI: 10.3389/fphar.2022.828513] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 01/07/2022] [Indexed: 12/12/2022] Open
Abstract
Lymphedema is a chronic disease that results in swelling and decreased function due to abnormal lymphatic fluid clearance and chronic inflammation. In Western countries, lymphedema most commonly develops following an iatrogenic injury to the lymphatic system during cancer treatment. It is estimated that as many as 10 million patients suffer from lymphedema in the United States alone. Current treatments for lymphedema are palliative in nature, relying on compression garments and physical therapy to decrease interstitial fluid accumulation in the affected extremity. However, recent discoveries have increased the hopes of therapeutic interventions that may promote lymphatic regeneration and function. The purpose of this review is to summarize current experimental pharmacological strategies in the treatment of lymphedema.
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13
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Xia Q, Dong H, Guo Y, Fang K, Hu M, Xu L, Lu F, Gong J. The role of lacteal integrity and junction transformation in obesity: A promising therapeutic target? Front Endocrinol (Lausanne) 2022; 13:1007856. [PMID: 36506056 PMCID: PMC9729342 DOI: 10.3389/fendo.2022.1007856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 11/08/2022] [Indexed: 11/26/2022] Open
Abstract
Lacteals are the central lymphatic vessels in the villi of the small intestine and perform nutrient absorption, especially dietary lipids, and the transportation of antigen and antigen-presenting cells. Remodeling, proliferation, and cell-cell junctions of lymphatic endothelial cells (LECs) in lacteals are the basis of the maintenance of lacteal integrity and dietary lipid absorption. Normal lipid absorption in the diet depends on sound lacteal development and proliferation, especially integrity maintenance, namely, maintaining the appropriate proportion of button-like and zipper-like junctions. Maintaining the integrity and transforming button-to-zipper junctions in lacteals are strongly connected with obesity, which could be regulated by intestinal flora and molecular signalings, such as vascular endothelial growth factor C-vascular endothelial growth receptor 3 (VEGFC-VEGFR3) signaling, Hippo signaling, Notch signaling, angiopoietin-TIE signaling, VEGF-A/VEGFR2 signaling, and PROX1. This manuscript reviews the molecular mechanism of development, integrity maintenance, and junction transformation in lacteal related to obesity.
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Affiliation(s)
- Qingsong Xia
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hui Dong
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yujin Guo
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ke Fang
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Meilin Hu
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Lijun Xu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Fuer Lu
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- *Correspondence: Jing Gong, ; Fuer Lu,
| | - Jing Gong
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- *Correspondence: Jing Gong, ; Fuer Lu,
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14
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Yin Y, Zhu ZX, Li Z, Chen YS, Zhu WM. Role of mesenteric component in Crohn’s disease: A friend or foe? World J Gastrointest Surg 2021; 13:1536-1549. [PMID: 35070062 PMCID: PMC8727179 DOI: 10.4240/wjgs.v13.i12.1536] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 08/01/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
Crohn’s disease (CD) is a complex and relapsing gastrointestinal disease with mesenteric alterations. The mesenteric neural, vascular, and endocrine systems actively take part in the gut dysbiosis-adaptive immunity-mesentery-body axis, and this axis has been proven to be bidirectional. The abnormalities of morphology and function of the mesenteric component are associated with intestinal inflammation and disease progress of CD via responses to afferent signals, neuropeptides, lymphatic drainage, adipokines, and functional cytokines. The hypertrophy of mesenteric adipose tissue plays important roles in the pathogenesis of CD by secreting large amounts of adipokines and representing a rich source of proinflammatory or profibrotic cytokines. The vascular alteration, including angiogenesis and lymphangiogenesis, is concomitant in the disease course of CD. Of note, the enlarged and obstructed lymphatic vessels, which have been described in CD patients, are likely related to the early onset submucosa edema and being a cause of CD. The function of mesenteric lymphatics is influenced by endocrine of mesenteric nerves and adipocytes. Meanwhile, the structure of the mesenteric lymphatic vessels in hypertrophic mesenteric adipose tissue is mispatterned and ruptured, which can lead to lymph leakage. Leaky lymph factors can in turn stimulate adipose tissue to proliferate and effectively elicit an immune response. The identification of the role of mesentery and the crosstalk between mesenteric tissues in intestinal inflammation may shed light on understanding the underlying mechanism of CD and help explore new therapeutic targets.
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Affiliation(s)
- Yi Yin
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Zhen-Xing Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Zhun Li
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Yu-Sheng Chen
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Wei-Ming Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
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15
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Lin J, Chen Y, Zhu H, Cheng K, Wang H, Yu X, Tang M, Chen J. Lymphatic Reconstruction in Kidney Allograft Aggravates Chronic Rejection by Promoting Alloantigen Presentation. Front Immunol 2021; 12:796260. [PMID: 34956231 PMCID: PMC8695730 DOI: 10.3389/fimmu.2021.796260] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 11/22/2021] [Indexed: 12/13/2022] Open
Abstract
Chronic rejection of the renal allograft remains a major cause of graft loss. Here, we demonstrated that the remodeling of lymphatic vessels (LVs) after their broken during transplantation contributes to the antigen presenting and lymph nodes activating. Our studies observed a rebuilt of interrupted lymph draining one week after mouse kidney transplantation, involving preexisting lymphatic endothelial cells (LECs) from both the donor and recipient. These expanding LVs also release C-C chemokine ligand 21 (CCL21) and recruit CCR7+ cells, mainly dendritic cells (DCs), toward lymph nodes and spleen, evoking the adaptive response. This rejection could be relieved by LYVE-1 specific LVs knockout or CCR7 migration inhibition in mouse model. Moreover, in retrospective analysis, posttransplant patients exhibiting higher area density of LVs presented with lower eGFR, severe serum creatinine and proteinuria, and greater interstitial fibrosis. These results reveal a rebuilt pathway for alloantigen trafficking and lymphocytes activation, providing strategies to alleviate chronic transplantation rejection.
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Affiliation(s)
- Jinwen Lin
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Ying Chen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Huijuan Zhu
- Department of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Kai Cheng
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Huiping Wang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xianping Yu
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Mengmeng Tang
- Department of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jianghua Chen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China,*Correspondence: Jianghua Chen,
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16
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Yin Y, Yang J, Pan Y, Guo Z, Gao Y, Huang L, Zhou D, Ge Y, Guo F, Zhu W, Song Y, Li Y. Chylomicrons-Simulating Sustained Drug Release in Mesenteric Lymphatics for the Treatment of Crohn's-Like Colitis. J Crohns Colitis 2021; 15:631-646. [PMID: 32978613 DOI: 10.1093/ecco-jcc/jjaa200] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND AND AIMS Alteration to both the structures and functions of mesenteric lymphatic vessels is a typical hallmark of Crohn's disease [CD]. Dysfunctional lymphatics was observed in patients with both CD and experimental colitis, suggesting mesenteric lymphatics could be potential therapeutic targets. This study aimed to develop a nano-delivery system which can enhance drug delivery in mesenteric lymphatic tissue [MLT] and evaluate the therapeutic effects in Crohn's colitis. METHODS We designed a mesoporous silica nanoparticle [MSN] conjugated with long-chain fatty acid [LMSN] and covered with enteric coating [ELMSN] which can be specifically transported via the mesenteric lymphatic system. The therapeutic efficacy of laquinimod-loaded nanoparticles [LAQ@ELMSN] was evaluated in the well-established interleukin [IL]-10-/- spontaneous experimental colitis. RESULTS ELMSNs induced sustainable drug release that markedly increased drug concentration in MLT. In experimental colitis, the lymphatics-targeting drug delivery system suppressed lymphangitis and promoted lymphatic drainage. The downregulation of pro-inflammatory cytokines and the downstream NF-κB-related proteins efficiently inhibited lymphangiogenesis and restored tight junctions of mesenteric lymphatic vessels [MLVs]. LAQ@ELMSN showed a superior therapeutic effect in ameliorating intestinal inflammation compared with free drug administration. Alteration of gut microbiota and metabolites in experimental colitis was also reversed by LAQ@ELMSN. CONCLUSION Our study demonstrates a convenient, orally administered drug delivery system which enhances drug release in MLT. The results confirm the contribution of the mesenteric lymphatic system to the pathogenesis of gut inflammation and shed light on the application of lymphatics-targeting drug delivery therapy as a potential therapeutic strategy for CD treatment.
