Cellular Origins of the Lymphatic Endothelium: Implications for Cancer Lymphangiogenesis

Abstract

The lymphatic system plays important roles in physiological and pathological conditions. During cancer progression in particular, lymphangiogenesis can exert both positive and negative effects. While the formation of tumor associated lymphatic vessels correlates with metastatic dissemination, increased severity and poor patient prognosis, the presence of functional lymphatics is regarded as beneficial for anti-tumor immunity and cancer immunotherapy delivery. Therefore, a profound understanding of the cellular origins of tumor lymphatics and the molecular mechanisms controlling their formation is required in order to improve current strategies to control malignant spread. Data accumulated over the last decades have led to a controversy regarding the cellular sources of tumor-associated lymphatic vessels and the putative contribution of non-endothelial cells to this process. Although it is widely accepted that lymphatic endothelial cells (LECs) arise mainly from pre-existing lymphatic vessels, additional contribution from bone marrow-derived cells, myeloid precursors and terminally differentiated macrophages, has also been claimed. Here, we review recent findings describing new origins of LECs during embryonic development and discuss their relevance to cancer lymphangiogenesis.

Keywords: development; lymphangiogenesis; lymphatic; origin; tumor.

FIGURE 1

Overview of the origins of lymphatic endothelial cells in embryonic development and cancer. Schematic illustrations depicting the origins of cells contributing to the formation of (A) early lymphatics in the zebrafish trunk, (B) organ-specific lymphatics in the mouse embryo and (C) tumor-associated lymphatics. (A) A cluster of angioblasts (yellow) located in the ventral side of the PCV are the source of the parachordal cells (green), the primordial lymphatic progenitors in the embryonic zebrafish trunk. Arteries are depicted in red and veins in blue. (B) Lineage-tracing experiments in mice revealed mixed origin of organ-specific lymphatic networks. Venous (blue), paraxial mesoderm (pink) and additional non-venous (orange) origins give rise to organ-specific LECs (detailed in Table1). (C) Distinct cell populations contribute to tumor lymphatics. Tumor LECs form primarily via sprouting lymphangiogenesis from pre-exiting lymphatics (green). In addition, BMDCs, including hematopoietic stem cells (HSCs), and cells of the myeloid lineage have also been identified as non-endothelial sources of tumor LECs.