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Nature Sep 2020Cancer cells, including melanoma cells, often metastasize regionally through the lymphatic system before metastasizing systemically through the blood; however, the...
Cancer cells, including melanoma cells, often metastasize regionally through the lymphatic system before metastasizing systemically through the blood; however, the reason for this is unclear. Here we show that melanoma cells in lymph experience less oxidative stress and form more metastases than melanoma cells in blood. Immunocompromised mice with melanomas derived from patients, and immunocompetent mice with mouse melanomas, had more melanoma cells per microlitre in tumour-draining lymph than in tumour-draining blood. Cells that metastasized through blood, but not those that metastasized through lymph, became dependent on the ferroptosis inhibitor GPX4. Cells that were pretreated with chemical ferroptosis inhibitors formed more metastases than untreated cells after intravenous, but not intralymphatic, injection. We observed multiple differences between lymph fluid and blood plasma that may contribute to decreased oxidative stress and ferroptosis in lymph, including higher levels of glutathione and oleic acid and less free iron in lymph. Oleic acid protected melanoma cells from ferroptosis in an Acsl3-dependent manner and increased their capacity to form metastatic tumours. Melanoma cells from lymph nodes were more resistant to ferroptosis and formed more metastases after intravenous injection than did melanoma cells from subcutaneous tumours. Exposure to the lymphatic environment thus protects melanoma cells from ferroptosis and increases their ability to survive during subsequent metastasis through the blood.
Topics: Animals; Cell Survival; Coenzyme A Ligases; Female; Ferroptosis; Glutathione; Humans; Iron; Lymph; Male; Melanoma; Mice; Neoplasm Metastasis; Oleic Acid; Oxidative Stress; Phospholipid Hydroperoxide Glutathione Peroxidase; Principal Component Analysis
PubMed: 32814895
DOI: 10.1038/s41586-020-2623-z -
Arteriosclerosis, Thrombosis, and... Jan 2021Extracellular vesicles (EVs) are a means of cell-to-cell communication and can facilitate the exchange of a broad array of molecules between adjacent or distant cells.... (Review)
Review
Extracellular vesicles (EVs) are a means of cell-to-cell communication and can facilitate the exchange of a broad array of molecules between adjacent or distant cells. Platelets are anucleate cells derived from megakaryocytes and are primarily known for their role in maintaining hemostasis and vascular integrity. Upon activation by a variety of agonists, platelets readily generate EVs, which were initially identified as procoagulant particles. However, as both platelets and their EVs are abundant in blood, the role of platelet EVs in hemostasis may be redundant. Moreover, findings have challenged the significance of platelet-derived EVs in coagulation. Looking beyond hemostasis, platelet EV cargo is incredibly diverse and can include lipids, proteins, nucleic acids, and organelles involved in numerous other biological processes. Furthermore, while platelets cannot cross tissue barriers, their EVs can enter lymph, bone marrow, and synovial fluid. This allows for the transfer of platelet-derived content to cellular recipients and organs inaccessible to platelets. This review highlights the importance of platelet-derived EVs in physiological and pathological conditions beyond hemostasis.
Topics: Animals; Blood Platelets; Bone Marrow; Cell Communication; Cell-Derived Microparticles; Hemostasis; Humans; Inflammation Mediators; Lymph; Platelet Activation; Synovial Fluid
PubMed: 33028092
DOI: 10.1161/ATVBAHA.120.314644 -
The Oncologist Feb 2020The detection of lymph node metastasis affects the management of patients with primary breast cancer significantly in terms of staging, treatment, and prognosis. The... (Review)
Review
The detection of lymph node metastasis affects the management of patients with primary breast cancer significantly in terms of staging, treatment, and prognosis. The main goal for the radiologist is to determine and detect the presence of metastatic disease in nonpalpable axillary lymph nodes with a positive predictive value that is high enough to initially select patients for upfront axillary lymph node dissection. Features that are suggestive of axillary adenopathy may be seen with different imaging modalities, but ultrasound is the method of choice for evaluating axillary lymph nodes and for performing image-guided lymph node interventions. This review aims to provide a comprehensive overview of the available imaging modalities for lymph node assessment in patients diagnosed with primary breast cancer. IMPLICATIONS FOR PRACTICE: The detection of lymph node metastasis affects the management of patients with primary breast cancer. The main goal for the radiologist is to detect lymph node metastasis in patients to allow for the selection of patients who should undergo upfront axillary lymph node dissection. Features that are suggestive of axillary adenopathy may be seen with mammography, computed tomography, and magnetic resonance imaging, but ultrasonography is the imaging modality of choice for evaluating axillary lymph nodes. A normal axillary lymph node is characterized by a reniform shape, a maximal cortical thickness of 3 mm without focal bulging, smooth margins, and, depending on size, a discernable central fatty hilum.