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Affiliation(s)
- Yi Yin
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jingjing Yang
- College of Engineering and Applied Sciences and Jiangsu Key Laboratory of Artificial Functional Materials, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, China
| | - Yongchun Pan
- College of Engineering and Applied Sciences and Jiangsu Key Laboratory of Artificial Functional Materials, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, China
| | - Zhen Guo
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yanfeng Gao
- College of Engineering and Applied Sciences and Jiangsu Key Laboratory of Artificial Functional Materials, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, China
| | - Liangyu Huang
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Dongtao Zhou
- College of Engineering and Applied Sciences and Jiangsu Key Laboratory of Artificial Functional Materials, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, China
| | - Yuanyuan Ge
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Feilong Guo
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Weiming Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yujun Song
- College of Engineering and Applied Sciences and Jiangsu Key Laboratory of Artificial Functional Materials, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, China
| | - Yi Li
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
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17
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Li W, Gauthier JM, Tong AY, Terada Y, Higashikubo R, Frye CC, Harrison MS, Hashimoto K, Bery AI, Ritter JH, Nava RG, Puri V, Wong BW, Lavine KJ, Bharat A, Krupnick AS, Gelman AE, Kreisel D. Lymphatic drainage from bronchus-associated lymphoid tissue in tolerant lung allografts promotes peripheral tolerance. J Clin Invest 2021; 130:6718-6727. [PMID: 33196461 DOI: 10.1172/jci136057] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 09/03/2020] [Indexed: 12/29/2022] Open
Abstract
Tertiary lymphoid organs are aggregates of immune and stromal cells including high endothelial venules and lymphatic vessels that resemble secondary lymphoid organs and can be induced at nonlymphoid sites during inflammation. The function of lymphatic vessels within tertiary lymphoid organs remains poorly understood. During lung transplant tolerance, Foxp3+ cells accumulate in tertiary lymphoid organs that are induced within the pulmonary grafts and are critical for the local downregulation of alloimmune responses. Here, we showed that tolerant lung allografts could induce and maintain tolerance of heterotopic donor-matched hearts through pathways that were dependent on the continued presence of the transplanted lung. Using lung retransplantation, we showed that Foxp3+ cells egressed from tolerant lung allografts via lymphatics and were recruited into donor-matched heart allografts. Indeed, survival of the heart allografts was dependent on lymphatic drainage from the tolerant lung allograft to the periphery. Thus, our work indicates that cellular trafficking from tertiary lymphoid organs regulates immune responses in the periphery. We propose that these findings have important implications for a variety of disease processes that are associated with the induction of tertiary lymphoid organs.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Jon H Ritter
- Pathology & Immunology, Washington University in St. Louis, St. Louis, Missouri, USA
| | | | | | | | | | - Ankit Bharat
- Department of Surgery, Northwestern University, Chicago, Illinois, USA
| | | | - Andrew E Gelman
- Departments of Surgery.,Pathology & Immunology, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Daniel Kreisel
- Departments of Surgery.,Pathology & Immunology, Washington University in St. Louis, St. Louis, Missouri, USA
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18
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Pro-lymphangiogenic VEGFR-3 signaling modulates memory T cell responses in allergic airway inflammation. Mucosal Immunol 2021; 14:144-151. [PMID: 32518367 PMCID: PMC7725864 DOI: 10.1038/s41385-020-0308-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 04/06/2020] [Accepted: 05/20/2020] [Indexed: 02/04/2023]
Abstract
In allergic airway inflammation, VEGFR-3-mediated lymphangiogenesis occurs in humans and mouse models, yet its immunological roles, particularly in adaptive immunity, are poorly understood. Here, we explored how pro-lymphangiogenic signaling affects the allergic response to house dust mite (HDM). In the acute inflammatory phase, the lungs of mice treated with blocking antibodies against VEGFR-3 (mF4-31C1) displayed less inflammation overall, with dramatically reduced innate and T-cell numbers and reduced inflammatory chemokine levels. However, when inflammation was allowed to resolve and memory recall was induced 2 months later, mice treated with mF4-31C1 as well as VEGF-C/-D knockout models showed exacerbated type 2 memory response to HDM, with increased Th2 cells, eosinophils, type 2 chemokines, and pathological inflammation scores. This was associated with lower CCL21 and decreased TRegs in the lymph nodes. Together, our data imply that VEGFR-3 activation in allergic airways helps to both initiate the acute inflammatory response and regulate the adaptive (memory) response, possibly in part by shifting the TReg/Th2 balance. This introduces new immunomodulatory roles for pro-lymphangiogenic VEGFR-3 signaling in allergic airway inflammation and suggests that airway lymphatics may be a novel target for treating allergic responses.
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19
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Duru G, van Egmond M, Heemskerk N. A Window of Opportunity: Targeting Cancer Endothelium to Enhance Immunotherapy. Front Immunol 2020; 11:584723. [PMID: 33262763 PMCID: PMC7686513 DOI: 10.3389/fimmu.2020.584723] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 10/19/2020] [Indexed: 12/19/2022] Open
Abstract
Vascular abnormalities in tumors have a major impact on the immune microenvironment in tumors. The consequences of abnormal vasculature include increased hypoxia, acidosis, high intra-tumoral fluid pressure, and angiogenesis. This introduces an immunosuppressive microenvironment that alters immune cell maturation, activation, and trafficking, which supports tumor immune evasion and dissemination of tumor cells. Increasing data suggests that cancer endothelium is a major barrier for traveling leukocytes, ranging from a partial blockade resulting in a selective endothelial barrier, to a complete immune infiltration blockade associated with immune exclusion and immune desert cancer phenotypes. Failed immune cell trafficking as well as immunosuppression within the tumor microenvironment limits the efficacy of immunotherapeutic approaches. As such, targeting proteins with key roles in angiogenesis may potentially reduce immunosuppression and might restore infiltration of anti-tumor immune cells, creating a therapeutic window for successful immunotherapy. In this review, we provide a comprehensive overview of established as well as more controversial endothelial pathways that govern selective immune cell trafficking across cancer endothelium. Additionally, we discuss recent insights and strategies that target tumor vasculature in order to increase infiltration of cytotoxic immune cells during the therapeutic window of vascular normalization hereby improving the efficacy of immunotherapy.
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Affiliation(s)
- Gizem Duru
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection & Immunity, Amsterdam, Netherlands
| | - Marjolein van Egmond
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection & Immunity, Amsterdam, Netherlands
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Surgery, Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Niels Heemskerk
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection & Immunity, Amsterdam, Netherlands
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20
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Kumar AS, Kamalasanan K. Drug delivery to optimize angiogenesis imbalance in keloid: A review. J Control Release 2020; 329:1066-1076. [PMID: 33091533 DOI: 10.1016/j.jconrel.2020.10.035] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 10/16/2020] [Accepted: 10/17/2020] [Indexed: 12/12/2022]
Abstract
The wound healing process involves three continuous stages. Where, any imbalance can lead to the formation of unwanted keloids, hypertrophic scar, or tumors. Keloids are any unpleasant, non-compliant comorbidity affecting a major section of people around the globe who acquire it either genetically or by pathological means as a result of a skin injury. Angiogenesis is unavoidable in the healing process after an injury or disruption of skin to promote tissue regeneration. Uncontrolled angiogenesis during the healing process can initiate the unwanted response in the wound that facilitate keloid. Angiogenic therapy is adapted to accelerate healing after an injury. Else ways, there exists a risk of keloid formation due to excessive angiogenesis during the wound healing process. There are numerous strategies to treat keloid. Anti-angiogenic factors are provided to patients post-surgery to prevent the keloid formation; however, they come into the picture after the formation of keloid. The available strategies to treat keloids are steroidal injections, surgical excision of the keloid, radiotherapy, pressure therapy, the use of cryosurgery, and many more. The available treatments are not promising in reducing the recurrent rate of keloids as there are chances of high re-occurrences with similar/larger lesions on the removed keloid site. In this review, we are discussing the importance of controlled angiogenesis with the help of controlled drug delivery strategies enabling the wound healing process without the induction of keloid.
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Affiliation(s)
- Aishwari S Kumar
- Department of Pharmaceutics, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, AIMS Ponekkara PO, Kochi, Kerala, 682041, India
| | - Kaladhar Kamalasanan
- Department of Pharmaceutics, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, AIMS Ponekkara PO, Kochi, Kerala, 682041, India.
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21
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Lymphatic Endothelial Cell Progenitors in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1234:87-105. [PMID: 32040857 DOI: 10.1007/978-3-030-37184-5_7] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Tumor lymphatics play a key role in cancer progression as they are solely responsible for transporting malignant cells to regional lymph nodes (LNs), a process that precedes and promotes systemic lethal spread. It is broadly accepted that tumor lymphatic sprouting is induced mainly by soluble factors derived from tumor-associated macrophages (TAMs) and malignant cells. However, emerging evidence strongly suggests that a subset of TAMs, myeloid-lymphatic endothelial cell progenitors (M-LECP), also contribute to the expansion of lymphatics through both secretion of paracrine factors and a self-autonomous mode. M-LECP are derived from bone marrow (BM) precursors of the monocyte-macrophage lineage and characterized by unique co-expression of markers identifying lymphatic endothelial cells (LEC), stem cells, M2-type macrophages, and myeloid-derived immunosuppressive cells. This review describes current evidence for the origin of M-LECP in the bone marrow, their recruitment tumors and intratumoral trafficking, similarities to other TAM subsets, and mechanisms promoting tumor lymphatics. We also describe M-LECP integration into preexisting lymphatic vessels and discuss potential mechanisms and significance of this event. We conclude that improved mechanistic understanding of M-LECP functions within the tumor environment may lead to new therapeutic approaches to suppress tumor lymphangiogenesis and metastasis to lymph nodes.
