1. Introduction
The extracellular matrix (ECM) of tissues consists primarily of collagen, elastin, and hyaluronic acid, which are expressed by connective tissue cells through the release of structural and functional biomolecules. The structural patterns of the ECM are formed by the organization of scaffolding biomolecules, while the secretory products of the cells enrich the structural framework of such a matrix with various growth factors and cytokines, which determine the molecular pattern of the ECM [1,2].
Tumor cells differ significantly from normal cells in their regulation of gene expression. Growing tumors use ‘ECM’ remodeling to create a microenvironment conducive to tumor growth and metastasis. The identification of a specific ECM in tumor tissues necessitated the introduction of the term ‘oncomatrix’ in 2002 to describe the specific ECM of tumor tissues whose endogenous properties facilitate the migration, adhesion, and proliferation of tumor cells [3,4]. The oncomatrix exerts a direct influence on tumor development and aggressiveness [5,6,7]. The properties of the matrix directly influence the effectiveness of treatment by regulating the access of chemotherapeutic agents to tumor cells and the resistance of tumors to ionizing radiation [8]. Tumor growth and development is accompanied by matrix remodeling, with tumor-associated fibroblasts playing a major role in remodeling the normal tissue matrix and synthesizing the oncomatrix [9].
Currently, the molecular patterns of the ECM that are directly associated with tumor progression have been well studied. Numerous studies suggest that biologically active molecules (peptides, proteins, and RNA) and extracellular vesicles deposited in the matrix may serve as targets for promising therapies or diagnostic markers [10,11,12]. However, the structural patterns of the matrix also influence tumor development through specific cellular mechanoreception [5,13]. For example, morphological patterns and matrix stiffness epigenetically regulate oncogenic processes by activating Yes-associated protein and stimulating cellular proliferation [14,15]. As tumor tissue matures, the composition and structure of the oncomatrix changes [16], reflecting the stages of tumor evolution at the macrostructural level [17,18,19].
Decellularized oncomatrix is used as a model to study the dynamics of normal and tumor cell properties when interacting with the oncomatrix [20]. It has been shown that the physicomechanical properties of the oncomatrix (stiffness, permeability, and density) stimulate tumor cell proliferation in vitro compared to in normal ECM [13,21,22,23].
An important property of the ECM is its ability to absorb soluble molecules such as growth factors, cytokines, and other proteins. Receptors on cell membranes interact with the structural components of the ECM and associated factors, mediating cellular adhesion and signal transduction. Various post-translational modifications of ECM components influence the interactions of the matrix with other molecules and cells [24,25,26].
As in the cases of genomics, proteomics, and other ‘omics’, the analysis of large data sets also distinguishes the matrisome, also known as the matrixome. The matrisome represents the total collection of all ECM molecules and consists of approximately 300 different types of macromolecules, including collagens, proteoglycans, and glycoproteins. The conformations of the protein components of the ECM can change through post-translational modifications induced by secreted remodeling enzymes both inside and outside the cell, increasing their diversity and forming a collection of ECM protein proteoforms [27,28,29].
The mechanical and microstructural properties of the ECM can influence cell function through mechanisms of mechanoreception and mechanotransduction [19,30]. Mechanoreception and mechanotransduction are the primary pathways of mechanical interaction between cells and the ECM. Mechanoreception refers to the molecular mechanisms by which cells sense the structural patterns of the ECM. Mechanotransduction involves the intracellular mechanisms that transmit external mechanical signals to alter cellular regulation. Mechanical and chemical signals from ECM components influence various processes such as proliferation, differentiation, migration, and apoptosis. During ECM degradation, the release of bound molecules can lead to local inflammation and changes in cell homing parameters, i.e., the ability of cells to migrate directionally within the organism [31,32].
Components of the ECM can be expressed and deposited by any cell in the body, with a tissue specificity that determines the differences in ECM properties between tissues. Thus, cell phenotype and the associated regulatory features influence the properties of the ECM. Conversely, changes in cell phenotype and regulation are accompanied by the remodeling of the ECM. This occurs, for example, during aging when there is an increase in the proportion of type I and III collagens in tissues [33].
