Therapeutic Targeting of the Lymphovascular System in Cancer: Promise and Challenge

Acquisition of the metastatic phenotype by cells within a solid tumor initiates a sequence of events that represent, for most cancer patients, the primary cause of morbidity and mortality of this disease. This realization gave birth to a field of research focused on unraveling the nature of the metastatic process and led to many groundbreaking scientific achievements. However, it has proven extremely difficult to translate these discoveries into efficacious treatments that target the metastatic process. While hematogenous dissemination of tumor cells through blood vessels is well understood, the contribution of lymphatic metastasis to the overall metastatic process is more controversial. We attempt to define the common ground that must be achieved by basic scientists, translational researchers, and clinicians before targeting of lymphatic metastasis can be attempted in the clinic. To better illustrate the key issues involved in this debate, we examine the controversies related to tumor dissemination through lymphatic vessels from two distinct points of view. First, we review the clinical data regarding invasive melanoma, a tumor with propensity for lymphatic metastasis as the initial route of metastasis. Second, we examine how the uncertainty regarding the clinical relevance of lymphatic metastasis affects the plans for clinical development of antibody antagonists of the vascular endothelial growth factor receptor-3 (VEGFR-3), an important mediator of tumor lymphangiogenesis. Our goal is to provide a framework for ongoing dialog in the field.