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Jumaniyazova, E.; Lokhonina, A.; Dzhalilova, D.; Kosyreva, A.; Fatkhudinov, T. Neoangiogenesis and Extracellular Matrix of HNSCC. Encyclopedia. Available online: (accessed on 14 June 2024).
Jumaniyazova E, Lokhonina A, Dzhalilova D, Kosyreva A, Fatkhudinov T. Neoangiogenesis and Extracellular Matrix of HNSCC. Encyclopedia. Available at: Accessed June 14, 2024.
Jumaniyazova, Enar, Anastasiya Lokhonina, Dzhuliia Dzhalilova, Anna Kosyreva, Timur Fatkhudinov. "Neoangiogenesis and Extracellular Matrix of HNSCC" Encyclopedia, (accessed June 14, 2024).
Jumaniyazova, E., Lokhonina, A., Dzhalilova, D., Kosyreva, A., & Fatkhudinov, T. (2023, November 29). Neoangiogenesis and Extracellular Matrix of HNSCC. In Encyclopedia.
Jumaniyazova, Enar, et al. "Neoangiogenesis and Extracellular Matrix of HNSCC." Encyclopedia. Web. 29 November, 2023.
Neoangiogenesis and Extracellular Matrix of HNSCC

Head and neck squamous cell cancer (HNSCC) is one of the ten most common malignant neoplasms, characterized by an aggressive course, high recurrence rate, poor response to treatment, and low survival rate. This creates the need for a deeper understanding of the mechanisms of the pathogenesis of this cancer. The tumor microenvironment (TME) of HNSCC consists of stromal and immune cells, blood and lymphatic vessels, and extracellular matrix. It is known that HNSCC is characterized by complex relationships between cancer cells and TME components. TME components and their dynamic interactions with cancer cells enhance tumor adaptation to the environment, which provides the highly aggressive potential of HNSCC and resistance to antitumor therapy.

head and neck squamous cell carcinoma HNSCC tumor microenvironments vascular component extracellular matrix

1. Introduction

Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide, causing more than 660,000 new cases and 325,000 deaths annually [1][2]. Modifiable risk factors for this pathology include tobacco use in one form or another, alcoholic beverages, human papillomavirus (HPV) infection (more commonly associated with oropharyngeal cancer), and Epstein–Barr virus (EBV) infection (especially for nasopharyngeal cancer). People in some countries eat areca nut, which also increases the risk of HNSCC. Previously, HNSCC was classified according to tumor location (tumor of the oral or nasal cavity, oropharynx, nasopharynx, larynx, or hypopharynx), TNM (tumor, nodus, and metastasis) stage, and histology, but the recognition of molecular genetic profiles now allows it to be more accurately classified into individual subtypes [3][4]. Today, the updated TNM classification (eighth edition, 2018), which has several differences from the previous seventh edition of 2010, should be used for staging this nosology. The main changes in HNSCC staging include adding depth of invasion for oral cavity tumors, introducing a pathomorphologic and clinical staging system for high-risk oropharyngeal tumors associated with papillomavirus infection (HPV+), and considering tumor extension beyond the lymph node capsule in high-risk HPV-negative oropharyngeal tumors and head and neck squamous cell carcinoma in other localizations, excluding nasopharyngeal cancer. Assessing the depth of invasion of oral cancer has prognostic value: deeper tumors show an increased risk of metastasis to lymph nodes and a decreased overall survival rate [5]. Extranodal extension, in turn, also serves as an unfavorable prognostic factor for HNSCC, with the exception of HPV+-related tumors [6]. A separate chapter in the eighth edition is devoted to nasopharyngeal cancer. The main changes are the inclusion of a T0 category for patients with metastatic cervical lymph nodes, EBV-positive patients with an unknown primary focus, and changes in the definition of regional lymph nodes. Unlike other localizations of head and neck cancer, for which surgery plays an important role in primary treatment, squamous cell cancer of the nasopharynx is primarily treated with radiation therapy, with or without chemotherapy. For this reason, pathologic classification is irrelevant in this disease of the nasopharyngeal region [7]. In 2022, the fifth edition of the World Health Organization (WHO) classification of head and neck tumors was published, focusing on the distinctive molecular genetic characteristics of head and neck tumors [8]. The delineation of the distinct molecular genetic signatures of HNSCC allows for a significant increase in diagnostic accuracy and also has prognostic value, which, in turn, leads to a personalized treatment approach for each patient.