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22
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Endogenous Calcitonin Gene–Related Peptide Deficiency Exacerbates Postoperative Lymphedema by Suppressing Lymphatic Capillary Formation and M2 Macrophage Accumulation. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:2487-2502. [DOI: 10.1016/j.ajpath.2019.08.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 08/08/2019] [Accepted: 08/15/2019] [Indexed: 02/06/2023]
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23
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Sestito LF, Thomas SN. Biomaterials for Modulating Lymphatic Function in Immunoengineering. ACS Pharmacol Transl Sci 2019; 2:293-310. [PMID: 32259064 DOI: 10.1021/acsptsci.9b00047] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Indexed: 12/13/2022]
Abstract
Immunoengineering is a rapidly growing and interdisciplinary field focused on developing tools to study and understand the immune system, then employing that knowledge to modulate immune response for the treatment of disease. Because of its roles in housing a substantial fraction of the body's lymphocytes, in facilitating immune cell trafficking, and direct immune modulatory functions, among others, the lymphatic system plays multifaceted roles in immune regulation. In this review, the potential for biomaterials to be applied to regulate the lymphatic system and its functions to achieve immunomodulation and the treatment of disease are described. Three related processes-lymphangiogenesis, lymphatic vessel contraction, and lymph node remodeling-are specifically explored. The molecular regulation of each process and their roles in pathologies are briefly outlined, with putative therapeutic targets and the lymphatic remodeling that can result from disease highlighted. Applications of biomaterials that harness these pathways for the treatment of disease via immunomodulation are discussed.
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Affiliation(s)
- Lauren F Sestito
- Wallace H. Coulter Department of Biomedical Engineering, George W. Woodruff School of Mechanical Engineering, and Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive NW, Atlanta, Georgia 30332, United States.,Department of Biomedical Engineering, Emory University, 201 Dowman Drive, Atlanta, Georgia 30322, United States
| | - Susan N Thomas
- Wallace H. Coulter Department of Biomedical Engineering, George W. Woodruff School of Mechanical Engineering, and Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive NW, Atlanta, Georgia 30332, United States.,Department of Biomedical Engineering, Emory University, 201 Dowman Drive, Atlanta, Georgia 30322, United States.,Wallace H. Coulter Department of Biomedical Engineering, George W. Woodruff School of Mechanical Engineering, and Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive NW, Atlanta, Georgia 30332, United States.,Wallace H. Coulter Department of Biomedical Engineering, George W. Woodruff School of Mechanical Engineering, and Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive NW, Atlanta, Georgia 30332, United States.,Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road NW, Atlanta, Georgia 30322, United States
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24
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Pei G, Yao Y, Yang Q, Wang M, Wang Y, Wu J, Wang P, Li Y, Zhu F, Yang J, Zhang Y, Yang W, Deng X, Zhao Z, Zhu H, Ge S, Han M, Zeng R, Xu G. Lymphangiogenesis in kidney and lymph node mediates renal inflammation and fibrosis. SCIENCE ADVANCES 2019; 5:eaaw5075. [PMID: 31249871 PMCID: PMC6594767 DOI: 10.1126/sciadv.aaw5075] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 05/22/2019] [Indexed: 06/01/2023]
Abstract
Lymphangiogenesis is associated with chronic kidney disease (CKD) and occurs following kidney transplant. Here, we demonstrate that expanding lymphatic vessels (LVs) in kidneys and corresponding renal draining lymph nodes (RDLNs) play critical roles in promoting intrarenal inflammation and fibrosis following renal injury. Our studies show that lymphangiogenesis in the kidney and RDLN is driven by proliferation of preexisting lymphatic endothelium expressing the essential C-C chemokine ligand 21 (CCL21). New injury-induced LVs also express CCL21, stimulating recruitment of more CCR7+ dendritic cells (DCs) and lymphocytes into both RDLNs and spleen, resulting in a systemic lymphocyte expansion. Injury-induced intrarenal inflammation and fibrosis could be attenuated by blocking the recruitment of CCR7+ cells into RDLN and spleen or inhibiting lymphangiogenesis. Elucidating the role of lymphangiogenesis in promoting intrarenal inflammation and fibrosis provides a key insight that can facilitate the development of novel therapeutic strategies to prevent progression of CKD-associated fibrosis.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Rui Zeng
- Corresponding author. (G.X.); (R.Z.)
| | - Gang Xu
- Corresponding author. (G.X.); (R.Z.)
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25
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Bovay E, Sabine A, Prat-Luri B, Kim S, Son K, Willrodt AH, Olsson C, Halin C, Kiefer F, Betsholtz C, Jeon NL, Luther SA, Petrova TV. Multiple roles of lymphatic vessels in peripheral lymph node development. J Exp Med 2018; 215:2760-2777. [PMID: 30355615 PMCID: PMC6219737 DOI: 10.1084/jem.20180217] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 08/15/2018] [Accepted: 10/04/2018] [Indexed: 12/18/2022] Open
Abstract
This work shows how blood and lymphatic vessels contribute to lymph node organogenesis. Both vessel types transport lymphoid tissue inducer cells, while lymphatics also generate interstitial flow, important for mechanical stromal activation and further lymph node expansion. The mammalian lymphatic system consists of strategically located lymph nodes (LNs) embedded into a lymphatic vascular network. Mechanisms underlying development of this highly organized system are not fully understood. Using high-resolution imaging, we show that lymphoid tissue inducer (LTi) cells initially transmigrate from veins at LN development sites using gaps in venous mural coverage. This process is independent of lymphatic vasculature, but lymphatic vessels are indispensable for the transport of LTi cells that egress from blood capillaries elsewhere and serve as an essential LN expansion reservoir. At later stages, lymphatic collecting vessels ensure efficient LTi cell transport and formation of the LN capsule and subcapsular sinus. Perinodal lymphatics also promote local interstitial flow, which cooperates with lymphotoxin-β signaling to amplify stromal CXCL13 production and thereby promote LTi cell retention. Our data unify previous models of LN development by showing that lymphatics intervene at multiple points to assist LN expansion and identify a new role for mechanical forces in LN development.
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Affiliation(s)
- Esther Bovay
- Department of Oncology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Epalinges, Switzerland
| | - Amélie Sabine
- Department of Oncology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Epalinges, Switzerland
| | - Borja Prat-Luri
- Department of Oncology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Epalinges, Switzerland
| | - Sudong Kim
- School of Mechanical and Aerospace Engineering, Seoul National University, Seoul, Republic of Korea
| | - Kyungmin Son
- School of Mechanical and Aerospace Engineering, Seoul National University, Seoul, Republic of Korea
| | | | - Cecilia Olsson
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Cornelia Halin
- Institute of Pharmaceutical Sciences, ETH Zürich, Zürich, Switzerland
| | - Friedemann Kiefer
- Max Planck Institute for Molecular Biomedicine, Münster, Germany.,European Institute for Molecular Imaging, University of Münster, Münster, Germany
| | - Christer Betsholtz
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.,Integrated Cardio Metabolic Centre, Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden
| | - Noo Li Jeon
- School of Mechanical and Aerospace Engineering, Seoul National University, Seoul, Republic of Korea
| | - Sanjiv A Luther
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
| | - Tatiana V Petrova
- Department of Oncology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Epalinges, Switzerland .,Ludwig Institute for Cancer Research, Epalinges, Switzerland.,Swiss Institute for Experimental Cancer Research, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.,Division of Experimental Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
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26
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Kwon S, Velasquez FC, Sevick-Muraca EM. Near-infrared fluorescence lymphatic imaging in vascular endothelial growth factor-C overexpressing murine melanoma. BIOMEDICAL OPTICS EXPRESS 2018; 9:4631-4637. [PMID: 30319891 PMCID: PMC6179422 DOI: 10.1364/boe.9.004631] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 07/31/2018] [Accepted: 08/10/2018] [Indexed: 06/08/2023]
Abstract
In this study we employ a near-infrared fluorescence lymphatic imaging (NIRFLI) technique to longitudinally image spatial and temporal changes in the lymphatics in mice bearing vascular endothelial growth factor (VEGF)-C overexpressing B16F10 (VEGF-C-B16F10) or mock-transduced B16F10 (mock-B16F10) melanoma tumors. Our NIRFLI data show that ICG-laden lymph accumulates into a VEGF-C-B16F10 tumor compared to mock-B16F10 at 3 days post implantation, presumably due to increased lymphatic vessel permeability. Quantification shows a significantly greater percentage of ICG-perfused area in VEGF-C-B16F10 (7.6 ± 2) as compared to MOCK-B16F10 (1 ± 0.5; p = 0.02), which is also confirmed by quantification of the lymphatic leakage of evans blue dye (optical density at 610nm; VEGF-C-B16F10, 10.5 ± 2; mock-B16F10, 5.1 ± 0.5; p = 0.009); thereafter, lymphatic leakage is visualized only in the peritumoral region. Our imaging data also show that anti-VEGF-C treatment in VEGF-C-B16F10 restores normal lymphatic vessel integrity and reduces dye extravasation. Because NIRFLI technology can be used to non-invasively detect lymphatic changes associated with cancer, it may provide a new diagnostic to assess the lack of lymphatic vessel integrity that promotes lymphovascular invasion and to assess therapies that could arrest invasion through normalization of the lymphatic vasculature.