The composition of growth factors and other signaling molecules in tumors is relatively well studied, but the structural patterns associated with the organization of oncomatrix macromolecules are not well understood. Questions regarding the composition and properties of the tumor ECM could be of great importance for diagnostics based on new physical principles, patient management, and treatment personalization based on matrix signatures, and intraoperative diagnostics.
2. Characteristics of Tumor and Normal ECM
Two primary forms of the ECM are distinguished based on their functions, composition, and localization: (1) the interstitial matrix and (2) the basement membrane matrix [4,34,35]. The interstitial matrix forms porous three-dimensional networks that connect cells within the stroma and can interface with the basement membrane, which is another organizational form of the ECM. The interstitial matrix provides structural integrity to tissues and organs and influences cell differentiation and migration. It is composed primarily of type I, III, and V collagens, fibronectin, and elastin. The structure and composition of the interstitial matrix varies among tissues in the body and can change in response to mechanical stress, inflammation, or regenerative processes [36]. Tumor cells, for example, stimulate fibroblasts to express type I and type III collagens and ECM-modifying enzymes such as lysyl oxidases and LOX-like proteins [37,38]. However, in both healthy tissue and tumors, the primary producers of ECM in the interstitial matrix are activated fibroblasts and myofibroblasts, whereas in cartilage and bone tissues, chondrocytes and osteoblasts, respectively, are the major ECM producers [39].
Oncologic transformation involves a remodeling of the interstitial ECM, leading to a variety of biophysical and biochemical changes that affect cellular mechanotransduction, ECM stiffness, cell migration, and tumor progression [40,41]. Tumor cell proliferation has been shown to be associated with changes in the physical properties of the ECM [41]. In contrast, basement membranes are more stable, sheet-like, dense structures that compartmentalize epithelial, muscle, and endothelial tissues [42]. The basement membrane is composed primarily of type IV collagen and laminins interconnected by various bridging proteins [43]. Cell attachment to the basement membrane is critical for establishing epithelial cell polarity and is essential for many developmental processes and the maintenance of tissue homeostasis [44]. During tumor growth, basement membrane remodeling is required for the invasion of stromal tissue by epithelial phenotype tumor cells and the formation of malignant tumors [45].
Changes in general ECM properties, such as scaffold molecule ratios, density, electrical conductivity, thermal conductivity, and other physicochemical properties, are accompanied by changes in topological properties, referred to as the microarchitecture of the ECM. Microarchitectonics refers to the three-dimensional spatial topology of the matrix, which is determined by the orientation, density, and connectivity of the structural molecules [46]. During ECM remodeling, the overall concentration, structure, and organization of its individual components change, leading to alterations in the three-dimensional spatial topology of the matrix and its biochemical and biophysical properties. Consequently, the influence of the ECM on cell fate changes [47].
The extracellular microenvironment of tumor cells plays a critical role in the development of oncological diseases by stimulating cell migration, selection, and proliferation. It is hypothesized that the segregation of cellular functions may be related to the properties of the ECM [48]. Thus, ECM properties in tumor tissues may support tissue homeostasis by ensuring the competitiveness of tumor cells under immune responses and the migration of normal cells into the tumor [49,50].
The question of whether the tumor ECM itself has sufficient carcinogenic potential in the absence of tumor cells remains controversial. It appears that the molecular and structural patterns of the tumor matrix inhibit its colonization by normal cells, including the infiltration of immune cells [51,52].
3. Protein Composition of Structural Components of the Extracellular Matrix
3.1. Macromolecular Components: Collagens, Laminin, Fibronectin, and Others
The primary and consistent protein components of the ECM include several types of collagens, elastin, laminin, fibronectin, and vitronectin. These major glycoproteins interact with the cell surface and form fibrillar structures with intermolecular covalent cross-links [53,54]. Cell-ECM interactions are largely mediated by the specific binding of transmembrane receptors—integrins—to their ligand, the RGD sequence (Arg-Gly-Asp), present in the polypeptide chains of collagens, laminin, fibronectin, vitronectin, tenascins, and thrombospondin. This binding initiates intracellular signaling cascades of protein kinase reactions that block anoikis and affect gene expression, cell adhesion, motility, proliferation, and differentiation [55]. It is believed that the interaction of integrins in cancer cells with ECM proteins stimulates the mechanisms of tumor invasion, metastasis, and resistance to therapeutic intervention [56].