There are many approaches to the treatment of HNSCC, but none of them are effective enough. In the early stages of the tumor (Stages I and II), surgical removal and radiation therapy are highly effective, but 70% of patients are diagnosed with later stages of the disease—III or IV, where the effectiveness of these methods of therapy sharply decreases [9][10]. The ineffectiveness of therapy in a number of patients dictates the need for a deeper understanding of the mechanisms of the pathogenesis of head and neck tumors. To solve this problem, many studies have been conducted to study the properties and relationships between tumor cells and the microenvironment. HNSCC is characterized by complex relationships between stromal, epithelial, and immune cells in the tumor microenvironment (TME) [11][12][13]. The HNSCC TME includes various cells, both stromal and immune, as well as the extracellular matrix (ECM), blood, and lymphatic vessels [12][14]. Recently, a number of authors have emphasized the role of stromal cells in the induction and maintenance of tumors [15][16][17] and have also shown the relationship stromal cells have with the resistance of tumor cells to therapy [18].

2. Vascular Component of the HNSCC TME

The formation of new vessels, or angiogenesis, is one of the signs of the tumor process [19] and is critical both for the growth of the primary tumor and for the development of distant metastases [20]. Tumor angiogenesis and neovascularization are structurally and functionally different from healthy angiogenesis, with tumor vessels having blunt ends and poor perfusion [21]. Tumor endothelial cells have numerous ruptures, which contribute not only to blood leakage but also to the formation of blood clots and tissue swelling [22]. Various factors are involved in the formation of blood vessels in the TME, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), interleukin-8 (IL-8), delta-like ligand 4 (Dll4), and transforming growth factor families (such as TGF-β) [23][24] (Figure 1).
Figure 1. Metastasis of HNSCC as a result of the dynamic interaction of the tumor with blood vessels.
VEGF is a hypoxia-dependent gene and a key factor in tumor vascularization [25] that plays a crucial role in the regulation of blood vessel formation and maintenance. It belongs to the PDGF superfamily, which also includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and the placental growth factor (PlGF) [26][27]. Each member of the family has its own sphere of action. The most well studied is VEGF-A, which induces angiogenesis and is involved in various physiological and pathological processes, including the growth of malignant neoplasms. VEGF-A initiates the proliferation, migration, and tube formation of endothelium. In already formed vessels, it increases the permeability of the wall, allowing proteins, growth factors, and immune cells to penetrate tissues [28]. The functional potential of VEGF-B in cancer is less pronounced: it can enhance blood vessel growth, improve tissue perfusion, and protect against tissue damage under conditions of severe hypoxia [29]. VEGF-B can also interact with co-receptors called neuropilins (NRP-1 and NRP-2). VEGF-C and VEGF-D are associated with the process of lymphangiogenesis, the formation of lymphatic vessels. Thus, the overexpression of these ligands will promote the metastasis of cancer cells to lymph nodes. The last member of the VEGF family is PlGF, which becomes active in tumors under hypoxic conditions. It also promotes the infiltration and activation of macrophages into tumor tissue, which in turn release pro-inflammatory and pro-angiogenic cytokines such as IL-1 and TNF-α [30]. The VEGF family of ligands plays its role through the cell surface receptor tyrosine kinases, VGFR-1, VGFR-2, and VGFR-3 [31][32]. In addition, as mentioned above, VEGF interacts with NRP-1 and NRP-2 [33][34][35], which both enhance the association between VEGF and its receptors, increasing their biological activity. VEGF induces the proliferation, differentiation, and migration of vascular endothelial cells [36][37]; increases capillary permeability [38]; and increases endothelial cell survival by preventing apoptosis [39][40]. In turn, VEGF secreted by endothelial cells can enhance the migration of tumor cells [41], protect them from apoptosis, and prevent anoikis through the activation of PI3K/AKT in HNSCC cancer stem cells [42]. In addition to all of these functions, VEGF has been shown in a number of preclinical studies to contribute to immune suppression. This immunosuppression can occur in several ways. Firstly, VEGF, by binding to VEGFR1 on stem cells of myeloid origin, prevents their differentiation into mature immune cells. Secondly, it induces the expression of the programmed ligand PD-L1 on antigen-presenting cells, which leads to a decrease in T cell activation [43][44].
