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].