Physiological models for in vivo imaging and targeting the lymphatic system: Nanoparticles and extracellular vesicles
Imaging of the lymphatic vasculature has gained great attention in various fields, not only because lymphatic vessels act as a key draining system in the body, but also for their implication in autoimmune diseases, organ transplant, inflammation and cancer. Thus, neolymphangiogenesis, or the generation of new lymphatics, is typically an early event in the development of multiple tumor types, particularly in aggressive ones such as malignant melanoma. Still, the understanding of how lymphatic endothelial cells get activated at distal (pre)metastatic niches and their impact on therapy is still unclear. Addressing these questions is of particular interest in the case of immune modulators, because endothelial cells may favor or halt inflammatory processes depending on the cellular context. Therefore, there is great interest in visualizing the lymphatic vasculature in vivo. Here, we review imaging tools and mouse models used to analyze the lymphatic vasculature during tumor progression. We also discuss therapeutic approaches based on nanomedicines to target the lymphatic system and the potential use of extracellular vesicles to track and target sentinel lymph nodes. Finally, we summarize main pre-clinical models developed to visualize the lymphatic vasculature in vivo, discussing their applications with a particular focus in metastatic melanoma. ; The authors gratefully acknowledge the support of the following sources of funding: M.S.S. is funded by grants from the Spanish Ministry of Economy and Innovation (SAF2017-89533-R), Team Science and Established Investigator awards by the Melanoma Research Alliance, grants from Worldwide Cancer Research and Fundación 'La Caixa' Health Research 2019, and a collaborative grant from the Asociación Española Contra el Cáncer (AECC). H.P. acknowledges RETOS SAF2017-82924-R (AEI/10.13039/501100011033/FEDER-UE), Fundación Ramón Areces and La Caixa Foundation (HR-18-00256). We are also grateful for the support of the Translational NeTwork for the CLinical application of Extracellular VesicleS, TeNTaCLES. RED2018-102411-T(AEI/10.13039/501100011033). D.O. is funded by grants from the Spanish Ministry of Health (AES-PIS PI18/1057) and 'Fundación BBVA-Becas Leonardo a Investigadores y Creadores Culturales 2018'. D.C.-W. was a recipient of a predoctoral fellowship from Fundación 'La Caixa' and currently with a Cancer Research Institute Irvington Postdoctoral Fellowship. E.C. is funded by the European Union's Horizon 2020 research and innovation programme "proEVLifeCycle" under the Marie Skłodowska-Curie grant agreement No 860303. ; No