Compared to normal tissue, the matrix of a growing solid tumor exhibits the increased activity of enzymes involved in collagen maturation and modification processes, leading to an increase in the density of cross-links between collagens, elastin, and laminin, as well as the accumulation of fibronectin [57] or vitronectin [58]. This effect increases the matrix ‘rigidity’ and results in the fibrotic ‘stiffness’ of the tumor, which correlates with poor prognosis [59]. In addition, the densely cross-linked (rigid) tumor matrix increases mechanical stress and slows oxygen diffusion within the tumor microenvironment, leading to hypoxia. These processes initiate phenotypic modulation and the selection of cancer cells, providing material for the evolutionary progression of the tumor [60,61].
Less abundant but pathogenetically important minor protein components of the tumor matrix include growth factors (EGF, FGF, TGF-β, etc.), chaperones (HSP90, HSP70, clusterin, etc.), enzymes that cross-link or degrade the ECM (transglutaminases, metalloproteinases, and hyaluronidase), and regulators of adhesion and angiogenesis (tenascins and thrombospondin). These proteins are secreted by tumor and stromal cells either as individual macromolecules or as part of exosomes, and this secretion influences the structure and properties of the ECM and promotes malignant growth [62,63].
3.2. Hyaluronic Acid and Other Proteoglycans
Hyaluronic acid (HA) is a structural biomolecule that maintains the water balance in tissues. Depending on its molecular weight, HA has been shown to act either as a tumor suppressor or as a mediator [57,64]. Low molecular weight HA (LMW-HA) interacts with cell receptors that regulate pro-tumor signaling cascades, including glycolysis—the primary energy source in tumors—and promotes cell migration. High levels of LMW-HA are associated with poor prognosis in certain cancers such as colon, breast, and prostate. The dysregulation of HA synthase and HA-degrading hyaluronidases leads to the accumulation of LMW-HA. The mechanotransduction of LMW-HA through CD44 signaling also stimulates stress resistance in tumor cells, potentially contributing to tumorigenesis [65].
Conversely, high-molecular-weight hyaluronic acid (HMW-HA)-associated mechanotransduction activates the expression of key tumor suppressor genes by binding to the CD44 receptor, leading to cell cycle arrest—a common mechanism of tumor growth inhibition. For example, the tumor resistance observed in the longest-lived rodent, the naked mole rat, is associated with the expression of a unique high-molecular-weight hyaluronic acid (HMW-HA) as a major component of its ECM, with a molecular mass of approximately 15–20 MDa [66]. The presence of proteoglycans in tumor tissue, such as chondroitin sulfates, heparan sulfates, dermatan sulfates, and keratan sulfates, regulates the ECM density and the deposition of growth factors [67]. Thus, it can be hypothesized that large macromolecules such as HMW-HA influence the inhibition of inflammation through interactions with the cellular cytoskeleton and the regulation of growth factor concentrations.
4. Structural and Functional Properties of the Oncomatrix
4.1. Microarchitecture of the Oncomatrix
An increased concentration of type I collagen in tumor tissue leads to an increase in its specific density, potentially protecting against immune cell migration and contributing to the formation of a specific tumor cell niche [68]. In addition, collagen fibers in closeproximity to the tumor boundary align and form cross-links [69,70], thereby supporting invasive tumor growth.
4.2. Density, Stiffness, and Rheological Properties of the Oncomatrix
Compared to the normal ECM, the density of the oncomatrix is higher, primarily due to the increased deposition of type I collagen and increased density of cross-links between low molecular weight components [10,71]. The increase in ECM density leads to higher tissue osmolarity and promotes tumor mineralization through the adsorption of salts. The rigid and dense oncomatrix exerts excessive mechanical stress on the surrounding normal tissues, contributing to inflammation and the disruption of the natural ECM structure of normal tissues, thereby creating conditions favorable for tumor cell invasion [6,10,72].
