Despite advances in targeted therapies, cytotoxic chemotherapy remains a mainstay in cancer treatment. Though decades of research have demonstrated the power of chemotherapy to inhibit tumor cell growth and survival, emerging evidence suggests tumor cells are not its only targets during cancer treatment. The tumor microenvironment has been shown to be a powerful force in tumor progression and metastasis. However, though it is chronically exposed to therapy during systemic chemotherapeutic delivery, the effects of these compounds on the tumor microenvironment remain largely unknown. The lymphatic vasculature is an important component of the tumor microenvironment and a first step in metastatic dissemination of many cancers. However, although lymphatics are responsible for drainage of residual chemotherapeutic drugs from the tumor, the impact of this exposure has not been studied.

The aim of this dissertation is to examine the effects of chemotherapy on lymphatic vasculature and the resulting consequences to cancer metastasis, the primary cause of mortality in cancer-related deaths and a major clinical hurdle. To this end, a host of techniques and analytic methods are employed, including the development and use of a novel tissue engineered human in vitro system to model the invasive interface between tumor and lymphatics, ex vivo rat mesentery models to visualize whole lymphovascular networks, a variety of animal models of cancer, and patient samples. Here, this dissertation discovers two classes of chemotherapies, taxanes and platinums, elicit rampant VEGFR3-dependent lymphangiogenesis and lymphatic remodeling to promote cancer metastasis via two distinct mechanisms. Importantly, chemotherapy-induced lymphangiogenesis can be successfully prevented through concurrent inhibition of VEGFR3, a receptor specific to lymphatics that drives their proliferation and survival. Together, this work uncovers a previously unknown counter-therapeutic effect of chemotherapy, reducing its efficacy and promoting metastasis. These findings will have broad-reaching implications for cancer patients receiving taxanes and platinums and may support the inclusion of anti-VEGFR3 therapy into these regimens for enhanced anti-cancer efficacy.