Topics: Axilla; Breast Neoplasms; Female; Humans; Lymph Node Excision; Lymph Nodes; Lymphatic Metastasis; Neoplasm Staging; Sensitivity and Specificity; Sentinel Lymph Node Biopsy
PubMed: 32043792
DOI: 10.1634/theoncologist.2019-0427 -
Science Immunology Dec 2021Saponins are potent and safe vaccine adjuvants, but their mechanisms of action remain incompletely understood. Here, we explored the properties of several saponin...
Saponins are potent and safe vaccine adjuvants, but their mechanisms of action remain incompletely understood. Here, we explored the properties of several saponin formulations, including immune-stimulatory complexes (ISCOMs) formed by the self-assembly of saponin and phospholipids in the absence or presence of the Toll-like receptor 4 agonist monophosphoryl lipid A (MPLA). We found that MPLA self-assembles with saponins to form particles physically resembling ISCOMs, which we termed saponin/MPLA nanoparticles (SMNP). Saponin-containing adjuvants exhibited distinctive mechanisms of action, altering lymph flow in a mast cell–dependent manner and promoting antigen entry into draining lymph nodes. SMNP was particularly effective, exhibiting even greater potency than the compositionally related adjuvant AS01 in mice, and primed robust germinal center B cell, T, and HIV tier 2 neutralizing antibodies in nonhuman primates. Together, these findings shed new light on mechanisms by which saponin adjuvants act to promote the immune response and suggest that SMNP may be a promising adjuvant in the setting of HIV, SARS-CoV-2, and other pathogens.
Topics: Adaptive Immunity; Adjuvants, Immunologic; Animals; B-Lymphocytes; CD4-Positive T-Lymphocytes; Female; Lymph; Macaca mulatta; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Nanoparticles; Rats; Rats, Wistar; Saponins; Toll-Like Receptors
PubMed: 34860581
DOI: 10.1126/sciimmunol.abf1152 -
Immunity Dec 2021Lymphangitis and the formation of tertiary lymphoid organs (TLOs) in the mesentery are features of Crohn's disease. Here, we examined the genesis of these TLOs and their...
Lymphangitis and the formation of tertiary lymphoid organs (TLOs) in the mesentery are features of Crohn's disease. Here, we examined the genesis of these TLOs and their impact on disease progression. Whole-mount and intravital imaging of the ileum and ileum-draining collecting lymphatic vessels (CLVs) draining to mesenteric lymph nodes from TNF mice, a model of ileitis, revealed TLO formation at valves of CLVs. TLOs obstructed cellular and molecular outflow from the gut and were sites of lymph leakage and backflow. Tumor necrosis factor (TNF) neutralization begun at early stages of TLO formation restored lymph transport. However, robustly developed, chronic TLOs resisted regression and restoration of flow after TNF neutralization. TNF stimulation of cultured lymphatic endothelial cells reprogrammed responses to oscillatory shear stress, preventing the induction of valve-associated genes. Disrupted transport of immune cells, driven by loss of valve integrity and TLO formation, may contribute to the pathology of Crohn's disease.
Topics: Animals; Cell Movement; Cells, Cultured; Crohn Disease; Disease Models, Animal; Endothelial Cells; Humans; Ileitis; Ileum; Lymph; Lymphangitis; Lymphatic Vessels; Mesentery; Mice; Mice, Knockout; Stress, Mechanical; Tertiary Lymphoid Structures; Tumor Necrosis Factor-alpha
PubMed: 34788601
DOI: 10.1016/j.immuni.2021.10.003 -
Cells Mar 2021Lymph nodes are the most common sites of metastasis in cancer patients. Nodal disease status provides great prognostic power, but how lymph node metastases should be... (Review)
Review
Lymph nodes are the most common sites of metastasis in cancer patients. Nodal disease status provides great prognostic power, but how lymph node metastases should be treated is under debate. Thus, it is important to understand the mechanisms by which lymph node metastases progress and how they can be targeted to provide therapeutic benefits. In this review, we focus on delineating the process of cancer cell migration to and through lymphatic vessels, survival in draining lymph nodes and further spread to other distant organs. In addition, emerging molecular targets and potential strategies to inhibit lymph node metastasis are discussed.
