The role of lymphangiogenesis and angiogenesis in tumor metastasis

Abstract

Background: Metastasis is the main cause of mortality in cancer patients. Two major routes of cancer cell spread are currently being recognized: dissemination via blood vessels (hematogenous spread) and dissemination via the lymphatic system (lymphogenous spread). Here, our current knowledge on the role of both blood and lymphatic vessels in cancer cell metastasis is summarized. In addition, I will discuss why cancer cells select one or both of the two routes to disseminate and I will provide a short description of the passive and active models of intravasation. Finally, lymphatic vessel density (LVD), blood vessel density (BVD), interstitial fluid pressure (IFP) and tumor hypoxia, as well as regional lymph node metastasis and the recently discovered primo vascular system (PVS) will be highlighted as important factors influencing tumor cell motility and spread and, ultimately, clinical outcome.

Conclusions: Lymphangiogenesis and angiogenesis are important phenomena involved in the spread of cancer cells and they are associated with a poor prognosis. It is anticipated that new discoveries and advancing knowledge on these phenomena will allow an improvement in the treatment of cancer patients.

Keywords: Angiogenesis; Lymph nodes; Lymphangiogenesis; Metastasis.

Fig. 1

Routes of cancer cell spread. Metastatic cells may enter directly into blood vessels (hematogenous spread) that vascularize the tumor mass and, in this way, disseminate to distant sites. Another trail of cancer cell spread may be the penetration into lymphatic vessels (lymphogenous spread) and dissemination via the lymph flow to sentinel and, subsequently, distant lymph nodes. Next, the cells may enter the thoracic duct, the subclavian vein and, ultimately, distant sites

Fig. 2

Origin of lymphatic endothelial cells. Endothelial cells that form neo-lymphatic vessels may originate from three alternative sources. First, they may originate from pre-existing lymphatic vessels in which lymphatic endothelial cells (LECs) proliferate and migrate, resulting in outgrowths that vascularize the tumor mass. Second, they may originate from pre-existing blood vessels in which blood endothelial cells (BECs), through the action of lymphatic growth factors, trans-differentiate into lymphatic endothelial cells. Third, they may originate from progenitor bone marrow-derived cells that, after recruitment to sites of lymphangiogenesis, in the presence of specific growth factors undergo trans-differentiation into lymphatic endothelial cells