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27
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García-Vilas JA, Medina MÁ. Updates on the hepatocyte growth factor/c-Met axis in hepatocellular carcinoma and its therapeutic implications. World J Gastroenterol 2018; 24:3695-3708. [PMID: 30197476 PMCID: PMC6127652 DOI: 10.3748/wjg.v24.i33.3695] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 06/28/2018] [Accepted: 07/16/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer and is the second leading cause of cancer death. Since the diagnosis of HCC is difficult, in many cases patients with HCC are diagnosed advanced stage of development. Hepatocyte growth factor (HGF)/c-mesenchymal-epithelial transition receptor (c-Met) axis is a key signaling pathway in HCC, either via canonical or non-canonical pathways. Available treatments against HCC based upon HGF/c-Met inhibition can increase patient lifespan, but do not reach the expected therapeutic benefits. In HCC, c-Met monomers can bind other receptor monomers, activating several noncanonical signaling pathways, leading to increased cell proliferation, invasion, motility, and drug resistance. All of these processes are enhanced by the tumor microenvironment, with stromal cells contributing to boost tumor progression through oxidative stress, angiogenesis, lymphangiogenesis, inflammation, and fibrosis. Novel treatments against HCC are being explored to modulate other targets such as microRNAs, methyltransferases, and acetyltransferases, which are all involved in the regulation of gene expression in cancer. This review compiles basic knowledge regarding signaling pathways in HCC, and compounds already used or showing potential to be used in clinical trials.
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Affiliation(s)
| | - Miguel Ángel Medina
- Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, Andalucía Tech, Universidad de Málaga, Málaga 29071, Spain
- Unidad 741 de CIBER “de Enfermedades Raras” (CIBERER), Málaga 29071, Spain
- Institute of Biomedical Research in Málaga, Málaga 29071, Spain
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28
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Sha M, Jeong S, Chen XS, Tong Y, Cao J, Sun HY, Xia L, Xu N, Wang X, Han LZ, Xi ZF, Zhang JJ, Kong XN, Xia Q. Expression of VEGFR-3 in intrahepatic cholangiocarcinoma correlates with unfavorable prognosis through lymphangiogenesis. Int J Biol Sci 2018; 14:1333-1342. [PMID: 30123080 PMCID: PMC6097481 DOI: 10.7150/ijbs.26045] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 07/03/2018] [Indexed: 12/15/2022] Open
Abstract
Background & aims: VEGFR-3 has been shown of great significance in lymph node metastasis and some malignancies, however, its expression in tumors and impact on outcome of intrahepatic cholangiocarcinoma (iCCA) remains unknown. The aim of this study was to assess the role of VEGFR-3 positive tumors for prognosis of iCCA and tumor-associated lymphangiogenesis. Methods: Clinicopathological features, prognostic factors and survival rate were analyzed to evaluate the influence of VEGFR-3 positive expression on prognosis of iCCA. In addition, tumor-associated lymphangiogenesis quantified as micro-lymphatic vessel density (MLVD) was assessed to explore the correlation between VEGFR-3 expression and lymph node metastasis for iCCA. Results: Patients with VEGFR-3 positive tumors had increased lymph node metastasis (p=0.025) and were more likely to suffer from tumor recurrence compared with VEGFR-3 negative tumors (p<0.001). VEGFR-3 expression in tumors was identified as an independent prognostic factor for both overall and recurrence-free survival in surgical resected patients with iCCA. In addition, higher MLVD was significantly associated with VEGFR-3 positive expression in tumors (p<0.001), which facilitate lymph node metastasis and significantly worse survival rates. Conclusions: Our study reveals that VEGFR-3 positive expression in tumors represents an independent prognostic factor for both overall and recurrence-free survival in hepatic resected patients with iCCA. VEGFR-3 positive tumors favor lymph node metastasis, tumor recurrence and worse outcomes through tumor-associated lymphangiogenesis.
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Affiliation(s)
- Meng Sha
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China
| | - Seogsong Jeong
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China
| | - Xiao-Song Chen
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China
| | - Ying Tong
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China
| | - Jie Cao
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China
| | - Han-Yong Sun
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China
| | - Lei Xia
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China
| | - Ning Xu
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China
| | - Xin Wang
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China
| | - Long-Zhi Han
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China
| | - Zhi-Feng Xi
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China
| | - Jian-Jun Zhang
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China
| | - Xiao-Ni Kong
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China
| | - Qiang Xia
- Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 Dongfang Road, Shanghai, 200127, China
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29
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Jha SK, Rauniyar K, Jeltsch M. Key molecules in lymphatic development, function, and identification. Ann Anat 2018; 219:25-34. [PMID: 29842991 DOI: 10.1016/j.aanat.2018.05.003] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 05/02/2018] [Accepted: 05/03/2018] [Indexed: 12/18/2022]
Abstract
While both blood and lymphatic vessels transport fluids and thus share many similarities, they also show functional and structural differences, which can be used to differentiate them. Specific visualization of lymphatic vessels has historically been and still is a pivot point in lymphatic research. Many of the proteins that are investigated by molecular biologists in lymphatic research have been defined as marker molecules, i.e. to visualize and distinguish lymphatic endothelial cells (LECs) from other cell types, most notably from blood vascular endothelial cells (BECs) and cells of the hematopoietic lineage. Among the factors that drive the developmental differentiation of lymphatic structures from venous endothelium, Prospero homeobox protein 1 (PROX1) is the master transcriptional regulator. PROX1 maintains lymphatic identity also in the adult organism and thus is a universal LEC marker. Vascular endothelial growth factor receptor-3 (VEGFR-3) is the major tyrosine kinase receptor that drives LEC proliferation and migration. The major activator for VEGFR-3 is vascular endothelial growth factor-C (VEGF-C). However, before VEGF-C can signal, it needs to be proteolytically activated by an extracellular protein complex comprised of Collagen and calcium binding EGF domains 1 (CCBE1) protein and the protease A disintegrin and metallopeptidase with thrombospondin type 1 motif 3 (ADAMTS3). This minireview attempts to give an overview of these and a few other central proteins that scientific inquiry has linked specifically to the lymphatic vasculature. It is limited in scope to a brief description of their main functions, properties and developmental roles.
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Affiliation(s)
- Sawan Kumar Jha
- Translational Cancer Biology Research Program, University of Helsinki, Finland
| | - Khushbu Rauniyar
- Translational Cancer Biology Research Program, University of Helsinki, Finland
| | - Michael Jeltsch
- Translational Cancer Biology Research Program, University of Helsinki, Finland; Wihuri Research Institute, Biomedicum Helsinki, Finland.
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30
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He W, Zhong G, Jiang N, Wang B, Fan X, Chen C, Chen X, Huang J, Lin T. Long noncoding RNA BLACAT2 promotes bladder cancer-associated lymphangiogenesis and lymphatic metastasis. J Clin Invest 2018; 128:861-875. [PMID: 29355840 PMCID: PMC5785244 DOI: 10.1172/jci96218] [Citation(s) in RCA: 150] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 12/07/2017] [Indexed: 12/11/2022] Open
Abstract
The prognosis for bladder cancer patients with lymph node (LN) metastasis is dismal and only minimally improved by current treatment modalities. Elucidation of the molecular mechanisms that underlie LN metastasis may provide clinical therapeutic strategies for LN-metastatic bladder cancer. Here, we report that a long noncoding RNA LINC00958, which we have termed bladder cancer-associated transcript 2 (BLACAT2), was markedly upregulated in LN-metastatic bladder cancer and correlated with LN metastasis. Overexpression of BLACAT2 promoted bladder cancer-associated lymphangiogenesis and lymphatic metastasis in both cultured bladder cancer cell lines and mouse models. Furthermore, we demonstrate that BLACAT2 epigenetically upregulated VEGF-C expression by directly associating with WDR5, a core subunit of human H3K4 methyltransferase complexes. Importantly, administration of an anti-VEGF-C antibody inhibited LN metastasis in BLACAT2-overexpressing bladder cancer. Taken together, these findings uncover a molecular mechanism in the lymphatic metastasis of bladder cancer and indicate that BLACAT2 may represent a target for clinical intervention in LN-metastatic bladder cancer.
