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Physiological Reviews Oct 2022The lymphatic system, composed of initial and collecting lymphatic vessels as well as lymph nodes that are present in almost every tissue of the human body, acts as an... (Review)
Review
The lymphatic system, composed of initial and collecting lymphatic vessels as well as lymph nodes that are present in almost every tissue of the human body, acts as an essential transport system for fluids, biomolecules, and cells between peripheral tissues and the central circulation. Consequently, it is required for normal body physiology but is also involved in the pathogenesis of various diseases, most notably cancer. The important role of tumor-associated lymphatic vessels and lymphangiogenesis in the formation of lymph node metastasis has been elucidated during the last two decades, whereas the underlying mechanisms and the relation between lymphatic and peripheral organ dissemination of cancer cells are incompletely understood. Lymphatic vessels are also important for tumor-host communication, relaying molecular information from a primary or metastatic tumor to regional lymph nodes and the circulatory system. Beyond antigen transport, lymphatic endothelial cells, particularly those residing in lymph node sinuses, have recently been recognized as direct regulators of tumor immunity and immunotherapy responsiveness, presenting tumor antigens and expressing several immune-modulatory signals including PD-L1. In this review, we summarize recent discoveries in this rapidly evolving field and highlight strategies and challenges of therapeutic targeting of lymphatic vessels or specific lymphatic functions in cancer patients.
Topics: Endothelial Cells; Humans; Immunotherapy; Lymphangiogenesis; Lymphatic Metastasis; Lymphatic Vessels
PubMed: 35771983
DOI: 10.1152/physrev.00039.2021 -
Cell Jan 2023Blood and lymphatic vessels form a versatile transport network and provide inductive signals to regulate tissue-specific functions. Blood vessels in bone regulate...
Blood and lymphatic vessels form a versatile transport network and provide inductive signals to regulate tissue-specific functions. Blood vessels in bone regulate osteogenesis and hematopoiesis, but current dogma suggests that bone lacks lymphatic vessels. Here, by combining high-resolution light-sheet imaging and cell-specific mouse genetics, we demonstrate presence of lymphatic vessels in mouse and human bones. We find that lymphatic vessels in bone expand during genotoxic stress. VEGF-C/VEGFR-3 signaling and genotoxic stress-induced IL6 drive lymphangiogenesis in bones. During lymphangiogenesis, secretion of CXCL12 from proliferating lymphatic endothelial cells is critical for hematopoietic and bone regeneration. Moreover, lymphangiocrine CXCL12 triggers expansion of mature Myh11 CXCR4 pericytes, which differentiate into bone cells and contribute to bone and hematopoietic regeneration. In aged animals, such expansion of lymphatic vessels and Myh11-positive cells in response to genotoxic stress is impaired. These data suggest lymphangiogenesis as a therapeutic avenue to stimulate hematopoietic and bone regeneration.
Topics: Aged; Animals; Humans; Mice; Bone Regeneration; Endothelial Cells; Lymphangiogenesis; Lymphatic Vessels
PubMed: 36669473
DOI: 10.1016/j.cell.2022.12.031 -
Cell Feb 2010The growth of lymphatic vessels (lymphangiogenesis) is actively involved in a number of pathological processes including tissue inflammation and tumor dissemination but... (Review)
Review
The growth of lymphatic vessels (lymphangiogenesis) is actively involved in a number of pathological processes including tissue inflammation and tumor dissemination but is insufficient in patients suffering from lymphedema, a debilitating condition characterized by chronic tissue edema and impaired immunity. The recent explosion of knowledge on the molecular mechanisms governing lymphangiogenesis provides new possibilities to treat these diseases.
Topics: Animals; Endothelial Cells; Humans; Inflammation; Lymphangiogenesis; Lymphatic Vessels; Neoplasms
PubMed: 20178740
DOI: 10.1016/j.cell.2010.01.045 -
Cardiovascular Research Mar 2023Lymphatics are essential for cardiac health, and insufficient lymphatic expansion (lymphangiogenesis) contributes to development of heart failure (HF) after myocardial...