In addition, the remodeling of the tumor ECM toward increased density and stiffness results in abnormal intercellular adhesion, the activation of integrin signaling, and the subsequent initiation of cellular stress resistance cascades, promoting tumor growth and progression [73,74,75,76,77]. Disease progression leads to the fragmentation of the tumor body; however, the specific stiffness and density of the oncomatrix fragments remain higher than those of the normal tissue ECM [13].
The physical properties of the oncomatrix facilitate cell migration and invasion into normal stromal tissue, a phenomenon known as ‘topotaxis’ [78]. The stiffness of the tumor matrix has been shown to influence malignant transformation, with a stiffer matrix promoting the migration of tumor cells beyond the tumor body [79]. Another phenomenon, ‘durotaxis’, is related to directed cell migration along gradients of substrate stiffness. Durotaxis plays an important role in processes such as tissue development, wound healing, and cancer metastasis. This process is often mediated by mechanotransduction pathways that translate mechanical signals into biochemical responses [80].
The another microarchitecture structure, glycocalyx, is a carbohydrate-rich layer that coats the surface of cells, playing a crucial role in cellular mechanics. The glycocalyx consists of glycoproteins, glycolipids, and proteoglycans, which contribute to cell-cell communication, adhesion, and protection against mechanical stress. Alterations in the composition and structure of the glycocalyx can influence tumor cell behavior, enhancing their ability to evade the immune system, migrate, and invade surrounding tissues [72]. The glycocalyx is a key regulator of cancer progression by modulating interactions with the extracellular matrix and other cells.
The properties of the ECM of the normal tissue and tumor are presented in Figure 1.
4.3. pH of the Extracellular Matrix
The pH of the oncomatrix is lower than that of the ECM in normal tissues (oncomatrix pH ∼6.8–7.0, normal ECM pH ∼7.4) for several reasons [81], including lactate released by tumor cells [82]. The reduced pH facilitates cell migration and invasion, in part by increasing the activity of acid-activated metalloproteinases that degrade cell-ECM contacts [83]. Interestingly, the intracellular pH of tumor cells is higher than that of normal cells [81]. Since pH is known to influence the rate of biochemical reactions, the acidification of the oncomatrix specifically activates enzymatic reactions and reduces the activity of immune cells.
4.4. Electrical Conductivity of the Extracellular Matrix
Tumor tissue is known to have a higher electrical conductivity than the surrounding healthy tissue [84]. Recent studies have shown that the electrical conductivity of tumor tissue is significantly higher over the entire frequency range (from 10 Hz to 1 MHz), with more pronounced differences at lower frequencies [85]. These differences may be due not only to variations in metabolite composition, but also to the composition and structure of the ECM in these tissues [86,87]. Differences in electrical conductivity have previously been used to screen for tumor disease.
4.5. Thermal Conductivity of the Extracellular Matrix
The thermal conductivity of the oncomatrix is higher than that of the ECM in normal tissue [88,89], which may be explained by the increased metabolic activity of cells and the need for increased heat dissipation to prevent overheating. This characteristic of tumors suggests that increased thermal conductivity could serve as a biomarker for tumors, which may be particularly useful in the diagnosis of malignant skin neoplasms [90].
4.6. Summarized Physical and Chemical Properties of Normal ECM and Oncomatrix
The summary of physical and chemical properties of normal ECM and oncomatrix are presented in Table 1.
5. Remodeling and Biodegradation of the Matrix during Oncogenesis
5.1. Matrix Remodeling and Biodegradation Processes
The natural degradation and renewal of the ECM is an integral part of its life cycle and is essential for facilitating cell migration and proliferation. Matrix metalloproteinases (MMPs), disintegrins, and other proteases are involved in matrix degradation, and their levels and activities within the ECM determine the intensity of remodeling [108,109].
Tumor cells express elevated levels of ECM-degrading proteases that serve multiple functions during tumor progression. First, the proteolytic degradation of the ECM components enables the progressive destruction of normal ECM in healthy tissue adjacent to the tumor, followed by its replacement by tumor-associated matrix (oncomatrix) [110,111]. Second, ECM degradation is a critical factor in facilitating cancer cell migration [112]. Third, the binding of soluble signaling molecules such as growth factors to the ECM renders them inactive, and remodeling releases these molecules from the ECM, triggering spontaneous cellular signaling [53,113,114].