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31
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Li M, Chen H, Diao L, Zhang Y, Xia C, Yang F. Caveolin-1 and VEGF-C promote Lymph Node Metastasis in the Absence of Intratumoral Lymphangiogenesis in Non-small Cell Lung Cancer. TUMORI JOURNAL 2018; 96:734-43. [DOI: 10.1177/030089161009600516] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Aims and background Caveolin-1 is a key component of membrane caveolae which plays an important role in cell transformation, cell migration, metastasis and angiogenesis. The mechanism of caveolin-1 and VEGF-C in lymphatic metastasis of non-small cell lung cancer (NSCLC) is still unclear. This study aimed to define the caveolin-1 and VEGF-C expression and lymph vessel density in NSCLC and look for correlations with clinicopathological features in NSCLC. Methods Caveolin-1, VEGF-C, and D2–40 protein expression were assessed by immunohistochemistry in a tissue microarray constructed from 70 NSCLCs and 12 normal lungs. Results Caveolin-1 expression was detected in 31 of 70 (44.3%) NSCLCs, which was significantly lower than its expression in normal lungs (9 of 12, 75%; P = 0.049). Expression of VEGF-C was detected in 49 of 70 (70%) NSCLCs and 4 of 12 (33.3%) normal lungs (P = 0.022). Both caveolin-1 and VEGF-C expression were correlated with lymph node metastasis of NSCLC (P = 0.001; P = 0.028). Moreover, caveolin-1 expression was correlated with tumor stage, histological type, and differentiation grade (P = 0.012; P = 0.038; P = 0.002). VEGF-C expression was correlated only with histological type (P = 0.020). There was no correlation between intratumoral lymph vessel density and any clinicopathological parameters including lymph node status. Furthermore, there was no correlation between caveolin-1 expression, VEGF-C expression, and lymph vessel density. Conclusions These findings indicated a reduction of caveolin-1 expression in NSCLC and suggested that caveolin-1 as well as VEGF-C might be involved in lymph node metastasis of NSCLC. The role of caveolin-1 in lymphatic metastasis and intratumoral lymphangiogenesis in NSCLC needs further study. Free full text available at www.tumorionline.it
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Affiliation(s)
- Minhua Li
- Department of Pathology, School of Basic Medicine Science, Wuhan University, Wuhan
- Department of Pathology, Shaoxing People's Hospital & The First Affiliated Hospital of Shaoxing University, Shaoxing
| | - Honglei Chen
- Department of Pathology, School of Basic Medicine Science, Wuhan University, Wuhan
| | - Luming Diao
- Department of Pathology, School of Basic Medicine Science, Wuhan University, Wuhan
| | - Yuxia Zhang
- Department of Pathology, School of Basic Medicine Science, Wuhan University, Wuhan
| | - Cong Xia
- Medical school, Jianghan University, Wuhan, China
| | - Fei Yang
- Department of Pathology, School of Basic Medicine Science, Wuhan University, Wuhan
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Emerging Roles for VEGF-D in Human Disease. Biomolecules 2018; 8:biom8010001. [PMID: 29300337 PMCID: PMC5871970 DOI: 10.3390/biom8010001] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 12/22/2017] [Accepted: 12/28/2017] [Indexed: 12/21/2022] Open
Abstract
Blood vessels and lymphatic vessels are located in many tissues and organs throughout the body, and play important roles in a wide variety of prevalent diseases in humans. Vascular endothelial growth factor-D (VEGF-D) is a secreted protein that can promote the remodeling of blood vessels and lymphatics in development and disease. Recent fundamental and translational studies have provided insight into the molecular mechanisms by which VEGF-D exerts its effects in human disease. Hence this protein is now of interest as a therapeutic and/or diagnostic target, or as a potential therapeutic agent, in a diversity of indications in cardiovascular medicine, cancer and the devastating pulmonary condition lymphangioleiomyomatosis. This has led to clinical trial programs to assess the effect of targeting VEGF-D signaling pathways, or delivering VEGF-D, in angina, cancer and ocular indications. This review summarizes our understanding of VEGF-D signaling in human disease, which is largely based on animal disease models and clinicopathological studies, and provides information about the outcomes of recent clinical trials testing agonists or antagonists of VEGF-D signaling.
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Kilarski WW, Güç E, Swartz MA. Dorsal Ear Skin Window for Intravital Imaging and Functional Analysis of Lymphangiogenesis. Methods Mol Biol 2018; 1846:261-277. [PMID: 30242765 DOI: 10.1007/978-1-4939-8712-2_17] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Postdevelopmental lymphangiogenesis occurs in chronic inflammation and wound healing, and here we describe a window preparation in the mouse ear in which lymphangiogenesis can be observed and manipulated. This model has many advantages, including access for intravital immunostaining and imaging to assess morphological features and regeneration kinetics, as well as functional assays such as lymphatic clearance. We describe five procedures: (1) the creation of a collagen-fibrin-filled window in the mouse ear as a model for regenerative lymphangiogenesis, (2) intravital immunostaining for live analysis of morphology and structure, (3) lymphatic clearance assay for functional quantification, (4) whole-mount imaging with tissue clearing for confocal imaging, and (5) postmortem lymphangiography. These procedures allow for identification of morphological and functional abnormalities in both preexisting and newly formed lymphatic vessels.
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Affiliation(s)
- Witold W Kilarski
- Institute for Molecular Engineering, The University of Chicago, Chicago, IL, USA.
| | - Esra Güç
- MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh Scotland, IL, USA
| | - Melody A Swartz
- Institute for Molecular Engineering, The University of Chicago, Chicago, IL, USA
- MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh Scotland, IL, USA
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Zhang W, Liu B, Feng Y, Liu J, Ma Z, Zheng J, Xia Q, Ni Y, Li F, Lin R. Anti-angiogenic activity of water extract from Euphorbia pekinensis Rupr. JOURNAL OF ETHNOPHARMACOLOGY 2017; 206:337-346. [PMID: 28602865 DOI: 10.1016/j.jep.2017.05.033] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 05/11/2017] [Accepted: 05/27/2017] [Indexed: 06/07/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Euphorbia pekinensis Rupr. (EP) is a Euphorbia species of Euphorbiaceae, which is widely used in traditional Chinese medicine. It has been reported to exhibit therapeutic effects on solid tumors, leukemias, and malignant ascites although underlying molecular mechanisms are poorly delineated. Anti-angiogenic therapy is a recognized strategy for treating cancer-based solid tumors, and is also associated with malignant ascites treatment. STUDY AIM To study the anti-angiogenic properties of the water extract of EP vinegar preparation (WEVEP). MATERIALS AND METHODS Following WEVEP treatment, intersegmental blood vessels were assessed during the development of transgenic Tg (flk: mCherry) zebrafish as was the proliferation, migration and network formation of HUVECs in vitro. mRNA expression of specific angiogenic-related genes including VEGF family members, Met, and NRP2 was also measured using quantitative real-time PCR (Q-PCR). RESULTS Data demonstrated that angiogenesis was inhibited by the WEVEP in zebrafish (from 100µg/mL to 250µg/mL, p < 0.0001) and in the HUVEC model (from 100µg/mL to 400µg/mL, p < 0.0001). In the zebrafish model, the mean vessel numbers of administered groups were 26.00 ± 1.29 (100µg/mL), 24.54 ± 2.20 (150µg/mL), 22.66 ± 2.68 (200µg/mL), 20.80 ± 1.75 (250µg/mL), compared to 27.67 ± 0.96 of control group. Relative quantitative gene expression in zebrafish treated with WEVEP demonstrated that only VEGFR3 was significantly increased and other 23 genes including Met, VEGFA, Flt-1 were significantly decreased. CONCLUSION WEVEP can positively modulate angiogenesis via multiple targeting mechanisms. Our novel results contribute towards the discovery of a possible mechanism(s) of the traditional use of EP in the treatment of cancer and malignant ascites.
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Affiliation(s)
- Wenting Zhang
- Beijing Key Lab for Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China.
| | - Bin Liu
- Beijing Key Lab for Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| | - Yaru Feng
- Beijing Key Lab for Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| | - Jie Liu
- Department of Ethnodrug, National Institute of Traditional Chinese Medicine, National Institutes for Food and Drug Control, Beijing 100050, China
| | - Zhiqiang Ma
- Beijing Key Lab for Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| | - Jian Zheng
- Department of Ethnodrug, National Institute of Traditional Chinese Medicine, National Institutes for Food and Drug Control, Beijing 100050, China
| | - Qing Xia
- Beijing Key Lab for Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| | - Yuanyuan Ni
- Beijing Key Lab for Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| | - Farong Li
- Key Laboratory of Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shanxi Normal University, Xi'an 710062, China
| | - Ruichao Lin
- Beijing Key Lab for Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China.
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Paquet-Fifield S, Roufail S, Zhang YF, Sofian T, Byrne DJ, Coughlin PB, Fox SB, Stacker SA, Achen MG. The fibrinolysis inhibitor α 2-antiplasmin restricts lymphatic remodelling and metastasis in a mouse model of cancer. Growth Factors 2017; 35:61-75. [PMID: 28697634 DOI: 10.1080/08977194.2017.1349765] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Remodelling of lymphatic vessels in tumours facilitates metastasis to lymph nodes. The growth factors VEGF-C and VEGF-D are well known inducers of lymphatic remodelling and metastasis in cancer. They are initially produced as full-length proteins requiring proteolytic processing in order to bind VEGF receptors with high affinity and thereby promote lymphatic remodelling. The fibrinolytic protease plasmin promotes processing of VEGF-C and VEGF-D in vitro, but its role in processing them in cancer was unknown. Here we explore plasmin's role in proteolytically activating VEGF-D in vivo, and promoting lymphatic remodelling and metastasis in cancer, by co-expressing the plasmin inhibitor α2-antiplasmin with VEGF-D in a mouse tumour model. We show that α2-antiplasmin restricts activation of VEGF-D, enlargement of intra-tumoural lymphatics and occurrence of lymph node metastasis. Our findings indicate that the fibrinolytic system influences lymphatic remodelling in tumours which is consistent with previous clinicopathological observations correlating fibrinolytic components with cancer metastasis.
