Prevention and Treatment of Lymphatic Metastasis by Antilymphangiogenic Therapy

Cancer cells escape a tumor by two primary routes—blood vessels and lymphatic vessels—to establish distant metastases. Thus, it seems reasonable to hypothesize that blocking the growth of new blood vessels (angiogenesis) and lymphatic vessels (lymphangiogenesis) will inhibit hematogenic and lymphogenic metastases, respectively. An impressive array of preclinical studies has demonstrated prevention and suppression of hematogenic metastases by antiangiogenic and antivascular approaches. Whether antilymphangiogenic and antilymphatic approaches will yield similar results for lymphogenic metastases remains to be seen. Both vascular endothelial growth factor (VEGF)-C and VEGF-D induce angiogenesis (1,2) and lymphangiogenesis (1,3–5) in tumors and are associated with lymphogenic metastasis in a variety of human tumors (6). Last year Stacker et al. (1) presented the first direct evidence for the prevention of lymphatic metastasis from a tumor grown in the mammary fat pad by blocking VEGF-D. In this issue of the Journal, He et al. (7) report similar findings in subcutaneously grown tumors that lack VEGF-D by blocking VEGF-C. Although Stacker et al. (1) used a blocking antibody against VEGF-D, He et al. (7) used a receptor-antibody fusion protein (VEGFR-3-Ig fusion protein) that can trap both VEGF-C and VEGF-D. The receptor-antibody was generated in vivo by cancer cells engineered to secrete soluble VEGFR-3-Ig or by the liver infected by an adenovirus expressing VEGFR-3-Ig. In both studies, treatment was initiated within a day after tumor implantation, before the primary tumor became established, and lymph nodes were examined for metastatic lesions 4–6 weeks later. Blocking VEGF-C or VEGF-D suppressed lymphangiogenesis associated with the primary tumor and regional lymph node metastasis. These are exciting and timely findings that raise many important questions about the biology and potential treatment of lymphatic metastases.