5.2. Deposition of Growth Factors and Proteases in the Matrix
The ensemble of growth factors deposited in the ECM constitutes the molecular pattern of the matrix. Under natural conditions, the ECM accumulates these deposited factors; however, increased MMP activity in the oncomatrix leads to active biodegradation and the release of biologically active compounds, both soluble and those encapsulated in microvesicles. The active release of biologically active molecules results in the abnormal cellular regulation of resident cells [115].
5.3. Angiogenic Properties of the Matrix
Hypoxia is known to be one of the key physiological features of tumors that stimulates active angiogenesis [116]. Tumors are characterized not only by an increased blood vessel density, but also often by an increase in their diameter [117]. Tumor vessels differ from those in normal tissue by having a higher proportion of large vessels. The increase in vessel caliber leads to the so-called ‘steal syndrome’, which stimulates the development of hypoxia in the surrounding tissues. Thus, hypoxia also contributes to the evolutionary selection of tumor cells by promoting the survival of hypoxia-resistant cells through specific regulation that affects the presence of vascular growth factors in the oncomatrix and its structural microarchitecture [116].
5.4. Oncomatrix as a Driver of Epithelial-Mesenchymal Transition (EMT) in Cancer Cells
Epithelial-mesenchymal transition (EMT) is a biological process that allows epithelial cells, which are typically characterized by tight cell–cell adhesion and a polarized structure, to undergo a series of changes that enable them to adopt a mesenchymal cell phenotype. This transition is critical for embryonic development, wound healing, fibrosis, and cancer metastasis during the period of enhanced ability to degrade and remodel the ECM, often through the upregulation of MMPs [118]. Partial EMT refers to an intermediate state in which cells exhibit both epithelial and mesenchymal characteristics without fully transitioning to a mesenchymal phenotype. This intermediate state is increasingly recognized as important in cancer metastasis and tissue regeneration, allowing cells to maintain some degree of cell–cell adhesion while gaining motility [119].
In vivo, as a result of EMT, cancer cells phenotypically transform into malignant fibroblast-like cells that actively migrate through the basement membrane (BM) and infiltrate blood vessels, leading to tumor invasion of adjacent organs and metastasis. Importantly, after EMT, cancer cells acquire many characteristics of cancer stem cells (CSCs), including resistance to radiation and anticancer drugs; such consequences of EMT characterize this phenomenon as one of the major challenges in cancer therapy [120,121].
The oncomatrix has been shown to be a potent stimulator of EMT in solid tumors [122]. One of the major components of the BM, hyaluronic acid (HA), can act as an inducer of EMT in carcinomas of various origins [122,123,124]. The membrane receptor for HA, CD44, is known to be a marker of CSCs and CSC-like cells that have undergone EMT. The interaction of CD44 in cancer cells with HA in the oncomatrix triggers intracellular signaling pathways that activate mechanisms for EMT induction and the maintenance of the CSC-like phenotype [65,122]. Other components of the oncomatrix, such as proteoglycans, collagens, fibronectin, and metalloproteinases, are also involved in the initiation and execution of the EMT program in tumor cells [122]. It has been shown that even relatively minor matrix proteins such as thrombospondin [125], tenascin-C [126], and clusterin [127] can act as inducers or promoters of EMT in various types of malignant tumors.
It is not only the individual components of the oncomatrix, but also its structural properties and state that can mechanistically stimulate EMT in cancer cells. For example, increased matrix stiffness due to a high density of collagen cross-links and/or increased fibronectin and vitronectin content in the oncomatrix becomes an initiator and driver of EMT, triggering signaling responses in cancer cells that promote EMT in response to mechanical stress [59,128,129]. Such an EMT induction caused by oncomatrix stiffness and mechanical stress is often associated with increased metastasis [128,129]. It is suggested that blocking EMT by inhibiting the progressive stiffening of the oncomatrix or the signaling responses of cancer cells to mechanical stress may be a promising strategy for cancer therapy [59]. In addition to structural stiffness, other features of the oncomatrix, such as its pH, hypoxic conditions, and permeability to exosomes, may be stimulating factors or promoters of EMT in cancer cells [130,131].
