**1. Introduction**

Many processes relevant to cancer, such as differentiation, maturation, and the malignant potential of tumor cells have all been shown to be influenced by extracellular matrix (ECM) stiffness [1]. In the general context of cancer, within the tumor ECM, various support cells

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(fibroblasts, Schwann cells), tumor‐associated immune cells, and vascular (blood and lymph) endothelial cells are found, lying among a network of various reticulin, collagen, and elastic fibers merged within the interstitial fluids (glycosaminoglycans, proteoglycans, and glycopro‐ teins) and gradients of several chemical species, which constantly interplay with cells and provide much of the structural support available to parenchymal cells in tissues, providing tensile strength and flexibility [2, 3].

Numerous studies have demonstrated that the tumor ECM not only responds to and supports carcinogenesis, but actively contributes to tumor initiation, progression, and metastasis, and must not only be understood as a reactive neighboring, but also as an active contributor [4]. In fact, it has been published that chronic growth stimulation, ECM remodeling, alteration of cell mechanics, and disruption of tissue architecture are a non‐genetic basis, influencing cancer progression [5–7]. Given the complexity both within and outside the cancer cell, and the interactions between cancer cells and the surrounding stroma, it is not surprising that a single perturbation within a tumor can create a cascade of changes in multiple pathways and networks, some of which may have lethal repercussions [8].

Tumor malignancy is driven, among other factors, by the remodeling of contiguous stromal tissue to foster growth, metastasis, and therapy resistance. Tumor cells alter the mechanical properties of the microenvironment to create favorable conditions for their proliferation and/ or dissemination [9]. They promote stiffening of their environment, which feeds back to increase malignant behaviors such as loss of tissue architecture and invasion [10]. Matrix remodeling by tumor‐associated stromal cells entails the assembly of a highly dense ECM, whose physicochemical attributes enhance malignancy through morphogenic deregulation, tumor cell proliferation, vascular recruitment, and stromal cell differentiation [11–13]. Both tumor and stromal cells produce and assemble a matrix of collagens, proteoglycans, and other molecules such as cytokines that hinder the transport of macromolecules and stimulate the otherwise quiescent host cells to initiate a variety of processes, including desmoplasia and angiogenesis [14, 15]. Mediated by increased deposition, unfolding, and crosslinking of fibrilar adhesion proteins, stiffening increases cell contractility which, in turn, can directly and indirectly modify gene expression via altering transcription factor activity and the release of matrix‐bound pro‐tumorigenic growth factors [16–19]. Similarly, changes in the microstruc‐ ture, elasticity, distribution of pore sizes, chemical composition, and fiber arrangement due to ECM remodeling can control aspects of tumor cell phenotype such as adhesion, mechanics, and motility [20–24]. The speed of malignant cells *in vitro* is also affected by the geometry of the ECM. Human glioma cells move faster through narrow channels than through wide channels or in non‐stretched 2D surfaces. This is thought to be triggered by an increase in the polarity of the traction forces between cell and ECM [25]. Recent publications describe that not only neoplastic ECM stiffness, but also the firmness of tumor cells play a significant role in tumor progression. Steadiness of tumor cells, especially the metastatic cells, is lower than that of the normal cells of the same sample, and is currently caused by the loss of actin filaments and/or microtubules, and the subsequent lower density of the scaffold [26, 27].

The study of ECM elements composing the architectural scaffolding and the blood vessels can be performed by means of automated or semi‐automated quantification. This technique can be used on histologic sections of all malignancies, providing important tumor characteristics such as the morphometric features and the spatial context of tumor and stromal cells at single‐ cell resolution. Differences in the ECM of different cancer subtypes can contribute to a more comprehensive understanding of the highly heterogeneous tumor microenvironment, and can provide abundant and novel targets for therapy.