AIMS
Lymphatics are essential for cardiac health, and insufficient lymphatic expansion (lymphangiogenesis) contributes to development of heart failure (HF) after myocardial infarction. However, the regulation and impact of lymphangiogenesis in non-ischaemic cardiomyopathy following pressure-overload remains to be determined. Here, we investigated cardiac lymphangiogenesis following transversal aortic constriction (TAC) in C57Bl/6 and Balb/c mice, and in end-stage HF patients.
METHODS AND RESULTS
Cardiac function was evaluated by echocardiography, and cardiac hypertrophy, lymphatics, inflammation, oedema, and fibrosis by immunohistochemistry, flow cytometry, microgravimetry, and gene expression analysis. Treatment with neutralizing anti-VEGFR3 antibodies was applied to inhibit cardiac lymphangiogenesis in mice. We found that VEGFR3-signalling was essential to prevent cardiac lymphatic rarefaction after TAC in C57Bl/6 mice. While anti-VEGFR3-induced lymphatic rarefaction did not significantly aggravate myocardial oedema post-TAC, cardiac immune cell levels were increased, notably myeloid cells at 3 weeks and T lymphocytes at 8 weeks. Moreover, whereas inhibition of lymphangiogenesis did not aggravate interstitial fibrosis, it increased perivascular fibrosis and accelerated development of left ventricular (LV) dilation and dysfunction. In clinical HF samples, cardiac lymphatic density tended to increase, although lymphatic sizes decreased, notably in patients with dilated cardiomyopathy. Similarly, comparing C57Bl/6 and Balb/c mice, lymphatic remodelling post-TAC was linked to LV dilation rather than to hypertrophy. The striking lymphangiogenesis in Balb/c was associated with reduced cardiac levels of macrophages, B cells, and perivascular fibrosis at 8 weeks post-TAC, as compared with C57Bl/6 mice that displayed weak lymphangiogenesis. Surprisingly, however, it did not suffice to resolve myocardial oedema, nor prevent HF development.
CONCLUSIONS
We demonstrate for the first time that endogenous lymphangiogenesis limits TAC-induced cardiac inflammation and perivascular fibrosis, delaying HF development in C57Bl/6 but not in Balb/c mice. While the functional impact of lymphatic remodelling remains to be determined in HF patients, our findings suggest that under settings of pressure-overload poor cardiac lymphangiogenesis may accelerate HF development.
Topics: Mice; Animals; Lymphangiogenesis; Heart; Heart Failure; Edema; Aortic Valve Stenosis; Fibrosis; Mice, Inbred C57BL; Disease Models, Animal; Ventricular Remodeling
PubMed: 35689481
DOI: 10.1093/cvr/cvac086 -
Nature Cancer Dec 2021Secreted extracellular vesicles (EVs) influence the tumor microenvironment and promote distal metastasis. Here, we analyzed the involvement of melanoma-secreted EVs in...
Secreted extracellular vesicles (EVs) influence the tumor microenvironment and promote distal metastasis. Here, we analyzed the involvement of melanoma-secreted EVs in lymph node pre-metastatic niche formation in murine models. We found that small EVs (sEVs) derived from metastatic melanoma cell lines were enriched in nerve growth factor receptor (NGFR, p75NTR), spread through the lymphatic system and were taken up by lymphatic endothelial cells, reinforcing lymph node metastasis. Remarkably, sEVs enhanced lymphangiogenesis and tumor cell adhesion by inducing ERK kinase, nuclear factor (NF)-κB activation and intracellular adhesion molecule (ICAM)-1 expression in lymphatic endothelial cells. Importantly, ablation or inhibition of NGFR in sEVs reversed the lymphangiogenic phenotype, decreased lymph node metastasis and extended survival in pre-clinical models. Furthermore, NGFR expression was augmented in human lymph node metastases relative to that in matched primary tumors, and the frequency of NGFR metastatic melanoma cells in lymph nodes correlated with patient survival. In summary, we found that NGFR is secreted in melanoma-derived sEVs, reinforcing lymph node pre-metastatic niche formation and metastasis.
