Tumor-Associated Lymphatic Vessel Features and Immunomodulatory Functions

Abstract

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.

Comprehensive review of targeted therapy for colorectal cancer

“…170,171 Activated VEGFR-3 mediates the differentiation, migration, proliferation and survival of lymphatic endothelial cells by activating the RAS/MAPK/ ERK pathway and the PI3K-AKT/PKB pathway. [169][170][171] Although the VEGFR-3 expression level in tumor cells remains controversial, high levels of VEGF-C and VEGF-D have been observed in tumors with lymphatic metastasis, which is considered a potential explanation for cancer migration through lymphatic vessels. 172 VEGF levels and VEGFR activity are elevated in patients with CRC and other cancers and are considered to be related to poor prognosis.…”

Cellular Origins of the Lymphatic Endothelium: Implications for Cancer Lymphangiogenesis

“…LECs were shown to recruit dendritic cells via CCL21-CCR7 signaling, that migrate to present specific tumor antigens to the T cells in the lymph nodes. Therefore, dysfunctional lymphatics hamper a proper immune activation and response (Garnier et al, 2019).…”

Lymphatic Programing and Specialization in Hybrid Vessels

“…The marker expression of these vessels further differ from valves, designed to block or allow intraluminal passage based on pressure gradients, and lymph node lymphatics which are more specialized for the presentation of antigens. Furthermore, the endothelia of these different lymphatic structures are influenced by signals from the local microand macro-environment, including from immune cells, extracellular matrix, and organ-specific cells and structures, which is most starkly exemplified by the changes that occur during tumorassociated lymphatic remodeling (Lutter and Makinen, 2014;Petrova and Koh, 2018;Wong et al, 2018;Garnier et al, 2019).…”