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The lymphatic system maintains tissue fluid balance, and dysfunction of lymphatic vessels and valves causes human lymphedema syndromes. Yet, our knowledge of the molecular mechanisms underlying lymphatic vessel development is still limited. Here, we show that cyclin-dependent kinase 5 (Cdk5) is an essential regulator of lymphatic vessel development. Endothelial-specific Cdk5 knockdown causes congenital lymphatic dysfunction and lymphedema due to defective lymphatic vessel patterning and valve formation. We identify the transcription factor Foxc2 as a key substrate of Cdk5 in the lymphatic vasculature, mechanistically linking Cdk5 to lymphatic development and valve morphogenesis. Collectively, our findings show that Cdk5–Foxc2 interaction represents a critical regulator of lymphatic vessel development and the transcriptional network underlying lymphatic vascular remodeling. The mechanisms regulating lymphatic vessel development and function are still largely unknown. Here, the authors show that the protein kinase Cdk5 is required for lymphatic vessel development by regulating the activity of the transcription factor Foxc2 and its target genes.

Background Many attempts to prevent lymphatic complications following therapeutic lymph node dissection (TLND) have included modifications in surgical techniques through the use of ultrasonic scalpels (USS) or lymphostatic agents. Previous randomized studies that enrolled heterogeneous groups of patients attempted to confirm the efficacy of such techniques. The aim of the present study was to evaluate the efficacy of the USS following TLND. Methods Between 2009 and 2013, patients undergoing inguinal or axillary TLND or completion lymph node dissection after positive sentinel lymph node biopsy for melanoma, squamous cell carcinoma or sarcoma were randomized into two surgical dissection technique groups. In the USS dissection arm, surgery was conducted using a USS. These were compared with a control group whereby ligation and monopolar electrocautery was utilized. For axillary dissection, a standardized level III lymphadenectomy was performed. A complete inguinal lymphadenectomy including Cloquet’s node was performed, and at the end of the procedure a Redon suction drain was routinely placed in the axilla and groin. The primary endpoint was to compare the time to drain removal in both groups, while the secondary endpoint was to evaluate the rate of complications (infection, fistula, lymphocele formation, wound dehiscence, lymphedema) between the two groups. Results A total of 80 patients were enrolled in this trial; 40 patients were randomly assigned to both the USS group and the control (C) group. No significant differences were observed in terms of duration of drainage (USS: 31 ± 20 vs. C: 32 ± 18; p  = 0.83); however, a significantly increased rate of lymphedema (defined as an increased circumference of the operated limb of more than 10 %) was identified in the USS group (USS: 50 % vs. C: 27.5 %; p  = 0.04). No other significant differences were recorded for postoperative complications, including surgical site infection (USS: 5 % vs. C: 7.5 %; p  = 0.68), lymphatic fistula (USS: 5 % vs. C: 2.5 %; p  = 0.62), lymphocele (USS: 32.5 % vs. C: 22.5 %; p  = 0.33), and hematoma (USS: 5 % vs. C: 2.5 %; p  = 0.62). Conclusion The use of USS failed to offer any significant reduction in length of drain usage and operative complication, but it seems to increase the rate of lymphedema formation.

Key Points The lymphatic system serves an integral role in fluid homeostasis, lipid metabolism and immune defence, and influences a diverse range of diseases, including infection, inflammatory and metabolic diseases, and cancer. Targeted delivery to the lymphatics and lymphoid tissues has the potential to improve oral bioavailability, enhance vaccination and tolerance induction, target delivery to lymph-resident cancer metastasis and infection, and promote the utility of treatments for diseases ranging from infections such as HIV to cancer and inflammatory and metabolic disease. Selective delivery to the lymph is largely dictated by size, as macromolecules or particulate carriers are excluded from access to blood capillaries, whereas interstitial fluid flow sweeps larger constructs into the more permeable lymphatics. Lymphatic targeting may be achieved via the delivery of macromolecular therapeutics (for example, proteins and peptides), small-molecule therapeutics in association with macromolecular carriers (for example, nanoparticles, polymers, liposomes and dendrimers) or small-molecule therapeutics that associate, in situ , with endogenous macromolecular constructs (for example, lipoproteins and proteins) or cells that are transported from interstitial tissues via lymphatic rather than blood capillaries. The design of lymphatic delivery systems ranges from simple systems that rely on passive lymphatic access to more complex structures that integrate into endogenous lymph transport processes. Recent studies have suggested the presence of active transport processes that facilitate entry across the lymphatic endothelium, and delivery systems that harness these processes are emerging. In many cases, disease progression results in lymphatic remodelling. Next-generation lymphatic targeting approaches will probably seek to harness a better understanding of changes to lymphatic structure and function in disease to promote targeting to the lymphatics and enhance therapeutic utility. Future efforts in lymphatic drug delivery might usefully address barriers to the clinical translation of lymphotropic delivery vehicles, such as the lack of well-validated models to predict lymphatic uptake in humans. Targeted delivery to the lymphatic system has the potential to improve bioavailability, enhance prophylactic and therapeutic vaccination or tolerance induction, and target drug delivery to lymph-resident infection or metastasis. In this Review, Trevaskis, Kaminskas and Porter provide an overview of lymphatic targeting and delivery strategies in drug development, and discuss the clinical applications of these approaches. The lymphatic system serves an integral role in fluid homeostasis, lipid metabolism and immune control. In cancer, the lymph nodes that drain solid tumours are a primary site of metastasis, and recent studies have suggested intrinsic links between lymphatic function, lipid deposition, obesity and atherosclerosis. Advances in the current understanding of the role of the lymphatics in pathological change and immunity have driven the recognition that lymph-targeted delivery has the potential to transform disease treatment and vaccination. In addition, the design of lymphatic delivery systems has progressed from simple systems that rely on passive lymphatic access to sophisticated structures that use nanotechnology to mimic endogenous macromolecules and lipid conjugates that 'hitchhike' onto lipid transport processes. Here, we briefly summarize the lymphatic system in health and disease and the varying mechanisms of lymphatic entry and transport, as well as discussing examples of lymphatic delivery that have enhanced therapeutic utility. We also outline future challenges to effective lymph-directed therapy.