Topics: Animals; Endothelial Cells; Extracellular Vesicles; Humans; Lymphangiogenesis; Lymphatic Metastasis; Melanoma; Mice; Nerve Tissue Proteins; Receptors, Nerve Growth Factor; Tumor Microenvironment
PubMed: 34957415
DOI: 10.1038/s43018-021-00272-y -
Nature Communications May 2022Autophagy has vasculoprotective roles, but whether and how it regulates lymphatic endothelial cells (LEC) homeostasis and lymphangiogenesis is unknown. Here, we show...
Autophagy has vasculoprotective roles, but whether and how it regulates lymphatic endothelial cells (LEC) homeostasis and lymphangiogenesis is unknown. Here, we show that genetic deficiency of autophagy in LEC impairs responses to VEGF-C and injury-driven corneal lymphangiogenesis. Autophagy loss in LEC compromises the expression of main effectors of LEC identity, like VEGFR3, affects mitochondrial dynamics and causes an accumulation of lipid droplets (LDs) in vitro and in vivo. When lipophagy is impaired, mitochondrial ATP production, fatty acid oxidation, acetyl-CoA/CoA ratio and expression of lymphangiogenic PROX1 target genes are dwindled. Enforcing mitochondria fusion by silencing dynamin-related-protein 1 (DRP1) in autophagy-deficient LEC fails to restore LDs turnover and lymphatic gene expression, whereas supplementing the fatty acid precursor acetate rescues VEGFR3 levels and signaling, and lymphangiogenesis in LEC-Atg5 mice. Our findings reveal that lipophagy in LEC by supporting FAO, preserves a mitochondrial-PROX1 gene expression circuit that safeguards LEC responsiveness to lymphangiogenic mediators and lymphangiogenesis.
Topics: Animals; Autophagy; Endothelial Cells; Fatty Acids; Lipid Droplets; Lymphangiogenesis; Lymphatic Vessels; Mice; Mitochondria; Transcription Factors
PubMed: 35589749
DOI: 10.1038/s41467-022-30490-6 -
Arteriosclerosis, Thrombosis, and... Jan 2023Lymphatic vessels are low-pressure, blind-ended tubular structures that play a crucial role in the maintenance of tissue fluid homeostasis, immune cell trafficking, and... (Review)
Review
Lymphatic vessels are low-pressure, blind-ended tubular structures that play a crucial role in the maintenance of tissue fluid homeostasis, immune cell trafficking, and dietary lipid uptake and transport. Emerging research has indicated that the promotion of lymphatic vascular growth, remodeling, and function can reduce inflammation and diminish disease severity in several pathophysiologic conditions. In particular, recent groundbreaking studies have shown that lymphangiogenesis, which describes the formation of new lymphatic vessels from the existing lymphatic vasculature, can be beneficial for the alleviation and resolution of metabolic and cardiovascular diseases. Therefore, promoting lymphangiogenesis represents a promising therapeutic approach. This brief review summarizes the most recent findings related to the modulation of lymphatic function to treat metabolic and cardiovascular diseases such as obesity, myocardial infarction, atherosclerosis, and hypertension. We also discuss experimental and therapeutic approaches to enforce lymphatic growth and remodeling as well as efforts to define the molecular and cellular mechanisms underlying these processes.
Topics: Humans; Lymphangiogenesis; Lymphatic Vessels; Heart; Myocardial Infarction; Metabolic Diseases
PubMed: 36453280
DOI: 10.1161/ATVBAHA.122.318406 -
Heart Failure Reviews Sep 2022Cardiac lymphangiogenesis plays an important physiological role in the regulation of interstitial fluid homeostasis, inflammatory, and immune responses. Impaired or... (Review)
Review
Cardiac lymphangiogenesis plays an important physiological role in the regulation of interstitial fluid homeostasis, inflammatory, and immune responses. Impaired or excessive cardiac lymphatic remodeling and insufficient lymph drainage have been implicated in several cardiovascular diseases including atherosclerosis and myocardial infarction (MI). Although the molecular mechanisms underlying the regulation of functional lymphatics are not fully understood, the interplay between lymphangiogenesis and immune regulation has recently been explored in relation to the initiation and development of these diseases. In this field, experimental therapeutic strategies targeting lymphangiogenesis have shown promise by reducing myocardial inflammation, edema and fibrosis, and improving cardiac function. On the other hand, however, whether lymphangiogenesis is beneficial or detrimental to cardiac transplant survival remains controversial. In the light of recent evidence, cardiac lymphangiogenesis, a thriving and challenging field has been summarized and discussed, which may improve our knowledge in the pathogenesis of cardiovascular diseases and transplant biology.