VEGF expression is influenced by various factors in the TME, including hypoxia, growth factors, cytokines, and transcription factors. For example, enhanced tumor vascularization is provided by the dynamic interaction between endothelial cells, immune cells, and CAFs, which actively secrete pro-angiogenic factors [45][46][47]. Thus, TME macrophages, especially under hypoxic conditions, secrete TGF-β/-α, VEGF, IL-1, IL-6, and IL-8; these factors act as inducers of angiogenesis in HNSCC. For example, IL-8, IL-6, and EGF induce the phosphorylation of STAT3 and ERK in endothelial cells, which increases their survival and proliferation [48]. TGF-β, which is produced by many TME cells (CAFs, T regulatory lymphocytes, etc.) and is found in high percentages in HNSCC, also increases angiogenesis [49]. The high expression of angiogenic factors correlates with more advanced disease, resistance to conventional cytotoxic agents, and poor prognosis [20][50][51]. At least 90% of HNSCCs have increased expression of angiogenic factors such as VEGF. The overexpression of VEGF is associated with aggressive disease and poor outcomes in HNSCC [52][53]. In addition, the increased production of VEGF by tumor cells is associated with lymph node metastasis [54]. Aggarwal et al. [55] reported that serum VEGF levels were significantly higher in patients with oral squamous cell cancer and that these expressions were directly correlated with clinical stage evolvement and neck lymph node involvement. The interaction between HNSCC cells and endothelial cells triggers MAPK and Notch signaling, thereby promoting and enhancing tumor angiogenesis [56]. In a meta-analysis of 12 studies including 1002 patients with cancer of the oral cavity (70.8% of patients), pharynx (15.2%), and larynx (14%), VEGF expression was assessed, and its positivity was associated with a twofold increase in mortality after 2 years [20]. In addition, the overexpression of TGF-β1 found in HNSCC ultimately leads to tumor growth and metastasis by facilitating angiogenesis [57].

3. Role of the ECM in HNSCC

As discussed above, HNSCC is composed of a collection of malignant epithelial cells and TME cells (e.g., fibroblasts, vascular cells, immune cells) that secrete ECM proteins and numerous signaling molecules. Although the initiating genomic changes associated with HNSCC occur in epithelial cells, the changes that occur in the TME facilitate tumor progression and provide various adaptation mechanisms when exposed to damaging factors from the outside (anticancer drugs, radiation therapy) [58]. The ECM is involved in virtually all stages of carcinogenesis, including cancer cell proliferation and invasion, angio- and lymphangiogenesis, the evasion of immune responses, the creation of an immunosuppressive environment, metastasis, and resistance to anti-tumor therapies [59]. The ECM is one of the main components of intercellular and intertissue interactions, providing signaling activity. It has a supporting and shaping function, providing the characteristic shape and size of organs and tissues [60][61]. The ECM is composed of fibrillar and non-fibrillar collagens, elastic fibers, and glycosaminoglycans (GAGs). The ECM is a key structural component of any normal and pathological tissue [11]; in turn, persistent disruption of its homeostasis can lead to the development of various pathological conditions, including cancer. In tumor tissue ECM undergoes changes—its composition, organization, and mechanical properties are altered. The altered composition of the ECM of tumors affects cancer cells, ensures cell insensitivity to growth inhibitors, promotes angiogenesis, and protects against antitumor agents [58]. Many solid tumors are characterized by an abundance of various ECM molecules, such as fibrillar collagens, fibronectin, elastin, laminins, and hyaluronic acid, with the predominance of one or another component depending on the type of cancer [62][63][64]. Recently, the ECM has been assigned one of the main roles in the oncogenesis, metastasis, and progression of malignant neoplasms [65]. An altered ECM composition is characteristic of most solid tumors. At the same time, the predominance of one or another ECM component depends on the anatomical location of the tumor, the causative factors of its origin, and the stage of the disease. [66]. In addition, tumor ECM is biochemically distinct from healthy tissue. Tumor stroma is usually stiffer than normal tissue stroma (~400 Pa versus 150 Pa, respectively) [67][68]. At the same time, the increase in stiffness and the remodeling of the ECM begin to be traced at the stage of precancerous changes, which, in turn, also contribute to the malignant transformation of cells. The dynamic interaction during carcinogenesis between tumor cells, microenvironmental cells, and the ECM leads to aberrant mechanotransduction and further malignant transformation [69].
The ECM of HNSCC is a collection of molecules with a variety of cytokines, intermediate metabolites, nutrients, hormones, and chemokines secreted by tumor and TME cells [70]. The ECM promotes the adhesion and migration of cancer cells, which causes tumor progression and metastasis (Table 1). Given its ability to bind secreted factors, the ECM is considered a functional bioregulatory platform on which the processes of carcinogenesis can take place [71]. Because HNSCC represents a diverse and complex set of diseases, it exhibits a high level of ECM heterogeneity. Indeed, malignancies arising in histologically distinct mucosal squamous epithelia such as the oral cavity, larynx, hypopharynx, and oropharynx may exhibit distinct stromal features. In oral squamous cell carcinoma, single-cell mRNA profiling has revealed a prominent stromal compartment with large numbers of matrix-producing CAFs in the majority of tumors examined [72]. The active production of ECM components by CAFs leads to increased tumor stiffness, which activates oncogenic intracellular signaling pathways, such as the β-catenin, Akt, PI3K, and focal adhesion kinase (FAK) pathways, and suppresses tumor suppressor genes such as phosphatase and tensin homolog [73][74].