6. Impact of Oncomatrix on Antitumor Therapy
6.1. Interaction of the Matrix with Chemotherapeutic Agents
The reduction in tumor sensitivity to drug therapy may be due, in part, to barriers to immune cell infiltration that depend on the properties of the tumor matrix (oncomatrix) [82]. For example, the increased density of the oncomatrix induced by chemotherapy compared to normal tissue may reduce the diffusion of drugs from the bloodstream, thereby decreasing tumor sensitivity to drug therapy. This phenomenon may serve as a compensatory mechanism to increase tumor resistance to treatment [132,133].
6.2. Interaction of the Oncomatrix with Ionizing Radiation
ECM properties can influence tissue sensitivity to ionizing radiation, with the ECM acting as a radiomodifier and facilitating cell recovery after exposure to ionizing radiation [134]. Regarding the oncomatrix, its specific properties may mediate the radioresistance of tumor cells [135]. In response to ionizing radiation, tumor cells produce an oncomatrix with less pronounced oncogenic properties [136]. Ionizing radiation induces increased structuring of paxillin-rich focal adhesions and cytoskeleton in resident tumor cells, resulting in increased tension at the level of actin filaments, causing cellular stiffness and consequently affecting cytoplasmic/nuclear morphology [137]. Thus, altering the composition and structure of the oncomatrix has the potential to increase tumor radiosensitivity during radiotherapy.
7. Discussion
Recent studies have increasingly focused on deeply understanding the complex interactions between tumor cells and their surrounding ECM. It has been hypothesized that the primary driving forces behind the remodeling of the tumor matrix are both the need to provide a microenvironment for tumor cells and the creation of a milieu that prevents the invasion of normal cells from surrounding tissues. Tumor evolution is accompanied by changes in the composition and properties of the oncomatrix, with a radical remodeling of the ECM being associated with increased tumor aggressiveness and the suppression of the efficacy of the therapeutics (Figure 2).
The hypoxic conditions in the oncomatrix force tumor cells to rely more on glycolysis rather than oxidative phosphorylation for energy production, a phenomenon known as the Warburg effect. This metabolic shift supports rapid cell proliferation, but also results in an acidic microenvironment that can promote further invasion and immune evasion. Hypoxia can enhance the invasive capabilities of tumor cells by upregulating MMPs, which degrade the ECM, allow cancer cells to invade surrounding tissues, and suppress the immune response by creating an immunosuppressive microenvironment [19,138]. For example, it can upregulate the expression of immune checkpoint molecules such as PD-L1 on tumor cells, leading to an inhibition of T-cell activity [139]. In addition, the hypoxic tumor cells are more resistant to radiation therapy because oxygen is a potent radiosensitizer [116]. Oxygen deprivation reduces the generation of reactive oxygen species (ROS), which cause DNA damage in cancer cells, and can induce the expression of drug efflux pumps and anti-apoptotic proteins, making tumor cells less susceptible to chemotherapeutic agents [140].
Another active immunomodulator, the resident microbiota, can modulate the immune response, either promoting or inhibiting tumor growth. Some bacteria can activate immune cells that attack the tumor, while others can create an immunosuppressive environment. The composition of the resident microbiota has been shown to influence the response to immune checkpoint inhibitors [141]. In fact, a diverse and balanced microbiota is generally associated with a better response to immunotherapy [142].
The composition of the oncomatrix may indicate tumor progression, as an oncomatrix associated with effective cellular selection indicates high aggressiveness. The prolonged process of pathologic ECM remodeling leads to the release of specific proteins into the bloodstream, which may also be of diagnostic significance, for example in lung, ovarian, breast, and colon tumors. In addition, pathological ECM remodeling itself contributes to carcinogenesis. For example, even before tumor development, the increased deposition of type I collagen and proteoglycans leads to increased tissue density, which is an independent risk factor for breast cancer [38,143,144]. Therefore, maintaining ECM homeostasis may be a novel mechanism to reduce the risk of carcinogenesis and prevent malignancy.