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Affiliation(s)
- Sophie Paquet-Fifield
- a Tumour Angiogenesis and Microenvironment Program , Peter MacCallum Cancer Centre , Melbourne , Australia
| | - Sally Roufail
- a Tumour Angiogenesis and Microenvironment Program , Peter MacCallum Cancer Centre , Melbourne , Australia
| | - You-Fang Zhang
- a Tumour Angiogenesis and Microenvironment Program , Peter MacCallum Cancer Centre , Melbourne , Australia
| | - Trifina Sofian
- b Australian Centre for Blood Diseases , Monash University , Prahran, Melbourne , Australia
| | - David J Byrne
- a Tumour Angiogenesis and Microenvironment Program , Peter MacCallum Cancer Centre , Melbourne , Australia
- c Department of Pathology , Peter MacCallum Cancer Centre , Melbourne , Australia
| | - Paul B Coughlin
- b Australian Centre for Blood Diseases , Monash University , Prahran, Melbourne , Australia
- d Eastern Health , Box Hill , Australia
| | - Stephen B Fox
- a Tumour Angiogenesis and Microenvironment Program , Peter MacCallum Cancer Centre , Melbourne , Australia
- c Department of Pathology , Peter MacCallum Cancer Centre , Melbourne , Australia
- e Sir Peter MacCallum Department of Oncology , University of Melbourne , Parkville , Australia
| | - Steven A Stacker
- a Tumour Angiogenesis and Microenvironment Program , Peter MacCallum Cancer Centre , Melbourne , Australia
- e Sir Peter MacCallum Department of Oncology , University of Melbourne , Parkville , Australia
| | - Marc G Achen
- a Tumour Angiogenesis and Microenvironment Program , Peter MacCallum Cancer Centre , Melbourne , Australia
- e Sir Peter MacCallum Department of Oncology , University of Melbourne , Parkville , Australia
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Komatsu E, Nakajima Y, Mukai K, Urai T, Asano K, Okuwa M, Sugama J, Nakatani T. Lymph Drainage During Wound Healing in a Hindlimb Lymphedema Mouse Model. Lymphat Res Biol 2017; 15:32-38. [DOI: 10.1089/lrb.2016.0026] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Emi Komatsu
- Division of Nursing, Nagoya University Hospital, Nagoya, Japan
| | - Yukari Nakajima
- Graduate Course of Nursing Science, Division of Health Science, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Kanae Mukai
- Faculty of Health Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Tamae Urai
- Graduate Course of Nursing Science, Division of Health Science, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Kimi Asano
- School of Nursing, Kanazawa Medical University, Uchinada, Japan
| | - Mayumi Okuwa
- Faculty of Health Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Junko Sugama
- Faculty of Health Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Toshio Nakatani
- Faculty of Health Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
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Zolfaghari Saravi Z, Seyedmajidi M, Sharbatdaran M, Bijani A, Mozaffari F, Aminishakib P. VEGFR-3 Expression in Oral Lichen Planus. Asian Pac J Cancer Prev 2017; 18:381-384. [PMID: 28345335 PMCID: PMC5454731 DOI: 10.22034/apjcp.2017.18.2.381] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Background and objective: Given the postulated the role of inflammation and possible contribution of
lymphangiogenesis in oral lichen planus, this study aimed to assess any associated presence of VEGFR-3. Material
and Methods: This cross-sectional study was performed on 52 formalin fixed and paraffin embedded blocks of oral
lichen planus (pathological diagnosis based on Modified WHO criteria), comprising 25 of erosive and 27 of reticular
type, along with 60 samples of normal mucosa (with minimal inflammation from clinical and histopathological aspects)
obtained at crown lengthening surgery. Four micron sections were cut from paraffin blocks and stained with H and
E for confirmation of diagnosis and by immunohistochemistry with primary antibodies against VEGFR-3. Negative
controls were provided by omission of primary antibody and placenta was considered as a positive control. Data were
analyzed by Chi-square, Mann-Whitney and Kruskal-wallis tests and P <0.05 was considered statistically significant.
Findings: VEGFR-3 expression was apparent in 61.5% of lichen planus specimens and 5% of those from normal
mucosa (p<0.001). Also, the average number of stained vessels was significantly higher in oral lichen planus than in
normal mucosa (p<0.001). VEGFR-3 expression in oral lichen planus (p=0.262) and the average number of stained
vessels (p=0.092) demonstrated no significant difference according to the type. Conclusion: It appears that VEGFR-3
expression might be involved in the pathogenesis of the oral lichen planus through increasing lymphatic vessels and
lymphangiogenesis.
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Affiliation(s)
- Zahra Zolfaghari Saravi
- Oral and Maxillofacial Pathology Department, Dental Faculty, Babol University of Medical Sciences, Babol, Iran.
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Lymphangiogenesis is a feature of acute GVHD, and VEGFR-3 inhibition protects against experimental GVHD. Blood 2017; 129:1865-1875. [PMID: 28096093 DOI: 10.1182/blood-2016-08-734210] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 01/09/2017] [Indexed: 01/01/2023] Open
Abstract
Lymph vessels play a crucial role in immune reactions in health and disease. In oncology the inhibition of lymphangiogenesis is an established therapeutic concept for reducing metastatic spreading of tumor cells. During allogeneic tissue transplantation, the inhibition of lymphangiogenesis has been successfully used to attenuate graft rejection. Despite its critical importance for tumor growth, alloimmune responses, and inflammation, the role of lymphangiogenesis has not been investigated during allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that acute graft-versus-host disease (aGVHD) is associated with lymphangiogenesis in murine allo-HSCT models as well as in patient intestinal biopsies. Inhibition of aGVHD-associated lymphangiogenesis by monoclonal antibodies against vascular endothelial growth factor receptor 3 (VEGFR-3) ameliorated aGVHD and improved survival in murine models. The administration of anti-VEGFR-3 antibodies did not interfere with hematopoietic engraftment and improved immune reconstitution in allo-HSCT recipients with aGVHD. Anti-VEGFR-3 therapy had no significant impact on growth of malignant lymphoma after allo-HSCT. We conclude that aGVHD is associated with lymphangiogenesis in intestinal lesions and in lymph nodes. Our data show that anti-VEGFR-3 treatment ameliorates lethal aGVHD and identifies the lymphatic vasculature as a novel therapeutic target in the setting of allo-HSCT.
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Borges VF, Elder AM, Lyons TR. Deciphering Pro-Lymphangiogenic Programs during Mammary Involution and Postpartum Breast Cancer. Front Oncol 2016; 6:227. [PMID: 27853703 PMCID: PMC5090124 DOI: 10.3389/fonc.2016.00227] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 10/10/2016] [Indexed: 12/12/2022] Open
Abstract
Postpartum breast cancers are a highly metastatic subset of young women’s breast cancers defined as breast cancers diagnosed in the postpartum period or within 5 years of last child birth. Women diagnosed with postpartum breast cancer are nearly twice as likely to develop metastasis and to die from breast cancer when compared with nulliparous women. Additionally, epidemiological studies utilizing multiple cohorts also suggest that nearly half of all breast cancers in women aged <45 qualify as postpartum cases. Understanding the biology that underlies this increased risk for metastasis and death may lead to identification of targeted interventions that will benefit the large number of young women with breast cancer who fall into this subset. Preclinical mouse models of postpartum breast cancer have revealed that breast tumor cells become more aggressive if they are present during the normal physiologic process of postpartum mammary gland involution in mice. As involution appears to be a period of lymphatic growth and remodeling, and human postpartum breast cancers have high peritumor lymphatic vessel density (LVD) and increased incidence of lymph node metastasis (1, 2), we propose that novel insight into is to be gained through the study of the biological mechanisms driving normal postpartum mammary lymphangiogenesis as well as in the microenvironment of postpartum tumors.
