Abstract
In addition to a multitude of genetic and biochemical alterations, abnormal morphological, structural, and mechanical changes in cells and their extracellular environment are key features of tumor invasion and metastasis. Furthermore, it is now evident that mechanical cues alongside biochemical signals contribute to critical steps of cancer initiation, progression, and spread. Despite its importance, it is very challenging to study mechanics of different steps of metastasis in the clinic or even in animal models. While considerable progress has been made in developing advanced in vitro models for studying genetic and biological aspects of cancer, less attention has been paid to models that can capture both biological and mechanical factors realistically. This is mainly due to lack of appropriate models and measurement tools. After introducing the central role of mechanics in cancer metastasis, we provide an outlook on the emergence of novel in vitro assays and their combination with advanced measurement technologies to probe and recapitulate mechanics in conditions more relevant to the metastatic disease.
Highlights
Metastatic disease is the major clinical complication in most types of cancer and the cause of more than 90% of cancerrelated deaths.[1−3] During this complex, multistep process (Figure 1), tumor cells that acquired an invasive phenotype[4−6] dislodge from the primary tumor,[7] enter the blood or lymphatic microvasculature,[8,9] and following survival in blood circulation,[10] possibly exit from microvessels of distal tissues[11] and form secondary tumors within vessels and in distant organs.[12]
Irregular mechanical alterations in cells and the extracellular environment has made it increasingly apparent that mechanics and mechanical signaling play a central role at all stages of the metastasis cascade.[13−15] despite notable progress in the development of in vitro 3D models capable of recapitulating key features of metastasis more realistically,[16−18] the cell mechanics and mechanobiology research have been predominantly concentrated on 2D cells in Petri dish models
Critical steps of cancer metastasis including tumor invasion, intravasation and extravasation are inherently 3D processes occurring in microenvironments rich in complex biomechanical cues
Summary
Metastatic disease is the major clinical complication in most types of cancer and the cause of more than 90% of cancerrelated deaths.[1−3] During this complex, multistep process (Figure 1), tumor cells that acquired an invasive phenotype[4−6] dislodge from the primary tumor,[7] enter the blood or lymphatic microvasculature (intravasate),[8,9] and following survival in blood circulation,[10] possibly exit from microvessels (extravasate) of distal tissues[11] and form secondary tumors (colonize) within vessels and in distant organs.[12]. Future efforts should point to novel model formulations for (1) the understanding of cell−ECM force interactions, paving the way for numerical frameworks for ECM degradation and remodelling, (2) linking spatiotemporal modeling scales (and generating multiscale models), (3) integrative hybrid discrete-continuum modeling strategies[104] toward a systems biology perspective that focuses on emergent properties of collective entity (applicable to cancer spheroids, tumorigenesis, or the endothelial barrier) rather than on the reductionist study of the parts Computational advances along these lines will continue to provide new insights into the mechanobiology of the complex metastatic milieu.
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