An analysis of changes in ECM composition and structure can be used for the early detection of oncologic diseases [4]. The characteristics of unique oncomatrix signatures of certain tumors change during progression, allowing for the prediction of clinical outcomes. Changes in matrix composition and structure allow the use of spectrophotometric methods to assess the ensemble of spectral patterns, especially in the far-IR region [145]. Based on the assessment of ECM properties, tests for tumor diagnosis have been developed; of particular note are those that utilize changes in matrix density, temperature, and electrical conductivity.
A spectral analysis of absorption and scattering parameters of tumor tissue can be used for optical biopsy. It has been shown that the absorption and scattering spectra of light on matrix components differ between normal ECM and oncomatrix, can be recorded by optical devices, and can potentially be used as spectral oncomarkers of tumors [146,147,148]. Currently, spectra of the ECM have been obtained under irradiation at various wavelengths ranging from the ultraviolet to the terahertz range [149]. The identification of resonant scattering and absorption frequencies allows the development of diagnostic and therapeutic tools based on new physical principles.
Specific features of the oncomatrix can also be exploited for adjuvant therapy aimed at the targeted destruction of the tumor microenvironment. It is known that adaptive phenotype modulations stimulated by hypoxia render tumor cells more radioresistant; thus, hypoxic tumors pose a significant challenge to radiotherapy [62,116]. Alkalizing agents for the tumor matrix to stimulate lymphoid cell migration, cross-linking agents to create a dense ECM that slows cancer cell migration, or conversely, enzymes to break down macromolecular cross-links, can collectively create conditions that reduce tumor cell resistance. The modification of matrix properties by various physical agents, such as laser irradiation, can alter surface properties and alter cellular chemotaxis [150].
In addition to resident cells, the tumor microenvironment can also alter the composition of the microbiota inhabiting the surface of human hollow epithelial organs [151,152]. Changes in the composition and properties of the ECM can stimulate the colonization and proliferation of exogenous bacteria, as well as create conditions for the contamination of tumor tissue with yeast and fungal cultures, as observed in clinical practice.
The oncogenic potential of a decellularized oncomatrix, including its implantation in laboratory animals to study its tumorigenic potential, is of particular interest [153]. However, an evaluation of the specific mechanical properties of such a matrix remains a complex methodological challenge in the context of the quantitative assessment of intertissue interaction parameters [154].
CAR-T cell therapy is an advanced form of immunotherapy in which a patient’s T cells are genetically engineered to express a chimeric antigen receptor (CAR) that specifically targets cancer cells. The ECM can act as both a physical barrier and a signaling environment that influences CAR-T cell migration, infiltration, and efficacy. Effective CAR-T cell therapy requires these cells to degrade and remodel the ECM to reach and eliminate tumor cells, often involving enzymes such as MMPs that degrade ECM components [155]. The targeted destruction of the oncomatrix is a key step in CAR-T cell therapy for solid tumors [11,156]. Therefore, the development of new adjuvant matrix-targeting drugs may be a promising direction for cancer therapy. Currently, clinical trials are underway for promising therapeutic modalities aimed at remodeling the tumor matrix under the influence of external factors, such as focal adhesion kinase inhibitors, renin-angiotensin system inhibitors, and hyaluronidase inhibitors [157,158,159]. These oncomatrix-targeted drugs can be considered to be potential adjuvants to existing chemo- and radiotherapies.
8. Conclusions
The ECM of normal and tumor tissue exhibits significant differences, including the amount and type of collagen synthesized and the secretion of specific signaling molecules. The ECM of tumor tissue changes its architecture and molecular composition, and the ECMs of different histologic types of cancer at the same site also show significant differences. The ECM is a structure that uniquely manifests itself at each step of the tumor maturation and evolution, and provides a distinct environment for a specific type of tumor cell. Thus, the composition of tumor tissue ECM is characterized not only by the presence of specific biomarkers, but also by structural features. The structural features of the oncomatrix can be used as promising targets and biomarkers. The remodeling of the oncomatrix corresponds to the stages of tumor progression and is associated with tumor evolution, with oncomatrix properties potentially stimulating tumor resistance or increasing tumor sensitivity to therapy. Maintaining ECM homeostasis may be a novel approach for cancer prevention.