Ageing is a major risk factor for many neurological pathologies, but its mechanisms remain unclear. Unlike other tissues, the parenchyma of the central nervous system (CNS) lacks lymphatic vasculature and waste products are removed partly through a paravascular route. (Re)discovery and characterization of meningeal lymphatic vessels has prompted an assessment of their role in waste clearance from the CNS. Here we show that meningeal lymphatic vessels drain macromolecules from the CNS (cerebrospinal and interstitial fluids) into the cervical lymph nodes in mice. Impairment of meningeal lymphatic function slows paravascular influx of macromolecules into the brain and efflux of macromolecules from the interstitial fluid, and induces cognitive impairment in mice. Treatment of aged mice with vascular endothelial growth factor C enhances meningeal lymphatic drainage of macromolecules from the cerebrospinal fluid, improving brain perfusion and learning and memory performance. Disruption of meningeal lymphatic vessels in transgenic mouse models of Alzheimer’s disease promotes amyloid-β deposition in the meninges, which resembles human meningeal pathology, and aggravates parenchymal amyloid-β accumulation. Meningeal lymphatic dysfunction may be an aggravating factor in Alzheimer’s disease pathology and in age-associated cognitive decline. Thus, augmentation of meningeal lymphatic function might be a promising therapeutic target for preventing or delaying age-associated neurological diseases. Meningeal lymphatic dysfunction promotes amyloid-β deposition in the meninges and worsens brain amyloid-β pathology, acting as an aggravating factor in Alzheimer’s disease and in age-associated cognitive decline; improving meningeal lymphatic function could help to prevent or delay age-associated neurological diseases.

Blood vessels form a closed circulatory system, whereas lymphatic vessels form a one-way conduit for tissue fluid and leukocytes. In most vertebrates, the main function of lymphatic vessels is to collect excess protein-rich fluid that has extravasated from blood vessels and transport it back into the blood circulation. Lymphatic vessels have an important immune surveillance function, as they import various antigens and activated antigen-presenting cells into the lymph nodes and export immune effector cells and humoral response factors into the blood circulation. Defects in lymphatic function can lead to lymph accumulation in tissues, dampened immune responses, connective tissue and fat accumulation, and tissue swelling known as lymphedema. This review highlights the most recent developments in lymphatic biology and how the lymphatic system contributes to the pathogenesis of various diseases involving immune and inflammatory responses and its role in disseminating tumor cells.

There are two vascular networks in mammals that coordinately function as the main supply and drainage systems of the body. The blood vasculature carries oxygen, nutrients, circulating cells, and soluble factors to and from every tissue. The lymphatic vasculature maintains interstitial fluid homeostasis, transports hematopoietic cells for immune surveillance, and absorbs fat from the gastrointestinal tract. These vascular systems consist of highly organized networks of specialized vessels including arteries, veins, capillaries, and lymphatic vessels that exhibit different structures and cellular composition enabling distinct functions. All vessels are composed of an inner layer of endothelial cells that are in direct contact with the circulating fluid; therefore, they are the first responders to circulating factors. However, endothelial cells are not homogenous; rather, they are a heterogenous population of specialized cells perfectly designed for the physiological demands of the vessel they constitute. This review provides an overview of the current knowledge of the specification of arterial, venous, capillary, and lymphatic endothelial cell identities during vascular development. We also discuss how the dysregulation of these processes can lead to vascular malformations, and therapeutic approaches that have been developed for their treatment.

