-
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 -
Seminars in Nuclear Medicine Sep 2022Breast cancer is the most frequent cancer diagnosed in women worldwide. Accurate lymph node staging is essential for both prognosis (of early-stage disease) and... (Review)
Review
Breast cancer is the most frequent cancer diagnosed in women worldwide. Accurate lymph node staging is essential for both prognosis (of early-stage disease) and treatment (for regional control of disease) in patients with breast cancer. The sentinel lymph nodes are the regional nodes that directly drain lymph from the primary tumor. No imaging modality is accurate enough to detect lymph node metastases when a primary breast cancer is at an early stage (I or II), but sentinel lymph node biopsy is a highly reliable method for screening axillary nodes and for identifying metastatic (including micro-metastatic) disease in regional lymph nodes. Despite the widespread use of sentinel lymph node biopsy for early-stage breast cancer, relevant variations have been described regarding practical aspects of the procedure, and some variability has initially been reported regarding the rates of intraoperative sentinel lymph node identification and of false-negative findings, most likely because of differences in the size of the populations being investigated and in lymphatic mapping techniques. Nevertheless, using adequate learning curves and once a multidisciplinary team is experienced with the procedure, improved levels of accuracy are achieved.
Topics: Axilla; Breast Neoplasms; Female; Humans; Neoplasm Staging; Sentinel Lymph Node; Sentinel Lymph Node Biopsy
PubMed: 35241267
DOI: 10.1053/j.semnuclmed.2022.01.006 -
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 -
Advanced Drug Delivery Reviews Dec 2021Strategies of improving vaccine targeting ability toward lymph nodes have been attracting considerable interest in recent years, though there are remaining delivery... (Review)
Review
Strategies of improving vaccine targeting ability toward lymph nodes have been attracting considerable interest in recent years, though there are remaining delivery barriers based on the inherent properties of lymphatic systems and limited administration routes of vaccination. Recently, emerging vaccine delivery systems using various materials as carriers are widely developed to achieve efficient lymph node targeting and improve vaccine-triggered adaptive immune response. In this review, to further optimize the vaccine targeting ability for future research, the design principles of lymph node targeting vaccine delivery based on the anatomy of lymph nodes and vaccine administration routes are first summarized. Then different designs of lymph node targeting vaccine delivery systems, including vaccine delivery systems in clinical applications, are carefully surveyed. Also, the challenges and opportunities of current delivery systems for vaccines are concluded in the end.
Topics: Adaptive Immunity; Antigens; Drug Administration Routes; Drug Delivery Systems; Humans; Lymph Nodes; Nanoparticle Drug Delivery System; Vaccines
PubMed: 34363861
DOI: 10.1016/j.addr.2021.113914 -
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