In Vitro, In Vivo, and In Silico Models of Lymphangiogenesis in Solid Malignancies

SIMPLE SUMMARY: Lymphangiogenesis is the formation of new lymphatic vessels in physiological conditions but has also been found to be associated with pathologies. For example, it has been proven to be involved in cancer progression and metastatic dissemination through the body. Thus, it became a key element to study in the management of this widespread disease. To date, the study of lymphangiogenesis takes place at the biological (in vitro and in vivo) and computational (in silico) levels. The association of these complementary fields combined with imaging techniques constitutes a real toolbox in pathological lymphangiogenesis understanding. ABSTRACT: Lymphangiogenesis (LA) is the formation of new lymphatic vessels by lymphatic endothelial cells (LECs) sprouting from pre-existing lymphatic vessels. It is increasingly recognized as being involved in many diseases, such as in cancer and secondary lymphedema, which most often results from cancer treatments. For some cancers, excessive LA is associated with cancer progression and metastatic dissemination to the lymph nodes (LNs) through lymphatic vessels. The study of LA through in vitro, in vivo, and, more recently, in silico models is of paramount importance in providing novel insights and identifying the key molecular actors in the biological dysregulation of this process under pathological conditions. In this review, the different biological (in vitro and in vivo) models of LA, especially in a cancer context, are explained and discussed, highlighting their principal modeled features as well as their advantages and drawbacks. Imaging techniques of the lymphatics, complementary or even essential to in vivo models, are also clarified and allow the establishment of the link with computational approaches. In silico models are introduced, theoretically described, and illustrated with examples specific to the lymphatic system and the LA. Together, these models constitute a toolbox allowing the LA research to be brought to the next level.