Lymphatic vessels in cancer

Abstract

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.

Pathological angiogenesis: mechanisms and therapeutic strategies

“…The assembly of the lymphatic system occurs during embryonic development through coordinated mechanisms involving precursor cells [110] and epigenetic pathways [111], some of which are recapitulated during lymphatic neogenesis (such as in cancer) [112][113][114][115][116][117]. The identification of a number of lymphaticselective molecular markers such as podoplanin, VEGFR3, LYVE-1, and PROX-1, has enabled detailed studies of the lymphatic vasculature and lymphangiogenesis [118][119][120]. The most studied agonists of lymphangiogenesis are VEGFC and VEGFD [121,122], that can bind to and signal through VEGFR3 [123].…”

Immunomodulatory Responses of Subcapsular Sinus Floor Lymphatic Endothelial Cells in Tumor-Draining Lymph Nodes

“…Tumor-draining LNs undergo massive enlargement and remodeling, which correlates with subsequent LN metastasis and poor patient outcome in various cancer types [ 9 , 10 , 11 ]. Of note, these changes may occur before metastatic colonization of the LNs, indicating the involvement of tumor-derived factors, such as extracellular vesicles (EVs) and soluble growth factors carried by afferent lymph [ 12 , 13 , 14 , 15 ].…”

Mechanisms of extracellular vesicle-mediated immune evasion in melanoma

“…Melanoma EVs are also present in the blood, implying that they may affect immune responses systemically. Additionally, there is considerable evidence that melanoma EVs can be taken up by tumor-associated lymphatic vessels and are transported to draining LNs, important sites not only for early melanoma metastasis but also for the initiation (and inhibition) of tumor-specific immune responses ( 48 , 49 ). In fact, initial lymphatic vessels, in contrast to blood vessels, are very permeable for particles up to 100-200 nm in diameter due to a specific junctional organization (“Button-like junctions”) between adjacent LECs.…”

“…In fact, initial lymphatic vessels, in contrast to blood vessels, are very permeable for particles up to 100-200 nm in diameter due to a specific junctional organization (“Button-like junctions”) between adjacent LECs. Furthermore, interstitial fluid dynamics facilitate EV transport towards lymphatic vessels within or around the tumor site ( 49 ). Indeed, in a seminal study in 2011, Joshua Hood and colleagues found that after interstitial injection, fluorescently labeled B16F10-derived EVs specifically and efficiently homed to draining LNs where they accumulated ( 50 ).…”