In HNSCC, signaling between malignant epithelial cells and stromal cells causes increased activity in ECM components that control carcinoma cell migration, modulate the cytokine milieu, and promote immune evasion in tumors [70]. During HNSCC carcinogenesis, changes also occur in the ECM: its composition and density are altered. In the early stages of HNSCC progression, nascent transformed epithelial cells induce a wound-healing-like response marked by the activation of stromal fibroblasts and the strong accumulation of ECM and ECM-related proteins collectively known as matrisomes [75]. CAFs are the main matrix-producing cells of the stroma. In a proteomic analysis of the ECM produced by CAFs isolated from HNSCC, collagens I, III, VI, and XII; fibronectin; tenascin C; and TGF-β-induced (TGFBI) fibrillin were among the major core components [76]. Proteins associated with the ECM deposited by these CAFs include galectin-1, annexin A2, the ECM regulator SERPINH1, tissue transglutaminase (TG2), HTRA1, and lysyl oxidase homolog 2 (LOXL2), while secreted factors associated with the ECM included insulin-like growth factor 2, several alarmins, Wnt5A, and FGF [70].
As mentioned above, stromal cells (to a greater extent) and cancer cells participate in the production of ECM. Reciprocal epithelial–mesenchymal interactions at the tumor–stroma interface enhance the expression of cancer cell matrisomal proteins and their incorporation into the ECM. To demonstrate the important role of these components in tumor progression, a proteomic study of pancreatic ductal adenocarcinoma was conducted, which showed that high levels of tumor-cell-derived matrisomal proteins correlate with poor patient survival [77].
Let us consider changes in some ECM components of HNSCC. As with other types of cancer, with HNSCC, there is a thickening of the ECM, in which collagen plays a significant role. During tumor growth, increased interstitial collagen deposition is accompanied by fiber reorganization and enzymatic cross-linking (lysyl oxidases and lysyl hydroxylases), which correlates with increased tumor invasive potential and poor patient survival [78][79]. To classify changes in collagen arrangement that accompany carcinoma progression, distinct patterns of fibrillar collagen organization, called “tumor-associated collagen signatures,” have been defined [80]. Also, collagen in the HNSCC ECM activates the tyrosine kinase DDR1 receptor in tumor epithelial cells, which triggers pro-tumor activity. Moreover, increased DDR1 expression is associated with worse overall survival [81]. DDRs (discoidin domain receptors) can spontaneously bind to collagen and are not regulated by intracellular or extracellular signals [82][83]. The issue of DDR expression in various cancers remains controversial today, but there is evidence of increased DDR expression in cancer. For example, the overexpression of DDR1 has been observed in HNSCC [84]. Lysyl oxidase-like 2 (LOXL2) is a member of the lysyl oxidase (LOX) family of secretory enzymes, which are lysine deaminases that cross-link ECM proteins such as collagen [85][86]. Increased levels of LOXL2 have been found in HNSCC tissue [87]. The increased expression of LOXL2 mRNA has also been detected in metastatic lesions of HNSCC [88].
Let us review the major glycoproteins of the ECM of HNSCC. Fibronectin (the major glycoprotein of the ECM) is significantly overexpressed in patients with this type of cancer and has been obviously correlated with higher pathological stages and poor prognosis [80][89]. The downregulation of this glycoprotein suppresses the proliferation, migration, and invasion of HNSCC cells and inhibits macrophage M2 polarization in vitro [89]. Another HNSCC ECM glycoprotein, tenascin C, which is involved in the modulation of the immune response in many diseases [90], is also subject to changes. Even in the last century, a number of studies have described the role of tenascin in carcinogenesis: it induces cell migration [91], angiogenesis [92], and the expression of MMPs [93], which themselves are involved in promoting tumor growth and invasion [94]. Tenascin C has also been shown to promote tumor progression in a carcinogen-induced immunocompetent mouse model of OSCC by stimulating the formation of an immunosuppressive stroma [95]. Laminin expression is also upregulated in HNSCC. Laminin-5 hyperexpression is associated with high rates of HNSCC budding, suggesting that it is associated with the establishment of an invasive phenotype [96].
