Long-term observation reveals time-course-dependent characteristics of tumour vascularisation.
Functional properties of tumour vasculature influence the process of metastasis and play a role in generating a heterogeneous metabolic microenvironment, which contributes to genetic instability and inefficiency of tumour therapies. Morphological and functional properties of tumour vasculature may vary from tumour onset to late-stage disease. The aim of this study was to identify the dynamic alteration in tumour microcirculation in a chronic observation model. Invasively-growing, non-disseminating, green fluorescent protein transfected, human bone marrow derived endothelial cells, were implanted into cranial windows of severe combined immunodeficient mice. Intravital fluorescence microscopy was performed over a period of 85 days to measure permeability, leucocyte-endothelial interaction (LEI) and tissue perfusion rate as functional parameters. Vessel density, branching pattern and scanning electron microscopy were monitored as morphological parameters. Concordant with an increasing count of transendothelial pores, the results show that the initial event following tumour cell implantation was a significant increase in the permeability of pre-existing vessels. The variations in newly formed vessels were characterised by sequentially-occurring functional and morphological alterations with the development of characteristics typical of tumour vessels, such as increased count of trifurcations and variation in vessel calibre by more than 100%. In parallel with the increasing vessel volume per area, the tissue perfusion rate increased until day 61. It is concluded from the step-specific sequential functional and morphological alterations that the efficiency of adjuvant therapies depends not only on their intrinsic efficiency but also on the timing of their initiation.
Hansen-Algenstaedt
Nils
N
Department of Orthopedic Surgery, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. nhansen@uke.uni-hamburg.de
Joscheck
Claudia
C
Schaefer
Christian
C
Lamszus
Katrin
K
Wolfram
Lars
L
Biermann
Tanja
T
Algenstaedt
Petra
P
Brockmann
Marc A
MA
Heintz
Carsten
C
Fiedler
Walter
W
Rüther
Wolfgang
W
D000818:Animals; D001783:Blood Flow Velocity / Q000502:physiology; D001808:Blood Vessels / Q000473:pathology; D002199:Capillary Permeability / Q000502:physiology; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000276:immunology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007962:Leukocytes / Q000502:physiology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008833:Microcirculation / Q000502:physiology; D008855:Microscopy, Electron, Scanning; D008856:Microscopy, Fluorescence / Q000379:methods; D009368:Neoplasm Transplantation / Q000473:pathology; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000276:immunology / Q000473:pathology; D018709:Statistics, Nonparametric; D013997:Time Factors
D049452:Green Fluorescent Proteins