Time-course-dependent microvascular alterations in a model of myeloid leukemia in vivo

Abstract

Functional and morphological properties of tumor microcirculation play a pivotal role in tumor progression, metastasis and inefficiency of tumor therapies. Despite enormous insights into tumor angiogenesis in solid tumors, little is known about the time-course-dependent properties of tumor vascularization in hematologic malignancies. The aim of this study was to establish a model of myeloid leukemia, which allows long-term monitoring of tumor progression and associated microcirculation. Red fluorescent protein-transduced human leukemic cell lines (M-07e) were implanted into cranial windows of severe combined immunodeficient mice. Intravital microscopy was performed over 55 days to measure functional (microvascular permeability, tissue perfusion rate and leukocyte-endothelium interactions) and morphological vascular parameters (vessel density, distribution and diameter). Tumor progression was associated with elevated microvascular permeability and an initial angiogenic wave followed by decreased vessel density combined with reduced tissue perfusion due to loss in small vessels and development of heterogenous tumor vascularization. Following altered geometric resistance of microcirculation, leukocyte-endothelium interactions were more frequent without increased leukocyte extravasation. It was concluded that time-dependent alterations of leukemic tumor vascularization exhibit strong similarities to those found in solid tumors. The potential contribution to the development of barriers to drug delivery in leukemic tumors is discussed.