Dynamic imaging of cancer invasion and metastasis: principles and preclinical applications

Clinical & Experimental Metastasis, Apr 2009

Peter Friedl

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Dynamic imaging of cancer invasion and metastasis: principles and preclinical applications

Peter Friedl 0 1 0 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 1 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 - 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)


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Peter Friedl. Dynamic imaging of cancer invasion and metastasis: principles and preclinical applications, Clinical & Experimental Metastasis, 2009, pp. 269-271, Volume 26, Issue 4, DOI: 10.1007/s10585-009-9243-1