Schematics were created using Servier Medical Art according to a Creative Commons Attribution 3.0 Unported License guidelines 3.0 ( ). Immune cells can now access the tumor to further suppress the tumor. The healthy environment stifles the tumor. (3b) The near ECM is broken down to reduce stiffness (by directly reducing cross-linking and degrading fibers or by healthy stromal cells’ actions). Cancer cells then migrate to the vasculature and metastasise. The tumor as a whole is enlarge and loses its circularity. Cells change morphology they elongate and become more flexible. The matrix is also locally degraded to facilitate cell migration. Cancer-associated stromal cells aid by remodelling the ECM to create track for the cancer cells to invade along. (3a) The cancer cells loosen their cell–cell adhesion and breach the basement membrane. This depends on various factors that are not yet fully understood. The cancer can next either evolve into (3a) or (3b). A gradient of stiffness appears, with the near ECM stiffer than the far ECM. This protects the tumor against exterior factors such as immune cells, chemical signaling and drugs. The cancer cells signal to the stromal cells to stiffens the ECM at the tumor–stroma interface. The healthy stroma that surrounds the tumor is composed of randomly aligned collagen fibers and healthy stromal cells such as fibroblasts, healthy epithelial cells, adipocytes and other organ specific cells. (1) The cancer cells are bound within a basement membrane. Evolution of onset epithelial cancer invasion. summaries all of the above methods in their review. Second harmonic generation (34) and scanning electron microscopy (SEM) (35) are both tools that can be used to this effect. Observation of fibers can indirectly serve as a stiffness measure, as increased deposition and alignment positively correlates to increased stiffness within the tissue. (27) For single cell level mechanical measurements, options are particle tracking micro rheometry, (28,29) optical trap-based microrheology, (30,31) micropipette aspiration, (32,33) and AFM. (26) It is, however, important to note that bulk stiffness, measured at large length scale (over millimeters) by SWE or MRE, is usually higher than local stiffness, measured by AFM or shear rheology, due to the heterogeneity of tissue components. Commonly used techniques are atomic force microscopy (AFM), (19−23) microindentation, (24,25) and shear rheometry. (17,18) As ex vivo measurements are easier to perform, a wider range of technologies are available. The most prevalent in vivo methods are shear wave elastography (SWE) (15,16) and magnetic resonance elastography (MRE). Conclusions: Taking this analysis into account, we inform on the type of experimental approaches that could be the most relevant and provide what would be a standardized protocol and reporting strategy.īiological tissues can be mechanically characterized on the macro, micro, or nano scale, in vivo, ex vivo, and in vitro. 100% of the studies outside biological stiffness range (above 20 kPa) report that stiffness does not promote cancer invasion. The stiffness of the 3D matrices varied from 0.5 to 300 kPa and 19% of these matrices’ stiffness were outside commonly accepted physiological range. Examples are the experimental timeframes used (24 h to 21 days), the type of polymer used (24 types), and choice of cell line (33 cell lines). Experimental approaches and data interpretations were varied, each affecting the invasion of cancer differently. Results: Meta-analysis revealed that 64% of studies report cancer invasion promotion as stiffness increases, while 36% report the opposite. We investigated questions such as the effect of matrix stiffening, activation of stromal cells, and identified potential advances in mechano-based therapies. Particular focus was placed on in vitro three-dimensional models of epithelial cancers. This was achieved by using a systematic approach and providing meta-analyses. Methods: This review provides an overview of current research on the role of the physical microenvironment in cancer invasion. Increased matrix deposition and realignment of the collagen fibers are detected by cancer cells, inducing epithelial-to-mesenchymal transition, which in turn stimulates cell motility and invasiveness. Background: Tumorigenesis is attributed to the interactions of cancer cells with the tumor microenvironment through both biochemical cues and physical stimuli.
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