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Affiliation(s)
- Virginia F Borges
- Young Women's Breast Cancer Translational Program, University of Colorado Cancer Center, Aurora, CO, USA; Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Alan M Elder
- Young Women's Breast Cancer Translational Program, University of Colorado Cancer Center, Aurora, CO, USA; Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Traci R Lyons
- Young Women's Breast Cancer Translational Program, University of Colorado Cancer Center, Aurora, CO, USA; Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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Jeon EJ, Davaatseren M, Hwang JT, Park JH, Hur HJ, Lee AS, Sung MJ. Effect of Oral Administration of 3,3'-Diindolylmethane on Dextran Sodium Sulfate-Induced Acute Colitis in Mice. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2016; 64:7702-7709. [PMID: 27700072 DOI: 10.1021/acs.jafc.6b02604] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
In patients with inflammatory bowel disease (IBD), inflammation is induced and maintained by lymphangiogenesis and angiogenesis. 3,3'-Diindolylmethane (DIM) is a natural product formed in acidic conditions from indole-3-carbinol in cruciferous vegetables, and it is known for its chemotherapeutic activity. This study evaluated DIM's effects on angiogenesis, lymphangiogenesis, and inflammation in a mouse colitis model. Experimental colitis was induced in mice by administering 3% dextran sulfate sodium (DSS) via drinking water. DIM remarkably attenuated the clinical signs and histological characteristics in mice with DSS-induced colitis. DIM suppressed neutrophil infiltration and pro-inflammatory cytokines. Moreover, it significantly suppressed the expression of vascular endothelial growth factor (VEGF)-A and VEGF receptor (VEGFR)-2, indicating that the mechanism may be related to the repression of pro-angiogenesis activity. DIM also remarkably suppressed the expression of VEGF-C, VEGF-D, VEGFR-3, and angiopoietin-2; thus, the mechanism may also be related to the suppression of lymphangiogenesis. Therefore, DIM is a possible treatment option for inflammation of the intestine and associated angiogenesis and lymphangiogenesis.
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Affiliation(s)
- Eun-Joo Jeon
- Research Division Emerging Innovative Technology, Korea Food Research Institute , Songnam, Keongki, Republic of Korea
| | - Munkhtugs Davaatseren
- Department of Food Science and Technology, Chung-ang University , Ansung, Keongki, Republic of Korea
| | - Jin-Taek Hwang
- Research Division Emerging Innovative Technology, Korea Food Research Institute , Songnam, Keongki, Republic of Korea
- Food Biotechnology, University of Science and Technology , Daejeon, Republic of Korea
| | - Jae Ho Park
- Research Division Emerging Innovative Technology, Korea Food Research Institute , Songnam, Keongki, Republic of Korea
- Food Biotechnology, University of Science and Technology , Daejeon, Republic of Korea
| | - Haeng Jeon Hur
- Research Division Emerging Innovative Technology, Korea Food Research Institute , Songnam, Keongki, Republic of Korea
| | - Ae Sin Lee
- Research Division Emerging Innovative Technology, Korea Food Research Institute , Songnam, Keongki, Republic of Korea
| | - Mi Jeong Sung
- Research Division Emerging Innovative Technology, Korea Food Research Institute , Songnam, Keongki, Republic of Korea
- Food Biotechnology, University of Science and Technology , Daejeon, Republic of Korea
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Venero Galanternik M, Stratman AN, Jung HM, Butler MG, Weinstein BM. Building the drains: the lymphatic vasculature in health and disease. WILEY INTERDISCIPLINARY REVIEWS-DEVELOPMENTAL BIOLOGY 2016; 5:689-710. [PMID: 27576003 DOI: 10.1002/wdev.246] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 06/30/2016] [Accepted: 07/01/2016] [Indexed: 02/06/2023]
Abstract
The lymphatic vasculature is comprised of a network of endothelial vessels found in close proximity to but separated from the blood vasculature. An essential tissue component of all vertebrates, lymphatics are responsible for the maintenance of fluid homeostasis, dissemination of immune cells, and lipid reabsorption under healthy conditions. When lymphatic vessels are impaired due to invasive surgery, genetic disorders, or parasitic infections, severe fluid build-up accumulates in the affected tissues causing a condition known as lymphedema. Malignant tumors can also directly activate lymphangiogenesis and use these vessels to promote the spread of metastatic cells. Although their first description goes back to the times of Hippocrates, with subsequent anatomical characterization at the beginning of the 20th-century, the lack of identifying molecular markers and tools to visualize these translucent vessels meant that investigation of lymphatic vessels fell well behind research of blood vessels. However, after years under the shadow of the blood vasculature, recent advances in imaging technologies and new genetic and molecular tools have accelerated the pace of research on lymphatic vessel development. These new tools have facilitated both work in classical mammalian models and the emergence of new powerful vertebrate models like zebrafish, quickly driving the field of lymphatic development back into the spotlight. In this review, we summarize the highlights of recent research on the development and function of the lymphatic vascular network in health and disease. WIREs Dev Biol 2016, 5:689-710. doi: 10.1002/wdev.246 For further resources related to this article, please visit the WIREs website.
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Affiliation(s)
- Marina Venero Galanternik
- National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Amber N Stratman
- National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Hyun Min Jung
- National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Matthew G Butler
- National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Brant M Weinstein
- National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
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Phase 1 study of the anti-vascular endothelial growth factor receptor 3 monoclonal antibody LY3022856/IMC-3C5 in patients with advanced and refractory solid tumors and advanced colorectal cancer. Cancer Chemother Pharmacol 2016; 78:815-24. [PMID: 27566701 DOI: 10.1007/s00280-016-3134-3] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 08/11/2016] [Indexed: 10/21/2022]
Abstract
PURPOSE Metastasis of solid tumors to regional lymph nodes is facilitated by tumor lymphangiogenesis, which is primarily mediated by the vascular endothelial growth factor receptor 3 (VEGFR-3). We conducted a phase 1 dose-escalation (part A) study of the VEGFR-3 human immunoglobulin G subclass 1 monoclonal antibody LY3022856 in advanced solid tumors, followed by a colorectal cancer (CRC) expansion (part B). METHODS Part A evaluated the safety profile and maximum tolerated dose (MTD) of LY3022856 in patients treated intravenously at doses of 5-30 mg/kg weekly (qwk). Part B further evaluated tolerability in CRC patients treated with 30 mg/kg. Secondary objectives were pharmacokinetics, anti-tumor activity, and pharmacodynamics (exploratory). RESULTS A total of 44 patients (23 in part A; 21 in part B) were treated; only one dose-limiting toxicity was observed at the lowest dose level. The MTD was not reached. Treatment-emergent adverse events (TEAEs) of any grade included in ≥15 % of all patients were: nausea (41 %), fatigue (32 %), vomiting (30 %), decreased appetite (27 %), pyrexia (25 %), peripheral edema (23 %), and urinary tract infection (UTI, 20 %). The most common grade 3/4 TEAEs included UTI and small intestinal obstruction (7 % each). No radiographic responses were noted. Median progression-free survival in part B was 6.3 weeks (95 % confidence interval: 5.1, 14.4), and a best overall response of stable disease was observed in 4 CRC patients (19.0 %). CONCLUSIONS LY3022856 was well tolerated up to a dose of 30 mg/kg qwk, but with minimal anti-tumor activity in CRC. CLINICALTRIALS. GOV IDENTIFIER NCT01288989.
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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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Investigation of cell death mechanisms in human lymphatic endothelial cells undergoing photodynamic therapy. Photodiagnosis Photodyn Ther 2016; 14:57-65. [DOI: 10.1016/j.pdpdt.2016.02.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 01/25/2016] [Accepted: 02/05/2016] [Indexed: 12/24/2022]
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Qi X, Du L, Chen X, Chen L, Yi T, Chen X, Wen Y, Wei Y, Zhao X. VEGF-D-enhanced lymph node metastasis of ovarian cancer is reversed by vesicular stomatitis virus matrix protein. Int J Oncol 2016; 49:123-32. [PMID: 27211072 PMCID: PMC4902071 DOI: 10.3892/ijo.2016.3527] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2016] [Accepted: 04/25/2016] [Indexed: 02/05/2023] Open
Abstract
Lymphatic metastasis is a poor prognostic factor in ovarian cancer, which correlates to the majority of cancer deaths. Matrix protein (MP) of vesicular stomatitis virus (VSV) exhibits potent antitumor and antiangiogenic activities through inducing apoptosis and inhibiting angiogenesis. In this study, the antitumor and antimetastatic effects of MP were further investigated. Wild-type SKOV3 (WT-SK) cells were successfully transfected with empty vector pcDNA3.1 plasmid, or pcDNA3.1-VEGF-D recombinant plasmid to construct cell lines named EV-SK, and VEGFD-SK, respectively. Inhibition of VEGFD-SK cell migration and invasion was detected by Transwell and wound healing assay. Then, lymphogenous metastatic model of ovarian cancer was established by injecting VEGFD-SK cells subcutaneously into the left hindlimb claw pad of nude mice. The inducted apoptotic effect of MP on VEGFD-SK cells were assessed by flow analysis and Hoechst-33258 staining, respectively, in vitro. The in vivo antitumor and antiangiogenic activities of MP gene were evaluated with lymphogenous metastatic model of ovarian cancer. Tumor volume and lymphatic metastasis rates were measured. Lymphatic vessels were delineated using Evan's blue and LYVE-1 staining. Expression of VEGF-D and MMP-2 were evaluated by immunostaining. Apoptosis of tumor cells was analyzed by Hoechst-33258 staining. Mice bearing VEGFD-SK tumor cells displayed more rapid tumorigenesis, higher lymphogenous metastatic tendency and increased lymphatic vessel density compared with the mice bearing WT-SK or EV-SK cells. However, VEGF-D-enhanced metastasis was evidently reversed by MP. MP significantly reduced the invasion of VEGFD-SK cells, tumor volume, lymphatic metastasis rates and lymphatic vessel density compared with control groups (P<0.05), accompanied with down-expression of VEGF-D and MMP-2 and increased apoptosis. Our data indicate that MP has strong antitumor and antimetastatic abilities, and it may be a promising therapeutic strategy against the lymphatic metastasis of human ovarian cancer.
