Tumor Regulation of Lymph Node Lymphatic Sinus Growth and Lymph Flow in Mice and in Humans

Abstract

The lymphatic vasculature collects and drains fluid and cells from the periphery through lymph nodes (LNs) for immune monitoring, and then returns lymph to the bloodstream. During immune responses LNs enlarge and remodel, featuring extensive growth of lymphatic sinuses (lymphangiogenesis). This LN lymphangiogenesis also arises in cancer, and is associated with altered lymph drainage through LNs. Studies of mouse solid tumor models identified lymphatic sinus growth throughout tumor-draining LNs (TDLNs), and increased lymph flow through the expanded sinuses. Mice developing B cell lymphomas also feature LN lymphangiogenesis and increased lymph flow, indicating that these changes occur in lymphoma as well as in solid tumors. These LN alterations may be key to promote tumor growth and metastasis to draining LNs and distant organs. Lymphatic sinus growth within the TDLN may suppress anti-tumor-immune responses, and/or the increased lymph drainage could promote metastasis to draining LNs and distant organs. Investigations of human cancers and lymphomas are now identifying TDLN lymphatic sinus growth and increased lymph flow, that correlate with metastasis and poor prognosis. Pathology assessment of TDLN lymphangiogenesis or noninvasive imaging of tumor lymph drainage thus could potentially be useful to assist with diagnosis and treatment decisions. Moreover, the expanded lymphatic sinuses and increased lymph flow could facilitate vaccine or drug delivery, to manipulate TDLN immune functioning or to treat metastases. The insights obtained thus far should encourage further investigation of the mechanisms and consequences of TDLN lymphatic sinus growth and lymph flow alterations in mouse cancer models, and in human cancer patients.