Dynamic imaging of cancer invasion and metastasis: principles and preclinical applications
Peter Friedl
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P. Friedl Rudolf-Virchow Center for Experimental Biomedicine and Department of Dermatology
, Venerology, and Allergology,
University of Wurzburg
, Josef-Schneider-Strasse 2, 97080 Wurzburg,
Germany
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P. Friedl (&) Microscopical Imaging Centre, Department of Cell Biology, Nijmegen Center for Molecular Life Science, Radboud University Nijmegen Medical Centre
, Geert Grooteplein 28, P.O. Box 9101, 6500 HB Nijmegen,
The Netherlands
Basic and applied cancer research are critically dependent upon methods to detect the size together with molecular and functional parameters of primary tumor lesions and metastases. For more than 150 years, the cellular basis of cancer growth and progression was predominantly studied using histopathological analysis of cells and tissues after fixation and staining. Only over the past decade, the advent of long-term 3D culture techniques, innovative live-cell multi-dimensional microscopy, and fluorescent reporter strategies have caused a middle-sized revolution in cancer research providing access to cell structure and function with cellular and subcellular resolution to living cells and molecules in 3D tissue environments in vitro and in vivo. Consequently, dynamic imaging has provided novel and often surprising insight into the hallmarks of cancer progression and metastatic dissemination. All authors articles included in this special issue of Clinical and Experimental Metastasis have substantially contributed to this progress. Old and often complicated questions begin to be elucidated, literally. How do cancer cells invade tissue? How do they coordinate their cytoskeleton with intracellular and extracellular proteases and adhesion cascades to generate a
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particular morphology and overcome tissue barriers? How
do cancer cells coopt the tumor microenvironment and
mislead the immune defense to maintain tolerance rather
than effective cytotoxic killing? How do metastatic seeding
and cross-talk with the stroma of secondary sites lead to
macroscopic outgrowth of life-threatening metastasis?
Lastly and importantly, how can we translate this
knowledge to identify and validate targeted single- and
multimodality therapy and combat cancer disease? The articles
included in this special issue of CEM cover the spectrum
from subcellular to whole-body imaging and discuss key
aspects of cancer imaging in basic reseach and preclinical
drug discovery.
The most basic basic process underlying cancer invasion
and metastasis is a dynamic actomyosin cytoskeleton that,
in response to external factors, drives cell polarity, turn
over of cell matrix interactions and migration of cancer
cells away from the primary lesion into surrounding tissues
and blood and lymph vasculature. Olson and Sahai [1]
review intracellular regulators of the actin cytoskeleton in
cancer using modern 3D in vitro culture and intravital
models monitored by sensitive microscopy. Whereas their
specific role in the invasion cascade remains to be
determined, it appears likely that at least some actin regulators
drive particular steps of metastatic dissemination and
cellular adaptation responses and, therefore, could be
amenable for therapeutic targeting.
Besides mechanical coupling of the cell to its
environment, the actin cytoskeleton also provides a scaffold that
coordinates adhesion and proteolytic events at the cell
surface. Whereas most studies address the location and
function of surface proteases in 2D models which probably
are inappropriate to capture cancer cell invasion into the
tissue stroma, Wolf and Friedl [2] show how 3D
multimodal confocal microscopy allows to identify location,
function and structural consequences of collagenase
activity in cancer cell migration. These studies provide a
subcellular-resolved map of quite different actin-rich
proteolytic cell structures that execute tissue remodeling
during invasion.
Cancer cell-derived proteases including matrix
metalloproteinases, serine proteases and cathepsins further
execute important functions in protein processing and cell
cell communication. Sameni et al. [3] present a live-cell
coculture model to dyamically monitor where and how
different protease classes become upregulated and
activated at the interface between cancer cells, extracellular
matrix, and reactive stroma cells. Because in many cancer
types upregulated proteases are strongly associated with
cancer progression and poor outcome, such methodology
may be useful for screening up- and downsstream
regulators of the tumor-stroma interaction and the identification
of drugs that may inhibit this tumor-promoting process.
As concequence of a deregulated tumor-stroma margin,
the normal tissue structure becomes replaced by a reactive
de-novo tissue comprising activated stromal cells, not
dissimilar to chronic non-healing wounds. Advanced
spectrally resolved multiphoton microscopy and the
detection of the fluorescence life-time can decipher an
emission signature of both, tumor, tumor-stroma an (...truncated)