1.2. Extracellular matrix (ECM):
The ECM is a complex and diverse network of more than a hundred proteins, including proteoglycans (heparan sulfate, chondroitin sulfate), fibrous proteins (elastin, collagen), glycoproteins (laminins, tenascin C (TNC), fibronectin 1 (FN1)), and glycosaminoglycans (hyaluronic acid), which plays a role as a scaffold of organs and tissues, as well as constitutes the largest component of the TME [6, 19, 98]. Although many tumor cells and diverse types of stromal cells can produce ECM proteins, CAFs have a main and significant role in the organization and composition of ECM [99, 100]. Moreover, the ECM contains cytokines, chemokines, and growth factors released by stromal and tumor cells [6]. The ECM regulates cell behavior and plays an important role in tissue function and maintenance [101, 102]. Accordingly, disruption of the mechanisms involved in the regulation of ECM degradation, production, and remodeling causes pathological conditions such as cancer and fibrosis [101, 103, 104]. Furthermore, necessary signals for cellular differentiation, growth, and migration are provided by ECM [102]. Each component of the extracellular matrix, through cell surface receptors, induces signaling pathways to cells and plays a role in tumor events including differentiation, survival, migration, and metabolism [105, 106]. Moreover, ECM heterogeneity provides evading growth suppressors, resisting cell death, and sustaining growth signals for cells, as a result, has a key role in tumor proliferation, also in tumor angiogenesis, metastasis, and invasion [106, 107]. The ECM is responsible for cellular migration out of the TME and cellular adhesion, although it functions as a physical scaffold for cells [19]. The presence of stored diverse soluble factors such as growth factors, cytokines, chemokines, and angiogenic factors in the extracellular matrix creates a continuous inflammatory condition that ultimately leads to the expansion of the cellular repertoire [19, 108, 109]. In this inflammatory condition, the deposition of a large amount of ECM protein occurs via facilitation in the transformation of stromal fibroblasts into myofibroblasts, which results in contraction and an increase in stiffness [109, 110]. One of the determining and important factors in TME involved in cancer treatment resistance is cell adhesion to ECM [111]. The interactions of ECM components such as laminin, fibronectin, and collagen with integrin provide a context for drug resistance mediated by cell adhesion [111]. The efficacy of many drugs depends on the composition of the cancer’s ECM [102]. The dynamic adaptation of ECM is involved in the invasion and progression of cancer and especially drug resistance, for instance, ECM can adequately hinder drug delivery by increasing the remodeling of microvascular endothelial cells [112]. Indeed, ECM remodeling creates a physical obstacle that delays or prevents drug delivery, thereby it increases drug resistance [113]. Furthermore, ECM can activate survival proteins through survival pathways including MAPK, p53, PI3K/AKT, and subsequently promote chemoresistance [102]. Alterations in stiffness and elasticity of ECM impact drug delivery to cancer cells, as well as pressure and diffusion, are factors related to drug delivery in the interstitial spaces [102]. Drugs are delivered to tumors through the pressure of blood circulation and the interstitial areas [111]. In the interstitial areas, the ECM organization causes an increase of fluid pressure through the physical obstacles of the tumor mass and subsequently extremely prevents the desired results of drug delivery [111]. In addition, an increase in the fluid flux from the neoplasms to the surrounding environment due to the ample proliferation of cancer cells prevents the adequate transfer of drugs [114]. Indeed, the density of ECM cells plays a key role in the low efficiency of drug delivery [115].
Although all ECM components play a key role in tumor progression, the role of collagen stands out [98]. Collagen can affect the behavior of tumor cells through discoidin domain receptors, tyrosine kinase receptors, integrins, and several signaling pathways [116]. Furthermore, collagen can affect the activity of cancer cells by interacting with ECM molecules including MMPs, lamins, fibronectin, and hyaluronic acid [117]. Exosomes and miRNAs are other components that have close interactions with collagen in cancer [118, 119]. In the status that tumors are rich in collagen, the hypoxic condition is common, leading to the promotion of cancer progression [116]. However, heparan sulfate (CGKRK peptide), gelatin (anginex, small geletic-1 binding peptide), laminin (IKVAV), fibronectin extra domain A and B (anti-EDB aptide), and aggrecan (a conjugate of quaternary ammonium) are some components of ECM that have therapeutic value [98].