Lymphatic Valves and Lymph Flow in Cancer-Related Lymphedema

Abstract

Lymphedema is a complex disease caused by the accumulation of fluid in the tissues resulting from a dysfunctional or damaged lymphatic vasculature. In developed countries, lymphedema most commonly occurs as a result of cancer treatment. Initially, impaired lymph flow causes edema, but over time this results in inflammation, fibrotic and fatty tissue deposition, limited mobility, and bacterial infections that can lead to sepsis. While chronically impaired lymph flow is generally believed to be the instigating factor, little is known about what pathophysiological changes occur in the lymphatic vessels to inhibit lymph flow. Lymphatic vessels not only regulate lymph flow through a variety of physiologic mechanisms, but also respond to lymph flow itself. One of the fascinating ways that lymphatic vessels respond to flow is by growing bicuspid valves that close to prevent the backward movement of lymph. However, lymphatic valves have not been investigated in cancer-related lymphedema patients, even though the mutations that cause congenital lymphedema regulate genes involved in valve development. Here, we review current knowledge of the regulation of lymphatic function and development by lymph flow, including newly identified genetic regulators of lymphatic valves, and provide evidence for lymphatic valve involvement in cancer-related lymphedema.

Keywords: VE-cadherin; cancer; congenital; fibrosis; inflammation; mechanotransduction; shear stress.

Figure 1

Pathological changes in the arm during the development of cancer-related lymphedema. In a healthy lymphatic vasculature (leftmost panel), valves prevent the retrograde flow of lymph, ensuring its efficient transport from the lymphatic capillaries to the lymph node. Following surgical intervention as part of cancer therapy, some patients will develop cancer-related lymphedema. Lymph node removal surgery reduces the flow of lymph through the lymphatic vasculature (middle panel). Over time, however, collecting lymphatic vessels exhibit increased inflammation, thickened basement membrane, increased smooth muscle cell coverage, and dilation (right panel). Reduced lymph flow results in reduced VE-cadherin-dependent mechanotransduction signaling that reduces the expression of transcription factors required for valve maintenance, leading to valve regression. Consequently, lymph flow moves in the retrograde direction and fluid is no longer transported out of the tissue, resulting in lymphedema and fibrosis.