Profiling distinct mechanisms of tumour invasion for drug discovery: imaging adhesion, signalling and matrix turnover.
Recent advances in microscopic imaging technology, fluorescent reporter reagents, 3-dimensional (3D) cell models and multiparametric image analysis have enhanced our ability to model and understand complex cell physiology. Extension of these approaches to live cell, kinetic studies allows further spatial and temporal understanding of a multitude of dynamic functional events, including tumour cell invasion. Recent in vivo and 3D in vitro studies reveal how tumour cells utilize a diverse variety of mechanisms to permit invasion through 3D tissue environments. Such high degrees of diversity and plasticity between invasion mechanisms present a significant challenge to the successful treatment of malignant cancer. This review examines how advances in time-resolved imaging has contributed to the characterization of distinct modes of invasion and their associated molecular mechanisms. Specifically, we highlight the development of fluorescent reporter molecules and their incorporation into more predictive 3D in vitro and in vivo models, to enhance mechanistic analysis of tumour invasion. We also highlight the latest advances in kinetic imaging instrumentation applicable to in vitro and in vivo models of tumour invasion. We discuss how multiparametric image analysis can be used to interpret image data generated by these approaches. We further discuss how these approaches can be integrated into drug discovery pipelines to facilitate evaluation and selection of candidate drugs and novel pharmaceutical compositions, targeting multiple invasive mechanisms.
Carragher
Neil O
NO
Advanced Science and Technology Laboratory, AstraZeneca Charnwood, Bakewell Road, Loughborough, UK. neil.carragher@astrazeneca.com
D000818:Animals; D002448:Cell Adhesion; D003952:Diagnostic Imaging; D055808:Drug Discovery; D005109:Extracellular Matrix / Q000473:pathology*; D006801:Humans; D009361:Neoplasm Invasiveness; D015398:Signal Transduction