Integrins are transmembrane heterodimers consisting of α- and β-subunits. Integrins can bind collagen [97] and bind to various proteins, such as fibronectin, fibrinogen, laminin, and vitronectin [98]. Integrins also connect the ECM to the intracellular actin cytoskeleton. In addition, integrins provide the process of mechanotransduction: integrins perceive the mechanical force of the ECM and then transmit signals to intracellular proteins, such as tyrosine kinases FAK and Src. The activation of αvβ3 integrin correlates with poor prognosis for patients with OSCC [99][100]. Integrin α5 (ITGA5) promotes the proliferation, migration, and invasion of HNSCC cells by regulating the activation of the PI3K/AKT signaling pathway, and increased expression is associated with poor prognosis [101]. The overexpression of integrin αvβ6 is observed in HNSCC and correlates with invasive potential and progression [99][102].
Perlecan is a heparin sulfate proteoglycan that has five domains and is one of the main components of the ECM, participating in cell proliferation and differentiation (through interaction with integrins) [103]. It plays an important role in lipid metabolism, inflammation, wound healing, thrombosis, and cancer angiogenesis [104]. In HNSCC, perlecan promotes tumor cell growth, chemoresistance, migration, and invasion, mainly by regulating heparin-binding growth factors such as FGF-2, VEGF-A, and Hedgehog (Hh) [59][105]. Periostin is another important proteoglycan of tumor ECM. According to one study [106], the overexpression of periostin can also be observed in HNSCC, which is associated with tumor proliferation and metastasis.
The ability of tumor cells and TME cells to synthesize ECM components critically influences tumor progression [107]. Understanding the nature of heterotypic interactions between tumor cells, the ECM, and CAFs in the TME will provide insight into the mechanisms underlying tumor progression and metastasis and identify new targets for antitumor agents. The densified structure of the ECM, observed in many types of cancer, determines tumor progression both by creating barriers to the entry of therapeutic agents and by creating certain conditions in the tumor tissue itself. Today, it is known that the densified structure of the ECM observed in various types of cancer leads to a loss of sensitivity to anticancer drugs [108] and radiation therapy [109]. In addition to creating a “protective shield” effect that is difficult for antitumor agents to overcome [110][111], dense ECM compresses blood vessels, which also prevents drugs from reaching tumor cells. The compression of blood vessels by dense ECM leads to local hypoxia [112][113], which, in turn, activates antiapoptotic pathways and stimulates neoangiogenesis [114]. Immune cells migrating toward tumor cells along a cytokine concentration gradient cannot reach the tumor because they will encounter a dense ECM. Thus, ECM density regulates the process of the infiltration of immune cells into tumor tissue [111][115]. Hypoxia and metabolic stress, which are a consequence of high ECM density, lead to an increase in the content of immunosuppressive factors IL-10, CCL18, CCL22, TGF-b, prostaglandin-E2, and VEGF-A [114][116][117]. In this case, TGF-b attracts T-reg cells into the tumor [118] and acts as an M-2 polarizer for macrophages [119]. Dense ECM induces the transition of tumor tissue cells into cancer stem cells (CSCs), which, in turn, actively proliferate in hypoxic environments. In addition, a number of studies have demonstrated the resistance of CSCs to anticancer drugs [69][120][121]. During HNSCC carcinogenesis, ECM destabilization occurs. The increased deposition of a number of proteoglycans and collagens leads to ECM remodeling. Remodeled ECM causes disruption in cell polarity and enhances growth factor transport, causing biochemical and biomechanical changes. These changes ultimately contribute to the metastatic cascade: cell migration into the interstitial matrix and then into the vasculature is stimulated [59][122].
The ECM (together with the basement membrane) is a barrier that tumor cells must overcome on the “pathway to vascular invasion” [123][124]. In this case, basal membrane disruption is defined as a critical event of tumor invasion that marks the beginning of the metastatic cascade [125][126]. The surface of HNSCC cancer cells is characterized by the presence of invadopodia, which play an important role in the process of tumor invasion. Invadopodia mediate tumor dissemination by degrading ECM-restrictive proteins with matrix MMPs [127]. MMPs are members of a family of calcium- and zinc-dependent endopeptidases that degrade other components of the ECM and thus ensure its constant renewal [128]. In total, about 24 members of the MMP family have been identified in humans. In addition to the above-mentioned function, MMPs destroy the basal membrane and capillary wall and stimulate neoangiogenesis; therefore, these enzymes have a key role in the progression of HNSCC [129][130][131]. A number of studies have demonstrated an increase in MMPs in HNSCC [132][133]. Interestingly, the level of MMP elevation depends on the anatomical localization of squamous cell cancer in the head and neck region.. For example, MMP1 and MMP10 are highly expressed in OSCC [134] and MMP3 expression is elevated in squamous cell carcinoma of the tongue [135]. The activity of MMP14, MMP2, and