Topics: Cardiovascular Diseases; Heart; Heart Transplantation; Humans; Lymphangiogenesis; Lymphatic Vessels
PubMed: 34735673
DOI: 10.1007/s10741-021-10188-5 -
Clinical and Translational Medicine Mar 2021Prolonged pressure overload triggers cardiac hypertrophy and frequently leads to heart failure (HF). Vascular endothelial growth factor-C (VEGF-C) and its receptor...
Prolonged pressure overload triggers cardiac hypertrophy and frequently leads to heart failure (HF). Vascular endothelial growth factor-C (VEGF-C) and its receptor VEGFR-3 are components of the central pathway for lymphatic vessel growth (also known as lymphangiogenesis), which has crucial functions in the maintenance of tissue fluid balance and myocardial function after ischemic injury. However, the roles of this pathway in the development of cardiac hypertrophy and dysfunction during pressure overload remain largely unknown. Eight- to 10-week-old male wild-type (WT) mice, VEGFR-3 knockdown (VEGFR-3 ) mice, and their WT littermates (VEGFR-3 ) were subjected to pressure overload induced by transverse aortic constriction (TAC) for 1-6 weeks. We found that cardiac lymphangiogenesis and the protein expression of VEGF-C and VEGFR-3 were upregulated in the early stage of cardiac hypertrophy but were markedly reduced in failing hearts. Moreover, TAC for 6 weeks significantly reduced cardiac lymphangiogenesis by inhibiting activation of VEGFR-3-mediated signals (AKT/ERK1/2, calcineurin A/NFATc1/FOXc2, and CX43), leading to increased cardiac edema, hypertrophy, fibrosis, apoptosis, inflammation, and dysfunction. These effects were further aggravated in VEGFR-3 mice and were dose-dependently attenuated by delivery of recombinant VEGF-C in WT mice. VEGF-C administration also reversed pre-established cardiac dysfunction induced by sustained pressure overload. Thus, these results demonstrate, for the first time, that activation of the VEGF-C-VEGFR-3 axis exerts a protective effect during the transition from cardiac hypertrophy to HF and highlight selective stimulation of cardiac lymphangiogenesis as a potential new therapeutic approach for hypertrophic heart diseases.
Topics: Animals; Cardiomegaly; Disease Models, Animal; Heart Failure; Lymphangiogenesis; Male; Mice; Mice, Inbred C57BL; Pressure; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor-3
PubMed: 33783987
DOI: 10.1002/ctm2.374 -
European Journal of Medical Research Oct 2023Increased lymphangiogenesis and lymph node (LN) metastasis are thought to be important steps in cancer metastasis, and are associated with patient's poor prognosis.... (Review)
Review
Increased lymphangiogenesis and lymph node (LN) metastasis are thought to be important steps in cancer metastasis, and are associated with patient's poor prognosis. There is increasing evidence that the lymphatic system may play a crucial role in regulating tumor immune response and limiting tumor metastasis, since tumor lymphangiogenesis is more prominent in tumor metastasis and diffusion. Lymphangiogenesis takes place in embryonic development, wound healing, and a variety of pathological conditions, including tumors. Tumor cells and tumor microenvironment cells generate growth factors (such as lymphangiogenesis factor VEGF-C/D), which can promote lymphangiogenesis, thereby inducing the metastasis and diffusion of tumor cells. Nevertheless, the current research on lymphangiogenesis in gastric cancer is relatively scattered and lacks a comprehensive understanding. Therefore, in this review, we aim to provide a detailed perspective on molecules and signal transduction pathways that regulate gastric cancer lymphogenesis, which may provide new insights for the diagnosis and treatment of cancer.
Topics: Humans; Lymphangiogenesis; Stomach Neoplasms; Lymphatic Metastasis; Signal Transduction; Tumor Microenvironment
PubMed: 37803421
DOI: 10.1186/s40001-023-01298-x