Metastasis is the major cause of mortality from malignant tumors. Metastatic cancer cells spread to various organs via the vascular system (hematogenic metastasis) and/or the lymphatic system (lymphogenic metastasis). Compared with our understanding of a tumor’s vascular system, our understanding of its lymphatic system is minimal, although it has been known for some time that lymphatic vessels are present in the margins of animal and human tumors. Indeed, invasion of peritumor lymphatics is considered to be a poor prognostic factor for patients with some tumors (eg, breast, colorectal, and endometrial cancers), and lymphatic metastasis is a major cause of morbidity and mortality for others (eg, melanoma, head and neck, lung, and cervical cancers; www. uptodate. com). For nearly a century, it has been a hotly debated issue whether anatomically defined lymphatic vessels are present within solid tumors (1) and, if so, whether they function (2)(Fig. 1). However, the discovery of two lymphangiogenic molecules, vascular endothelial growth factor (VEGF)-C and VEGF-D, and their receptor VEGFR3 changed the landscape for lymphatic studies by providing the critical molecular players and tools (3). A series of recent reports (4–8) suggests that overexpression of VEGF-C or-D is associated with lymphangiogenesis in tumors and with increased lymphatic metastasis in mice. Despite the aforementioned studies (4–8), many questions remain regarding the molecular mechanisms of lymphangiogenesis, the specificity of growth factors and lymphatic markers, and the ability of lymphatics to function within tumors.

What molecular mechanisms are involved in lymphangiogenesis in tumors? VEGF-C or VEGF-D can induce lymphangiogenesis via the activation of signaling pathways through VEGFR3 on lymphatic endothelial cells (3) and are associated with lymphogenic metastasis in a variety of tumors (Table 1). However, they can also increase vascular angiogenesis (4, 8, 9) and increase distant metastasis in some tumors (5), indicating that they lack specificity for lymphatic vessels. Like vascular angiogenesis, other positive and negative regulators, such as angiopoietins (10), and other receptors, such as ß-chemokine receptor D6 and neuropilin-2 (11), may be involved in lymphangiogenesis, and mechanisms analogous to cooption, intussusception, sprouting, and vasculogenesis may operate in lymphatic growth (12). Similar to the recently discovered organ-specific angiogenic molecule (EG-VEGF)(13) and endothelial precursor cells (14), there may be organ-specific lymphangiogenic molecules and lymphatic endothelial precursor cells that contribute to tumor-associated lymphangiogenesis. Moreover, the proteolytic processing of lymphangiogenic molecules as well as the phenotype and function of the resulting lymphatics may depend not only on the tumor type but also on the host organ in which the tumor is growing (3, 8, 9).