In vivo imaging defines vascular interplay in the development of lymphocytic leukemia in zebrafish models

Abstract

The vascular microenvironment at the primary tumor site is represented by functionally diverse types of vessels that contribute to metabolic supply, trafficking/dissemination of tumor cells, and delivery of chemotherapeutics. However, the role of leukemia-associated vascular networks in leukemia progression remains poorly understood. We utilized a MYC-induced T cell leukemia model in zebrafish to assess the involvement of vascular endothelial growth factor A-dependent (VEGFR2+), VEGFA-independent vasculature (VEGFR2-), and lymphatics in the initial stages of leukemia cell dissemination using intravital microscopy. Leukemogenesis underwent sequential progression, from initial successive emigration of single leukemic cells from the thymus towards the kidney marrow, followed by collective migration in a dorsal-lateral direction with scattered migration from the ventral thymus towards the aortic arches, before streaming towards the rostral kidney area. Trafficking appeared independent of VEGFR2+ vasculature but was closely associated with VEGFR2-microvessels, and, interestingly, leukemic cells did not utilize lymphatics during initial dissemination. Overall, leukemic cells appeared to utilize the same routes as normal T cell progenitors during development but in a reverse order, and primarily recruited VEGFR2-microvessels during the initial stages of progression. Ultimately, interfering with leukemia cell migration by targeting vascular networks may represent a new therapeutic strategy to control leukemia progression.