Cancer metastasis is the process by which primary cancer cells invade through the lymphatic or blood vessels to distant sites. The molecular mechanisms by which cancer cells spread either through the lymphatic versus blood vessels or both are not well established. Two major developments have helped us to understand the process more clearly. First, the development of the sentinel lymph node (SLN) concept which is well established in melanoma and breast cancer. The SLN is the first lymph node in the draining nodal basin to receive cancer cells. Patients with a negative SLN biopsy show a significantly lower incidence of distant metastasis, suggesting that the SLN may be the major gateway for cancer metastasis in these cancer types. Second, the discovery and characterization of several biomarkers including VEGF-C, LYVE-1, Podoplanin and Prox-1 have opened new vistas in the understanding of the induction of lymphangiogenesis by cancer cells. Cancer cells must complete multiple steps to invade the lymphatic system, some of which may be enabled by the evolution of new traits during cancer progression. Thus, cancer cells may spread initially through the main gateway of the SLN, from which evolving cancer clones can invade the blood vessels to distant sites. Cancer cells may also enter the blood vessels directly, bypassing the SLN to establish distant metastases. Future studies need to pinpoint the molecules that are used by cancer cells at different stages of metastasis via different routes so that specific therapies can be targeted against these molecules, with the goal of stopping or preventing cancer metastasis.

Key Points The lymphatic vasculature is essential for immune function, tissue fluid homeostasis and the absorption of dietary fat. The process of lymphangiogenesis involves the formation of new lymphatic vessels from pre-existing lymphatics; this occurs during embryonic development, wound healing and in various pathological contexts, including cancer. Tumour cells and cells of the tumour microenvironment produce growth factors that promote lymphangiogenesis from initial lymphatics, as well as the enlargement of initial and collecting lymphatic vessels in and around solid tumours. The enlargement of collecting lymphatics can involve remodelling of these vessels by smooth muscle cells. Lymphangiogenic factors (such as vascular endothelial growth factor C (VEGFC) and VEGFD) can induce the metastatic spread of tumours in mouse models of cancer. Clinicopathological studies have shown that the production of lymphangiogenic factors, lymphangiogenesis and lymphatic remodelling can correlate with cancer progression. Lymphatic vessels provide a therapeutic target for modulating the immune response to cancer and restricting metastasis; clinical trials of agents that target lymphangiogenic signalling pathways are underway. Mouse models and genome-wide functional screening approaches might identify further important signalling pathways in tumour lymphangiogenesis that could be potential diagnostic and therapeutic targets. The past decade has been exciting in terms of research into the molecular and cellular biology of lymphatic vessels in cancer. This Review discusses the specific roles of distinct lymphatic vessel subtypes in cancer, and the potential diagnostic and therapeutic opportunities. The generation of new lymphatic vessels through lymphangiogenesis and the remodelling of existing lymphatics are thought to be important steps in cancer metastasis. The past decade has been exciting in terms of research into the molecular and cellular biology of lymphatic vessels in cancer, and it has been shown that the molecular control of tumour lymphangiogenesis has similarities to that of tumour angiogenesis. Nevertheless, there are significant mechanistic differences between these biological processes. We are now developing a greater understanding of the specific roles of distinct lymphatic vessel subtypes in cancer, and this provides opportunities to improve diagnostic and therapeutic approaches that aim to restrict the progression of cancer.

Whether cancer cells metastasize from the primary site to the distant sites via the lymphatic vessels or the blood vessels directly into the circulation is still under intense study. In this review article, we follow the journey of cancer cells metastasizing to the sentinel lymph nodes and beyond to the distant sites. We emphasize cancer heterogeneity and microenvironment as major determinants of cancer metastasis. Multiple molecules have been found to be associated with the complicated process of metastasis. Based on the large sentinel lymph node data, it is reasonable to conclude that cancer cells may metastasize through the blood vessels in some cases but in most cases, they use the sentinel lymph nodes as the major gateway to enter the circulation to distant sites.

The lymphatic system is fundamentally important to cardiovascular disease, infection and immunity, cancer, and probably obesity--the four major challenges in healthcare in the 21st century. This Review will consider the manner in which new knowledge of lymphatic genes and molecular mechanisms has demonstrated that lymphatic dysfunction should no longer be considered a passive bystander in disease but rather an active player in many pathological processes and, therefore, a genuine target for future therapeutic developments. The specific roles of the lymphatic system in edema, genetic aspects of primary lymphedema, infection (cellulitis/erysipelas), Crohn's disease, obesity, cancer, and cancer-related lymphedema are highlighted.