Regulation of pathological lymphangiogenesis requires factors distinct from those governing physiological lymphangiogenesis

Physiological lymphangiogenesis requires key factors such as vascular endothelial growth factor (VEGF)-C and the homeodomain transcription factor Prox1 to induce the formation of primitive lymph sacs from veins during mammalian development. However, pathological lymphangiogenesis, defined as new lymphatic vessel growth resulting from pathogenic stimuli, may utilize additional signaling pathways and/or cell types in conditions such as tumor progression or inflammatory responses. In fact, although both physiological and pathological lymphatic vascular development share fundamental mechanisms, pleiotropic growth factors and/or pro-inflammatory cytokines mediate lymphangiogenesis in experimental models of pathologic lymphangiogenesis. This review summarizes molecular mechanisms underlying lymphangiogenesis in pathological conditions and focuses in particular on current findings relevant to tumor-associated lymphangiogenesis.