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Intravital microscopy of tumor angiogenesis and regression in the dorsal skin fold chamber: mechanistic insights and preclinical testing of therapeutic strategies

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Abstract

Tumor angiogenesis is a major step in tumor progression to clinically symptomatic cancer and thus a potential target for cancer therapy. It is essential to understand the fundamental mechanisms of the angiogenic processes to provide a rational for testing inhibitory strategies for cancer treatment. The dorsal skin fold chamber provides a suitable (chronic) model for intravital microscopy to monitor the same tumor in time-lapse imaging series and in real-time functional analysis e.g., of blood flow. Adaptation of this model to several rodent species and tumor types has led to numerous physical and drug based therapy options. With modification of implantation techniques, motility and invasion of individual cells can be visualized, in addition to angiogenesis and microcirculation. Modern fluorescent techniques such as ex vivo labelling of specific cell populations and the introduction of stably fluorescent protein expressing cell lines further enhance the suitability of this technique. In addition, laser scanning and multiphoton microscopy in combination with genetically altered mouse strains and cell lines are making the DCSF even more attractive for mechanistic and interventional studies in cancer research. Here we review the preparation as well as the applications of the DCSF in tumor angiogenesis.

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Abbreviations

CFSE:

Carboxyfluorescein succinimidyl ester

DiI:

1,1′-Dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate

DSFC:

Dorsal skin fold chamber

FITC:

Flourescin isothiocyanate

FRAP:

Fluorescence recovery after photobleaching

FVD:

Functional vascular density (perfused vessels/area)

GFP:

Green fluorescent protein

HUVEC:

Human umbilical cord vein endothelial cells

HMVEC:

Human microvascular endothelial cells

MVD:

Microvasular density (vessel length/area)

PDT:

Photodynamic therapy

RBCF:

Red blood cell flow

ROI:

Region of interest

SCID:

Severe combined immunodeficiency

TRITC:

Tetramethyl rhodamine isothiocyanate

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Acknowledgments

We would like to thank several people for their contributions. First, we want to thank our many past and present colleagues at the University of Regensburg for their contributions, including especially Dr. Markus Steinbauer and Dr. Markus Guba for their expertise with the DSFC model. We also appreciate collaborations with Dr. Oliver Stoeltzing, Dr. Sven Lang and Dr. Christiane Bruns, who allowed adaptation of their tumor models to the DSFC system. Furthermore, we appreciate the efforts of Dr. Ferdinand Wagner in helping to provide images for this publication. Finally, we want to thank Dr. Philipp Babilas (Department of Dermatology) for Fig. 4, and for valuable comments.

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Koehl, G.E., Gaumann, A. & Geissler, E.K. Intravital microscopy of tumor angiogenesis and regression in the dorsal skin fold chamber: mechanistic insights and preclinical testing of therapeutic strategies. Clin Exp Metastasis 26, 329–344 (2009). https://doi.org/10.1007/s10585-008-9234-7

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