Topics: Animals; Cell Movement; Cell Survival; Humans; Lymph Nodes; Lymphatic Metastasis; Lymphatic Vessels; Neoplasm Invasiveness; Neoplasms; Prognosis; Tumor Escape
PubMed: 33808959
DOI: 10.3390/cells10030627 -
Physiological Reports May 2022The lymphatic system is compromised in different groups of patients. To recognize pathology, we must know what is healthy. We use Near-Infrared Fluorescence (NIRF) to...
The lymphatic system is compromised in different groups of patients. To recognize pathology, we must know what is healthy. We use Near-Infrared Fluorescence (NIRF) to assess peripheral lymphatic function in humans. We have shown that external factors such as exercise, hyperthermia, and pharmacological mediators influence the function of peripheral lymphatic vessels. In this study, we explored the impact on lymphatic vessels by the ever-present external factor-gravity. We used NIRF imaging to investigate the lymphatic changes to gravity. Gravity was assessed by changing body position from supine to standing. We extracted following lymphatic functional parameters: lymphatic packet propulsion frequency (contractions/min), velocity (cm/s), and pressure (mmHg). Raw data analysis was performed using a custom-written Labview program. All sequences were analyzed by two observers and interclass correlation scores were calculated. All statistical analysis was performed using RStudio Team (2021). RStudio: Integrated Development Environment for R. RStudio, PBC. Healthy participants (n = 17, 11 males, age 28.1 ± 2.6 years) were included. The lymphatic packet propulsion frequency at baseline was 0.5 ± 0.2 contractions/min and rose within 3 min significantly to a maximum of 1.2 ± 0.5 contractions/min during upright posture and remained significantly higher than the baseline lymphatic packet propulsion frequency after lying down again for up to 6 min. The lymph velocity was 1.5 ± 0.4 cm/s at baseline and changed in both directions and without a specific pattern at different points in time during standing. Lymph pressure was significantly higher while standing (mean increase 9 mmHg, CI: 2-15 mmHg). The ICC scores were 89.8% (85.9%-92.7%), 59.3% (46.6%-69.6%) and 89.4% (79.0%-94.8%) in lymphatic packet propulsion frequency (130 observations), velocity (125 observations), and pressure (30 observations), respectively. The lymphatic system responds within few minutes to gravitational changes by increasing lymphatic packet propulsion frequency and pressure.
Topics: Adult; Gravitation; Humans; Lymph; Lymphatic Vessels; Male; Optical Imaging; Posture
PubMed: 35586957
DOI: 10.14814/phy2.15289 -
Cellular and Molecular Life Sciences :... May 2019Hippocratic Corpus, a collection of Greek medical literature, described the functional anatomy of the lymphatic system in the fifth century B.C. Subsequent studies in... (Review)
Review
Hippocratic Corpus, a collection of Greek medical literature, described the functional anatomy of the lymphatic system in the fifth century B.C. Subsequent studies in cadavers and surgical patients firmly established that lymphatic vessels drain extravasated interstitial fluid, also known as lymph, into the venous system at the bilateral lymphovenous junctions. Recent advances revealed that lymphovenous valves and platelet-mediated hemostasis at the lymphovenous junctions maintain life-long separation of the blood and lymphatic vascular systems. Here, we review murine models that exhibit failure of blood-lymph separation to highlight the novel mechanisms and molecular targets for the modulation of lymphatic disorders. Specifically, we focus on the transcription factors, cofactors, and signaling pathways that regulate lymphovenous valve development and platelet-mediated lymphovenous hemostasis, which cooperate to maintain blood-lymph separation.
