Prostate Restored
Prostate Restored
Photo: Donald Tong
Metastatic progression of solid tumors can be divided into five major steps: (1) invasion of the basement membrane and cell migration; (2) intravasation into the surrounding vasculature or lymphatic system; (3) survival in the circulation; (4) extravasation from vasculature to secondary tissue; and finally, (5) ...
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Read More »Metastasis is initiated during invasion and migration where cancer cells penetrate the basement membrane and navigate as single cells or via collective means through the stromal microenvironment, respectively.9 Invasion through the basement membrane is considered the differentiating step between pre-cancerous neoplasia and malignant cancer in which increased collagen deposition, fiber thickness, and linearized fiber architecture contribute to a stiffer environment.10,11 Cells mechanically remodel ECM through a cycle of cell protrusion and contraction, and chemically degrade the matrix using metalloproteinases as they migrate.12 In addition, cancer cell contractility and matrix stiffness create a positive feedback loop causing downstream effects on cell behavior during metastatic progression.13 As such, accurate invasion and migration models must incorporate ECM with tunable stiffness, adjustable pore size, and measurable and/or controllable degradability. Despite advances in tissue-engineered models, in vitro tumor models rarely capture the full complexity of spatiotemporal heterogeneities inherent in tumor progression due to cell culture time scales and construct size limits. The use of organoids partly overcomes these limitations by better representing genotypic and phenotypic diversity in a structured in vitro microenvironment. These structures, derived directly from human tumor tissue samples, preserve three-dimensional architecture and patient-specific phenotypes while in culture (Fig. 2a).14,15 Organoids capture many of the genomic variations present in solid tumors and serve as preclinical drug-screening tumor models, shown to correlate with clinical response to common cancer therapeutics.14,15 Long-term culture is still challenging due to insufficient nutrient and oxygen supply at the core, yet attempts at vascularization are being investigated to enhance cell maturation and model longevity.16 Fig. 2 3D in vitro models of cancer cell invasion. a Tumor spheroids facilitate cell–cell interactions while mimicking the invasion process. b Organoids are self-assembled structures derived directly from human patients to recapitulate tumor environment. c Physiologically relevant architectures such as microtracks can be recapitulated using micropatterning and seeded with cancer cells to observe migration in these unique environments Full size image Alternatively, spheroids are cell aggregates used to study invasion and migration (Fig. 2b).17 Growth kinetics, heterogeneity, protein signaling, and gene expression can be captured in single or co-culture models, allowing specific characterization of the tumor microenvironment.17,18,19 In addition, spheroids can be maintained for nearly 3 weeks in ultra-low adhesion, multi-well plates, making them ideal for high-throughput screening.17 Reproducibility and stability make these models ideal for identifying features of the tumor microenvironment that drive metastatic cell behavior. For example, induction of hypoxia in a spheroid model was shown to be essential in eliciting the cancer stem-like cell phenotype, a major target in current cancer therapeutics.19 By modeling the relationship between cell behavior and the tumor microenvironment, more specific therapeutics can be developed. Spheroid models also provide a platform to study the distinguishing factors between single cell and collective migration.9,20 Collectively migrating cells exhibit distinct leader-follower behavior in spheroids, with cancer cells either being led by other cancer cells or being directed by matrix fiber orientation.20,21 Models employing micromolding and spheroid formation in a microwell-array platform permit stromal-tumor cell interactions that can affect both the chemical and mechanical microenvironment to influence cell differentiation and migration.22,23 As more information is obtained on the role of cell–cell communication during invasion, engineered models must also reflect these interactions. For example, myoepithelial cells surrounding the basement membrane are thought to possess a tumor-suppressor role that can be lost during pre-cancerous neoplasia.24 These cells were shown to restrain and recapture cancer cells in a spheroid co-culture model. Thus, incorporation of important stromal cell types such as myoepithelial cells into invasion assays may be a promising avenue for increasing physiological relevance. It is likely that stromal-tumor cell interactions are also heterogeneous across patients, which these in vitro platforms could help define.
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Read More »Cancer cells can be seeded directly into collagen matrix to investigate cell speed, direction, and morphology during migration.25,26,27 Importantly, there is now significant evidence to suggest that collagen fiber alignment is a signature of metastatic disease and can be used to predict patient outcomes.28 These aligned fiber architectures can be replicated in vitro through application of mechanical strain, thereby providing cells with guidance cues to direct migration.29,30 In addition to fiber alignment, confinement imposed by the matrix can direct cancer cell migration. Narrow tracks which confine migrating cells, polydimethylsiloxane (PDMS) posts modeling various levels of substrate rigidity, and synthesized networks of tunable porosity mimic features in tumor architecture during disease progression.26,31,32 To observe confined migration in a more physiologically relevant system, collagen can be micro-molded to create tracks of tunable geometries recapitulating in vivo collagen structures (Fig. 2c), offering significant advantage over stiff, PDMS-based microchannel devices.25,26,27 Collagen microtracks can provide insight into pathways driving confined migration, such as revealing the role of specific focal-adhesion proteins necessary for cell directionality, providing specific targets for clinical drug development.27 Perhaps one of the most significant advances of recent in vitro platforms is their ability to collect cells following invasion and migration to further analyze their physical and genetic attributes with respect to their migratory behavior.33,34 As just one example of the utility of this approach, cells collected post-chemotactic migration exhibited increased levels of RhoC GTPase and p38γ, which are associated with poor cancer prognosis.34 Although these approaches are still in early stages, they show promise in understanding the diverse molecular signatures contributing to successful migration and invasion and may lead to a better understanding of phenotypic and molecular changes cells undergo during dissemination.
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