MMP9 in the ECM is significantly increased in HNSCC cell lines with high metastatic potential, as well as in samples from patients with oral cancer with lymph node involvement [136][137]. MMP14 plays a key role in the early stages of tumor invasion and cancer progression. MMP14 is concentrated on the surface of cancer cell invadopodia and destroys a number of VSMC components: collagen types I, II, and III; fibronectin; tenascin; and perlecan. A recent study [138] demonstrated an association between MMP14 levels and the extranodal extension of OSCC. In addition, ECM metalloproteinase inducer (EMMPRIN, also known as CD147) is an additional factor involved in tumor invasion and metastasis. In hypopharyngeal squamous cell carcinoma, CD147 appears to mediate ECM degradation by stimulating the synthesis of MMPs and promote angiogenesis by stimulating VEGF expression [139]. One study [140] showed that MMP3 can be used as a potential biomarker for oral cancer progression. In addition, a recent study [133] found that MMP family expression correlates with the levels of infiltration of six immune cells, B cells, CD8 + T cells, CD4 + T cells, macrophages, neutrophils, and dendritic cells, suggesting that the MMP family may reflect immune status and serve as a prognostic sign in HNSCC. Kudo et al. demonstrated that the highly invasive HNSCC cell line MSCC-inv1 significantly overexpresses MMP19 [141]. MMPs have the molecular function of modulating a number of latent signaling proteins located in the ECM, including cytokines and growth factors such as resting TGF-β, which forms a complex with TGF-β-binding protein-1 in the ECM. Thus, TGF-β modulates MMP expression, resulting in a bidirectional regulatory loop that enhances TGF-β signaling and promotes cancer progression [142]. The MMP family can be used as therapeutic targets and prognostic biomarkers for HNSCC depending on their role in the disease. Some scientists have used sesamin extracted from the sesame oil of pepper bark to regulate MMP2, thereby inhibiting HNSCC migration and invasion [143]. Another team of researchers showed that mulberry leaf extract can inhibit the activity of MMP2 and MMP9 and inhibit the migration and invasion of HNSCC [144]. Considering the multicomponent nature of the ECM, not all possible roles of its components in the development and progression of HNSCC have been described to date. Increased knowledge about the role of ECM components in HNSCC will help guide the search for new diagnostic and treatment options.
Table 1. Role of ECM components in the progression of HNSCC.
Main Components of the HNSCC ECM What Are the Effects on HNSCC Progression?
Create migration pathways for cancer cells and affect their invadopodia [145], thereby promoting invasion and metastasis [146].
Promote PI3 kinase (PI3K) activity and induce invasion [147].
Induce resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) through the activation of mTOR via the AKT-independent pathway [148].
Promote the proliferation and invasion of cancer cells via the activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) signaling pathway [149].
A positive correlation has been observed between elastin degradation and the degree and stage of the disease [150].
Takes part in the transformation of cancer cells into stem cancer cells; stimulates their growth, proliferation, and evasion of growth suppressors.
Stimulates angiogenesis by increasing the content and transmission of VEGF-mediated signaling [151].
Provides resistance of cancer cells to anoikis through a mechanism involving fibronectin and αv/FAK integrin receptor signaling [152].
Activate EGFR/MAPK signaling [153].
High expression is positively correlated with tumor = invasive potential and poor prognosis [154][155][156].
Participates in the activation of the migration, survival, and chemoresistance of cancer stem cells [157].
Stimulates proliferation, migration, angiogenesis, and metastasis [158].
Induces epithelial–mesenchymal transition.
Induces and activates other signaling pathways in cancer cells such as JNK, Wnt, Notch, AKT/HIF1α, and TGF-β.
Creates barriers for T-lymphocytes to enter the tumor.
Provide radioresistance [159].
Integrin αvβ3 is actively involved in tumor angiogenesis [160].
Overexpression of αv integrin subunit is associated with tumor invasion and metastasis [161].
Participate in HNSCC proliferation and invasion by activating the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) signaling pathway [149].
In nasopharyngeal carcinoma, the mRNA and protein expression levels of integrin αv also correlate with tumor size and lymph node spread [162].
Increased expression of MMP 2 in HNSCC is positively correlated with aggressive invasion, poor survival, and metastasis to lymph nodes.
Destroys type IV collagen, a major component of the basal membrane, promoting invasion and metastasis [162].
Enhances the bioavailability of VEGF, thereby increasing the amount of VEGF in the tumor microenvironment [163].
MMP9 overexpression is associated with tumor recurrence, metastasis to lymph nodes, and the development of secondary primary cancer [164].
Increases the secretion of VEGF-A [165].
Overexpression is associated with extranodal spread and is associated with poor prognosis [138].
Assists in cell invasion.
Stimulates movement of amoeboid cells in tumor tissue and invadopodia [166].
Induced by HIF1-⍺-mediated hypoxia and enhances metastasis [166].
