The lymphatic system comprises a network of lymphoid tissues and vessels that drains the extracellular compartment of most tissues. During tumor development, lymphatic endothelial cells (LECs) substantially expand in response to VEGFR-3 engagement by VEGF-C produced in the tumor microenvironment, a process known as tumor-associated lymphangiogenesis. Lymphatic drainage from the tumor to the draining lymph nodes consequently increases, powering interstitial flow in the tumor stroma. The ability of a tumor to induce and activate lymphatic growth has been positively correlated with metastasis. Much effort has been made to identify genes responsible for tumor-associated lymphangiogenesis. Inhibition of lymphangiogenesis with soluble VEGFR-3 or with specific monoclonal antibodies decreases tumor spread to LNs in rodent models. Importantly, tumor-associated lymphatics do not only operate as tumor cell transporters but also play critical roles in anti-tumor immunity. Therefore, metastatic as well as primary tumor progression can be affected by manipulating tumor-associated lymphatic remodeling or function. Here, we review and discuss our current knowledge on the contribution of LECs immersed in the tumor microenvironment as immunoregulators, as well as a possible functional remodeling of LECs subsets depending on the organ microenvironment.
Highlights d ACKR4 is expressed in a flow-dependent manner in afferent lymphatic collectors d ACKR4 scavenges CCR7 ligands like CCL21 and removes them from the collector surface d Chemokine scavenging prevents T cell accumulation in inflamed dermal collectors d In the absence of ACKR4, T cell migration to draining lymph nodes is reduced
To fulfill their function of immune defense and surveillance, most leukocytes are not stationary positioned in the body but constantly migrate within tissues or circulate between tissues and organs. 1,2 Considering that active interstital migration is very slow, leukocytes use blood and lymphatic vessels to rapidly move between different sites of the body. Over the past decades, the process of immune cell migration out of blood vessels has been studied in great detail, culminating in the identification of the intravascular adhesion cascade and a plethora of molecules involved in leukocyte extravasation from different blood vascular beds in steady-state and in inflammation. [3][4][5]
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