Abstract
From the development of self-aggregating, scaffold-free multicellular spheroids to the inclusion of scaffold systems, 3D models have progressively increased in complexity to better mimic native tissues. The inclusion of a third dimension in cancer models allows researchers to zoom out from a significant but limited cancer cell research approach to a wider investigation of the tumor microenvironment. This model can include multiple cell types and many elements from the extracellular matrix (ECM), which provides mechanical support for the tissue, mediates cell-microenvironment interactions, and plays a key role in cancer cell invasion. Both biochemical and biophysical signals from the extracellular space strongly influence cell fate, the epigenetic landscape, and gene expression. Specifically, a detailed mechanistic understanding of tumor cell-ECM interactions, especially during cancer invasion, is lacking. In this review, we focus on the latest achievements in the study of ECM biomechanics and mechanosensing in cancer on 3D scaffold-based and scaffold-free models, focusing on each platform’s level of complexity, up-to-date mechanical tests performed, limitations, and potential for further improvements.
Highlights
Morphological imaging by atomic force microscopy (AFM) showed that the basement membrane cultured with cancer and stromal cells had higher roughness and more holes during the tumor breaching process but became softer upon cancer cell and fibroblast growth, clearly suggesting basement membrane mechanics are dynamic during cancer invasion and metastasis [68]
We explore the latest achievements in the field of 3D culturing systems used for the dissection of solid tumor tumor microenvironment (TME) mechanical changes and the reported effects on cancer and stromal cell gene expression, behavior, and epigenetic machinery
Researchers showed that culturing breast cancer cells in 3D scaffolds that mimic the in vivo tumor-like microenvironment enhances their metastatic potential
Summary
Alterations in tumor mechanics can derive from imbalances between matrix deposition and degradation [8,9,10]; increases in matrix crosslinking [11,12]; defective lymphatic drainage and leaking from blood vessels (increase in oncotic and fluid pressure) [13,14]; and deregulated growth and high cell densities that generate solid pressure and cell “jamming”, which prevents cell movements [15,16] These mechanical signals are transduced into biochemical signals from the cytoskeleton to the nucleus, actively affecting tumor cell behavior (Figure 1). Linkers of and cytoskeleton protein (LINC) complexes on the nuclear membrane physically connect nucleoskeleton and cytoskeleton protein (LINC) complexes on the nuclear membrane the cytoskeleton to the nucleoskeleton [23,24]. Chromatin modification [26,29]
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