Topics: Animals; Blood Platelets; Gene Expression Regulation, Developmental; Hemostasis; Humans; Lymph; Lymphangiogenesis; Lymphatic Vessels; Mice; Signal Transduction
PubMed: 30758642
DOI: 10.1007/s00018-019-03042-3 -
Immunogenetics Mar 2019Every biological fluid, blood, interstitial fluid and lymph, urine, saliva, lacrimal fluid, nipple aspirate, and spinal fluid, contains a peptidome-degradome derived... (Review)
Review
Every biological fluid, blood, interstitial fluid and lymph, urine, saliva, lacrimal fluid, nipple aspirate, and spinal fluid, contains a peptidome-degradome derived from the cellular secretome along with byproducts of the metabolic/catabolic activities of each parenchymal organ. Clement et al. (J Proteomics 78:172-187, 2013), Clement et al. (J Biol Chem 291:5576-5595, 2016), Clement et al. (PLoS One 5:e9863, 2010), Clement et al. (Trends Immunol 32:6-11, 2011), Clement et al. (Front Immunol 4:424, 2013), Geho et al. (Curr Opin Chem Biol 10, 50-55, 2006), Interewicz et al. (Lymphology 37:65‑72, 2004), Leak et al. (Proteomics 4:753‑765, 2004), Popova et al. (PLoS One 9:e110873, 2014), Zhou et al. (Electrophoresis 25:1289‑1298, 2004), D'Alessandro et al. (Shock 42:509‑517, 2014), Dzieciatkowska et al. (Shock 42:485‑498, 2014), Dzieciatkowska et al. (Shock 35:331‑338, 2011), Jordan et al. (J Surg Res 143:130‑135, 2007), Peltz et al. (Surgery 146:347‑357, 2009), Zurawel et al. (Clin Proteomics 8:1, 2011), Ling et al. (Clin Proteomics 6:175‑193, 2010), Sturm et al. (Nat Commun 4:1616, 2013). Over the last decade, qualitative and quantitative analysis of the biological fluids peptidome and degradome have provided a dynamic measurement of tissue homeostasis as well as the tissue response to pathological damage. Proteomic profiling has mapped several of the proteases and resulting degradation by-products derived from cell cycle progression, organ/tissue remodeling and cellular growth, physiological apoptosis, hemostasis, and angiogenesis. Currently, a growing interest lies in the degradome observed during pathological conditions such as cancer, autoimmune diseases, and immune responses to pathogens as a way to exploit biological fluids as liquid biopsies for biomarker discovery Dzieciatkowska et al. (Shock 42:485-498, 2014), Dzieciatkowska et al. (Shock 35:331-338, 2011), Ling et al. (Clin Proteomics 6:175-193, 2010), Ugalde et al. (Methods Mol Biol 622:3-29, 2010), Quesada et al. (Nucleic Acids Res 37:D239‑243, 2009), Cal et al. (Front Biosci 12, 4661-4669, 2007), Shen et al. (PLoS One 5:e13133, 2010a), Antwi et al. (Mol Immunol 46:2931-2937, 2009a), Antwi et al. (J Proteome Res 8:4722‑4731, 2009b), Bedin et al. (J Cell Physiol 231, 915‑925, 2016), Bery et al. (Clin Proteomics 11:13, 2014), Bhalla et al. (Sci Rep 7:1511, 2017), Fan et al. (Diagn Pathol 7:45, 2012a), Fang et al. (Shock 34:291‑298, 2010), Fiedler et al. (Clin Cancer Res 15:3812‑3819, 2009), Fredolini et al. (AAPS J 12:504‑518, 2010), Greening et al. (Enzymes 42:27‑64, 2017), He et al. (PLoS One 8:e63724, 2013), Huang et al. (Int J Gynecol Cancer 28:355‑362, 2018), Hashiguchi et al. (Med Hypotheses 73:760‑763, 2009), Liotta and Petricoin (J Clin Invest 116:26‑30, 2006), Petricoin et al. (Nat Rev Cancer 6:961‑967, 2006), Shen et al. (J Proteome Res 9:2339‑2346, 2010a), Shen et al. (J Proteome Res 5:3154‑3160, 2006), Smith (Clin Proteomics 11:23, 2014), Wang et al. (Oncotarget 8:59376‑59386, 2017), Yang et al. (Clin Exp Med 12:79‑87, 2012a), Yang et al. (J Clin Lab Anal 26:148‑154, 2012b), Yang et al. (Anat Rec (Hoboken) 293:2027‑2033, 2010), Zapico-Muniz et al. (Pancreas 39:1293‑1298, 2010), Villanueva et al. (Mol Cell Proteomics 5:1840‑1852, 2006), Robbins et al. (J Clin Oncol 23:4835‑4837, 2005), Klupczynska et al. (Int J Mol Sci 17:410, 2016). In this review, we focus on the current knowledge of the degradome/peptidome observed in two main biological fluids (plasma and lymph) during physiological and pathological conditions and its importance for immune surveillance.
Topics: Animals; HLA Antigens; Humans; Ligands; Lymph; Peptide Fragments; Plasma; Proteolysis
PubMed: 30343358
DOI: 10.1007/s00251-018-1093-z