Conceptualization, I.K. and A.S.; methodology, I.K.; formal analysis, A.Y. and A.E.K.; investigation, D.A., D.P., V.A.S., Y.S., E.Y., M.I., E.E. and M.K.; writing—original draft preparation, I.K. and A.E.K.; writing—review and editing, A.E.K., D.S. and D.B.; visualization, I.K.; supervision, V.N.S., S.I., P.S. and A.D.K. All authors have read and agreed to the published version of the manuscript.
Not applicable.
Not applicable.
Data related to this article are available on demand by contacting the corresponding author.
The authors declare no conflicts of interest.
Footnotes
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Enlarge this image.Figure 1. Extracellular matrix in normal tissue and tumor (oncomatrix). Created with Biorender.com.
Enlarge this image.Figure 2. The properties of the oncomatrix influence the efficacy of the therapeutics. Created with Biorender.com.
Physical and chemical properties of normal ECM and oncomatrix.
| Parameter | Oncomatrix | Normal ECM | Refs. |
| Density | Predominantly higher than that of normal tissues | Density depends on the tissue type | [ |
| Biopolymer composition | Reduced macromolecule length | Natural tissue parameters | [ |
| Cross-linking of biopolymers | Higher cross-link density | Low cross-link density | [ |
| Stiffness | Higher stiffness due to cross-link formation | Stiffness of the matrix depends on the tissue type | [ |
| ECM microstructure | Highly linearized | Predominantly random | [ |
| ECM remodeling | Higher due to increased metalloproteinase ) activity | Natural level of ECM remodeling | [ |
| Deposition of signaling molecules | Lower than in normal ECM | Deposition depends on the tissue type | [ |
| Hydrogen ion concentration (pH) | ∼6.8–7.0 (slightly acidic) | ∼7.4 (alkaline) | [ |
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; Smirnova, Anna 2 ; Yakimova, Anna 2
; Kabakov, Alexander E 2
; Atiakshin, Dmitri 3
; Petrenko, Daria 4
; Shestakova, Victoria A 5
; Sulina, Yana 4
; Yatsenko, Elena 2 ; Stepanenko, Vasiliy N 4 ; Ignatyuk, Michael 3 ; Evstratova, Ekaterina 2 ; Krasheninnikov, Michael 6 ; Sosin, Dmitry 7
; Baranovskii, Denis 8 ; Ivanov, Sergey 2 ; Shegay, Peter 2 ; Kaprin, Andrey D 8 1 National Medical Research Radiological Center of the Ministry of Health of Russian Federation, 249036 Obninsk, Russia; Obninsk Institute of Nuclear Power Engineering of the National Research Nuclear University MEPhI, 249034 Obninsk, Russia; Scientific and Educational Resource Center for Innovative Technologies of Immunophenotyping, Digital Spatial Profiling and Ultrastructural Analysis, Peoples’ Friendship University of Russia (RUDN University), 117198 Moscow, Russia
2 National Medical Research Radiological Center of the Ministry of Health of Russian Federation, 249036 Obninsk, Russia
3 Scientific and Educational Resource Center for Innovative Technologies of Immunophenotyping, Digital Spatial Profiling and Ultrastructural Analysis, Peoples’ Friendship University of Russia (RUDN University), 117198 Moscow, Russia
4 Department of Obstetrics and Gynecology, Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia
5 National Medical Research Radiological Center of the Ministry of Health of Russian Federation, 249036 Obninsk, Russia; Obninsk Institute of Nuclear Power Engineering of the National Research Nuclear University MEPhI, 249034 Obninsk, Russia
6 Scientific and Educational Resource Center for Cellular Technologies, Peoples’ Friendship University of Russia (RUDN University), 117198 Moscow, Russia
7 Center for Strategic Planning and Management of Medical and Biological Health Risks of the FMBA of Russia, 119121 Moscow, Russia
8 National Medical Research Radiological Center of the Ministry of Health of Russian Federation, 249036 Obninsk, Russia; Scientific and Educational Resource Center for Innovative Technologies of Immunophenotyping, Digital Spatial Profiling and Ultrastructural Analysis, Peoples’ Friendship University of Russia (RUDN University), 117198 Moscow, Russia