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Affiliation(s)
- Xiaorong Qi
- Department of Gynecology and Obstetrics, Key Laboratory of Obstetric and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Licheng Du
- Provincial Hospital Affiliated to Shandong University, Jinan, P.R. China
| | - Xiancheng Chen
- State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Lijuan Chen
- State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Tao Yi
- Department of Gynecology and Obstetrics, Key Laboratory of Obstetric and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xiang Chen
- State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yanjun Wen
- State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yuquan Wei
- State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xia Zhao
- Department of Gynecology and Obstetrics, Key Laboratory of Obstetric and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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Fagiani E, Lorentz P, Bill R, Pavotbawan K, Kopfstein L, Christofori G. VEGF receptor-2-specific signaling mediated by VEGF-E induces hemangioma-like lesions in normal and in malignant tissue. Angiogenesis 2016; 19:339-58. [PMID: 27038485 DOI: 10.1007/s10456-016-9508-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Accepted: 03/22/2016] [Indexed: 12/24/2022]
Abstract
UNLABELLED Viral VEGF-E (ovVEGF-E), a homolog of VEGF-A, was discovered in the genome of Orf virus. Together with VEGF-A, B, C, D, placental growth factor (PlGF) and snake venom VEGF (svVEGF), ovVEGF-E is a member of the VEGF family of potent angiogenesis factors with a bioactivity similar to VEGF-A it induces proliferation, migration and sprouting of cultured vascular endothelial cells and proliferative lesions in the skin of sheep, goat and man that are characterized by massive capillary proliferation and dilation. These biological functions are mediated exclusively via its interaction with VEGF receptor-2 (VEGFR-2). Here, we have generated transgenic mice specifically expressing ovVEGF-E in β-cells of the endocrine pancreas (Rip1VEGF-E; RVE). RVE mice show an increase in number and size of the islets of Langerhans and a distorted organization of insulin and glucagon-expressing cells. Islet endothelial cells of RVE mice hyper-proliferate and form increased numbers of functional blood vessels. In addition, the formation of disorganized lymphatic vessels and increased immune cell infiltration is observed. Upon crossing RVE single-transgenic mice with Rip1Tag2 (RT2) transgenic mice, a well-studied model of pancreatic β-cell carcinogenesis, double-transgenic mice (RT2;RVE) display hyper-proliferation of endothelial cells resulting in the formation of hemangioma-like lesions. In addition, RT2;RVE mice exhibit activated lymphangiogenesis at the tumor periphery and increased neutrophil and macrophage tumor infiltration and micro-metastasis to lymph nodes and lungs. These phenotypes markedly differ from the phenotypes observed with the transgenic expression of the other VEGF family members in β-cells of normal mice and of RT2 mice.
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Affiliation(s)
- Ernesta Fagiani
- Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058, Basel, Switzerland.
| | - Pascal Lorentz
- Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058, Basel, Switzerland
| | - Ruben Bill
- Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058, Basel, Switzerland
| | - Kirusigan Pavotbawan
- Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058, Basel, Switzerland
| | - Lucie Kopfstein
- Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058, Basel, Switzerland
| | - Gerhard Christofori
- Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058, Basel, Switzerland
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Astin JW, Crosier PS. Lymphatics, Cancer and Zebrafish. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 916:199-218. [DOI: 10.1007/978-3-319-30654-4_9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Yang JF, Walia A, Huang YH, Han KY, Rosenblatt MI, Azar DT, Chang JH. Understanding lymphangiogenesis in knockout models, the cornea, and ocular diseases for the development of therapeutic interventions. Surv Ophthalmol 2015; 61:272-96. [PMID: 26706194 DOI: 10.1016/j.survophthal.2015.12.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Revised: 12/08/2015] [Accepted: 12/09/2015] [Indexed: 01/05/2023]
Abstract
A major focus of cancer research for several decades has been understand the ability of tumors to induce new blood vessel formation, a process known as angiogenesis. Unfortunately, only limited success has been achieved in the clinical application of angiogenesis inhibitors. We now know that lymphangiogenesis, the growth of lymphatic vessels, likely also plays a major role in tumor progression. Thus, therapeutic strategies targeting lymphangiogenesis or both lymphangiogenesis and angiogenesis may represent promising approaches for treating cancer and other diseases. Importantly, research progress toward understanding lymphangiogenesis is significantly behind that related to angiogenesis. A PubMed search of "angiogenesis" returns nearly 80,000 articles, whereas a search of "lymphangiogenesis" returns 2,635 articles. This stark contrast can be explained by the lack of molecular markers for identifying the invisible lymphatic vasculature that persisted until less than 2 decades ago, combined with the intensity of research interest in angiogenesis during the past half century. Still, significant strides have been made in developing strategies to modulate lymphangiogenesis, largely using ocular disease models. Here we review the current knowledge of lymphangiogenesis in the context of knockout models, ocular diseases, the biology of activators and inhibitors, and the potential for therapeutic interventions targeting this process.
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Affiliation(s)
- Jessica F Yang
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Amit Walia
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Yu-hui Huang
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Kyu-yeon Han
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Mark I Rosenblatt
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Dimitri T Azar
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Jin-Hong Chang
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, Illinois, USA.
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Three-dimensional biomimetic model to reconstitute sprouting lymphangiogenesis in vitro. Biomaterials 2015; 78:115-28. [PMID: 26691234 DOI: 10.1016/j.biomaterials.2015.11.019] [Citation(s) in RCA: 106] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Revised: 10/30/2015] [Accepted: 11/06/2015] [Indexed: 02/07/2023]
Abstract
Formation of new lymphatic vessels, termed lymphangiogenesis, is central for diverse biological processes during development, inflammation and tumor metastasis. However, reliable in vitro model is still under demand for detailed elucidation of how sprouting lymphangiogenesis is initiated and coordinated. Here, we describe a microfluidic platform optimized for close reconstitution of lymphangiogenesis, achieved by on-chip integration of salient constituents of lymphatic microenvironment found in vivo. With flexible and precise control over the factors that include biochemical cues, interstitial flow (IF), and endothelial-stromal interactions, we found that orchestrated efforts of multiple environmental factors are necessary for robust lymphatic sprouting in 3D extracellular matrix. Especially, we demonstrate that IF serves as a central regulatory cue which defines lymphangiogenic responses and phenotypes of lymphatic endothelial cells. When synergized with pro-lymphangiogenic factors, IF significantly augmented initiation and outgrowth of lymphatic sprouts toward upstream of the flow while suppressing downstream-directed sprouting. In an appropriate synergism, lymphatic sprouts exhibited structural, molecular signatures and cellular phenotypes that closely approximate sprouting lymphatic neovessels in vivo, and precisely reflected the modulatory effects of pro- and anti-lymphangiogenic stimuli. Our study not only reveals critical but unappreciated role of mechanical cue that regulates lymphangiogenic sprouting, but also provides a novel biomimetic model that may leverage further biological studies as well as phenotypic drug screening.
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Bernier-Latmani J, Cisarovsky C, Demir CS, Bruand M, Jaquet M, Davanture S, Ragusa S, Siegert S, Dormond O, Benedito R, Radtke F, Luther SA, Petrova TV. DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport. J Clin Invest 2015; 125:4572-86. [PMID: 26529256 DOI: 10.1172/jci82045] [Citation(s) in RCA: 140] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
The small intestine is a dynamic and complex organ that is characterized by constant epithelium turnover and crosstalk among various cell types and the microbiota. Lymphatic capillaries of the small intestine, called lacteals, play key roles in dietary fat absorption and the gut immune response; however, little is known about the molecular regulation of lacteal function. Here, we performed a high-resolution analysis of the small intestinal stroma and determined that lacteals reside in a permanent regenerative, proliferative state that is distinct from embryonic lymphangiogenesis or quiescent lymphatic vessels observed in other tissues. We further demonstrated that this continuous regeneration process is mediated by Notch signaling and that the expression of the Notch ligand delta-like 4 (DLL4) in lacteals requires activation of VEGFR3 and VEGFR2. Moreover, genetic inactivation of Dll4 in lymphatic endothelial cells led to lacteal regression and impaired dietary fat uptake. We propose that such a slow lymphatic regeneration mode is necessary to match a unique need of intestinal lymphatic vessels for both continuous maintenance, due to the constant exposure to dietary fat and mechanical strain, and efficient uptake of fat and immune cells. Our work reveals how lymphatic vessel responses are shaped by tissue specialization and uncover a role for continuous DLL4 signaling in the function of adult lymphatic vasculature.
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