Promotes EMT; facilitates migration of cancer cells across the basal membrane [167].
Involved in adhesion and migration of cancer cells.
Overexpression is associated with resistance of HNSCC cancer cells to cisplatin [168].

4. Conclusions

The TME is a key component of this cascade of events, as it is involved in phenotype changes (cancer cells acquire a stem cell phenotype, immune cells acquire a pro-tumor phenotype) and the modulation of the behavior of both tumor cells and all cellular components of tumor tissue. Analyzing the relationships between TME components, one gains an impression of some “vicious circles” that condition the aggressive potential of HNSCC. Understanding the peculiarities of heterotypic interactions between cancer cells, new vessels, CAF, ECM, and hypoxia will allow us to understand the mechanisms mediating rapid tumor progression and its resistance to antitumor drugs and radiation therapy. Basic research aimed at studying the role of TME components in HNSCC carcinogenesis may serve as a key to the discovery of both new biomarkers–predictors of prognosis and targets for new antitumor strategies.


  1. Nordemar, S.; Kronenwett, U.; Auer, G.; Högmo, A.; Lindholm, J.; Edström, S.; Tryggvasson, K.; Linder, S.; Munck-Wikland, E. Laminin-5 as a predictor of invasiveness in cancer in situ lesions of the larynx. Anticancer Res. 2001, 21, 509–512.
  2. Berndt, A.; Hyckel, P.; Könneker, A.; Katenkamp, D.; Kosmehl, H. Oral squamous cell carcinoma invasion is associated with a laminin-5 matrix re-organization but independent of basement membrane and hemidesmosome formation. Clues from an in vitro invasion model. Invasion Metastasis 1997, 17, 251–258.
  3. Meireles Da Costa, N.; Mendes, F.A.; Pontes, B.; Nasciutti, L.E.; Ribeiro Pinto, L.F.; Palumbo Júnior, A. Potential therapeutic significance of laminin in head and neck squamous carcinomas. Cancers 2021, 13, 1890.
  4. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F.; Bsc, M.F.B.; Me, J.F.; Soerjomataram, M.I.; et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249.
  5. Johnson, D.E.; Burtness, B.; Leemans, C.R.; Lui, V.W.Y.; Bauman, J.E.; Grandis, J.R. Head and neck squamous cell carcinoma. Nat. Rev. Dis. Primers 2020, 6, 92.
  6. Lawrence, M.S.; Sougnez, C.; Lichtenstein, L.; Cibulskis, K.; Lander, E.; Gabriel, S.B.; Liu, W.; Lu, Y.; Mills, G.; Motter, T.; et al. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 2015, 517, 576–582.
  7. Zhang, P.; Li, S.; Zhang, T.; Cui, F.; Shi, J.H.; Zhao, F.; Sheng, X. Characterization of Molecular Subtypes in Head and Neck Squamous Cell Carcinoma with Distinct Prognosis and Treatment Responsiveness. Front. Cell Dev. Biol. 2021, 9, 711348.
  8. Ebrahimi, A.; Gil, Z.; Amit, M.; Yen, T.C.; Liao, C.T.; Chaturvedi, P.; Agarwal, J.P.; Kowalski, L.P.; Kreppel, M.; Cernea, C.R.; et al. Primary tumor staging for oral cancer and a proposed modification incorporating depth of invasion: An international multicenter retrospective study. JAMA Otolaryngol. Head Neck Surg. 2014, 140, 1138–1148.
  9. Zanoni, D.K.; Patel, S.G.; Shah, J.P. Changes in the 8th Edition of the American Joint Committee on Cancer (AJCC) Staging of Head and Neck Cancer: Rationale and Implications. Curr. Oncol. Rep. 2019, 21, 52.
  10. Nosé, V.; Lazar, A.J. Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumors: Familial Tumor Syndromes. Head Neck Pathol. 2022, 16, 143–157.
  11. Badoual, C. Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumors: Oropharynx and Nasopharynx. Head Neck Pathol. 2022, 16, 19–30.
  12. Lemaire, F.; Millon, R.; Young, J.; Cromer, A.; Wasylyk, C.; Schultz, I.; Muller, D.; Marchal, P.; Zhao, C.; Melle, D.; et al. Differential expression profiling of head and neck squamous cell carcinoma (HNSCC). Br. J. Cancer 2003, 89, 1940–1949.
  13. Saussez, S.; Duray, A.; Demoulin, S.; Hubert, P.; Delvenne, P. Immune suppression in head and neck cancers: A review. Clin. Dev. Immunol. 2010, 2010, 701657.
  14. Plzák, J.; Bouček, J.; Bandúrová, V.; Kolář, M.; Hradilová, M.; Szabo, P.; Lacina, L.; Chovanec, M.; Smetana, K. The head and neck squamous cell carcinoma microenvironment as a potential target for cancer therapy. Cancers 2019, 11, 440.
