Cellular Origins of the Lymphatic Endothelium: Implications for Cancer Lymphangiogenesis

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.