Advances in Drugs Targeting Lymphangiogenesis for Preventing Tumor Progression and Metastasis

Abstract

Metastasis of cancer cells from the primary tumor to other organs and tissues in the body is the leading cause of death in patients with malignancies. One of the principal ways cancer cells travel is through lymphatic vessels, and tumor invasion into the regional lymph nodes is a hallmark of early metastasis; thus, the formation of especially peritumoral lymphatic vessels is essential for tumor transportation that gives rise to further progression. In the past few decades, tumor-induced lymphangiogenesis has been testified to its tight correlation with lymphatic metastasis and poor clinical outcomes in multiple types of human malignancies, which warrants novel potential therapeutic targets for cancer treatment. As the understanding of underlying molecular mechanisms has grown tremendously over the years, an inexorable march of anti-lymphangiogenic therapy also aroused terrific interest. As a result, a great number of drugs have entered clinical trials, and some of them exhibited predominant contributions in cancer management. Herein, this review provides an updated summary of the current advances in therapies preventing lymphatic metastasis and discusses the validity of different applications.

Keywords: HGF; VEGF-C/-D; VEGFR-2/-3; angiogenesis; antibody; lymphangiogenesis; metastasis; tyrosine kinase inhibitor.

Figure 1

Brief scheme representing major lymphangiogenic pathways and drugs targeting lymphangiogenesis. Tumor cells and tumor-associated inflammatory cells induce LEC (lymphatic endothelial cell) proliferation, migration mainly through VEGF-C/-D expression, which activates subsequent VEGFR-2/-3 phosphorylation, leading to lymphangiogenesis. Various antibody drugs are shown to suppress the corresponding growth factors directly; membrane receptors, including VEGFRs, Tie2, and HGFRs, are also promising therapeutic targets. TKIs against VEGFRs and HGFRs work alongside the mAb (monoclonal antibody) and neutralizing antibodies; 3AOA (3-O-Acetyloleanolic acid) is a novel agent dampening Tie2 receptor. In addition, many drugs exert an inhibitory effect on the essential downstream pathways of the receptors: EEDW (Hedyotis diffusa Willd) and GSPP (Gekko Sulfated Glycopeptide) inhibit ERK signaling while Fucoidan and Aspirin effectively suppress NF-kB; TSA (Trichostatin A) and DMF (Dimethyl fumarate) could induce cell cycle arrest via upregulating p21 dependent pathways; Kallistatin and SiRNA VEGF-C are examples of drugs inhibiting VEGF-C and VEGFR-3 expression, respectively. The figure was created with BioRender.com.