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.

In Vitro and In Vivo Antitumor Assay of Mitochondrially Targeted Fluorescent Half-Sandwich Iridium(III) Pyridine Complexes

“…Tumor metastasis (diffusion) is the process of cancer cells spreading from the original tumor location to other organs and tissues and then continuing to grow. , This feature is the main cause of poor prognosis and treatment failure and poses a potentially fatal threat to patients. In this study, a wound healing assay was used to evaluate the antimigration ability of these complexes .…”

Modeling lymphangiogenesis: Pairing in vitro and in vivo metrics

“…As lymphangiogenesis has been overlooked in the past compared to other physiological players, many current studies rely on the fact that drugs already approved for their anti‐angiogenic effects also tend to hinder lymphangiogenesis 173 . Preclinical models have played a vital role in uncovering anti‐lymphangiogenic therapies, such as antibodies targeting the VEGF‐C/VEGFR‐2/3 axes, leading to recent clinical trials 174 . As preclinical models of lymphangiogenesis carefully increase in complexity and relevance, their ability to uncover and explore potential therapeutics will lead to immense progress toward treating lymphatic‐involved pathologies.…”

“…173 Preclinical models have played a vital role in uncovering anti-lymphangiogenic therapies, such as antibodies targeting the VEGF-C/VEGFR-2/3 axes, leading to recent clinical trials. 174 As preclinical models of lymphangiogenesis carefully increase in complexity and relevance, their ability to uncover and explore potential therapeutics will lead to immense progress toward treating lymphatic-involved pathologies. Further, the development of models and knowledge surrounding lymphatics in other tissues (such as gynecological tissues) and diseases, will offer even more opportunity for novel models and discoveries surrounding these important vessels.…”

Translational Value of Tumor-Associated Lymphangiogenesis in Cholangiocarcinoma

“…Ramucirumab, a mAb against VEGFR-2, was shown to be effective in modulating angiogenesis and metastasis in metastatic CRC [ 82 ]. Several mAbs have also been developed against VEGF-C and its VEGFR-3 receptor, but with limited efficacy [ 90 ]. Among the anti-VEGF-C mAbs, VGX-100 is in clinical trial phase I for the treatment of glioblastoma, prostate cancer, and metastatic CRC [ 83 ], while a single-chain fragment variable (scFv) is still in the preclinical study phase [ 84 ].…”

“…However, the effectiveness of these treatments is dampened due to the redundancy of the signals regulating lymphangiogenesis, and thus, targeting other proangiogenic pathways, such as Ang-1 and Ang-2, has been proposed. Among these, trebananib, a neutralizing peptide for Ang-1/Ang-2, is the one in the most advanced study phase (phase III for the treatment of recurrent ovarian cancer) [ 89 ], while many other neutralizing mAbs, such as CVX-060, AMG780, and nesvacumab, are in study phase I, but data on their effectiveness are still controversial [ 90 ].…”