  15. Wang, G.; Zhang, M.; Cheng, M.; Wang, X.; Li, K.; Chen, J.; Chen, Z.; Chen, S.; Chen, J.; Xiong, G.; et al. Tumor microenvironment in head and neck squamous cell carcinoma: Functions and regulatory mechanisms. Cancer Lett. 2021, 507, 55–69.
  16. Elmusrati, A.; Wang, J.; Wang, C.Y. Tumor microenvironment and immune evasion in head and neck squamous cell carcinoma. Int. J. Oral Sci. 2021, 13, 24.
  17. Petrova, V.; Annicchiarico-Petruzzelli, M.; Melino, G.; Amelio, I. The hypoxic tumour microenvironment. Oncogenesis 2018, 7, 10.
  18. Castells, M.; Thibault, B.; Delord, J.P.; Couderc, B. Implication of tumor microenvironment in chemoresistance: Tumor-associated stromal cells protect tumor cells from cell death. Int. J. Mol. Sci. 2012, 13, 9545–9571.
  19. Almangush, A.; Alabi, R.O.; Troiano, G.; Coletta, R.D.; Salo, T.; Pirinen, M.; Mäkitie, A.A.; Leivo, I. Clinical significance of tumor-stroma ratio in head and neck cancer: A systematic review and meta-analysis. BMC Cancer 2021, 21, 480.
  20. Meads, M.B.; Gatenby, R.A.; Dalton, W.S. Environment-mediated drug resistance: A major contributor to minimal residual disease. Nat. Rev. Cancer 2009, 9, 665–674.
  21. Jumaniyazova, E.; Lokhonina, A.; Dzhalilova, D.; Kosyreva, A.; Fatkhudinov, T. Immune Cells in Head-and-Neck Tumor Microenvironments. J. Pers. Med. 2022, 12, 1521.
  22. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674.
  23. Kyzas, P.A.; Cunha, I.W.; Ioannidis, J.P.A. Prognostic significance of vascular endothelial growth factor immunohistochemical expression in head and neck squamous cell carcinoma: A meta-analysis. Clin. Cancer Res. 2005, 11, 1434–1440.
  24. Rad, H.S.; Shiravand, Y.; Radfar, P.; Ladwa, R.; Perry, C.; Han, X.; Warkiani, M.E.; Adams, M.N.; Hughes, B.G.; O’Byrne, K.; et al. Understanding the tumor microenvironment in head and neck squamous cell carcinoma. Clin. Transl. Immunol. 2022, 11, e1397.
  25. Lee, P.; Chandel, N.S.; Simon, M.C. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond. Nat. Rev. Mol. Cell Biol. 2020, 21, 268–283.
  26. Kato, Y.; Ozawa, S.; Miyamoto, C.; Maehata, Y.; Suzuki, A.; Maeda, T.; Baba, Y. Acidic extracellular microenvironment and cancer. Cancer Cell Int. 2013, 13, 89.
  27. Lugano, R.; Ramachandran, M.; Dimberg, A. Tumor angiogenesis: Causes, consequences, challenges and opportunities. Cell. Mol. Life Sci. 2020, 77, 1745–1770.
  28. Watanabe, S.; Kato, M.; Kotani, I.; Ryoke, K.; Hayashi, K. Lymphatic vessel density and vascular endothelial growth factor expression in squamous cell carcinomas of lip and oral cavity: A clinicopathological analysis with immunohistochemistry using antibodies to D2-40, VEGF-C and VEGF-D. Yonago Acta Med. 2013, 56, 29–37.
  29. Christopoulos, A.; Ahn, S.M.; Klein, J.D.; Kim, S. Biology of vascular endothelial growth factor and its receptors in head and neck cancer: Beyond angiogenesis. Head Neck 2010, 33, 1220–1229.
  30. Carla, C.; Daris, F.; Cecilia, B.; Francesca, B.; Francesca, C.; Paolo, F. Angiogenesis in head and neck cancer: A review of the literature. J. Oncol. 2011, 2012, 358472.
  31. Pradeep, C.R.; Sunila, E.S.; Kuttan, G. Expression of vascular endothelial growth factor (VEGF) and VEGF receptors in tumor angiogenesis and malignancies. Integr. Cancer Ther. 2005, 4, 315–321.
  32. Dumitru, C.S.; Raica, M. Vascular Endothelial Growth Factor Family and Head and Neck Squamous Cell Carcinoma. Anticancer Res. 2023, 43, 4315–4326.
  33. Kim, K.J.; Cho, C.S.; Kim, W.U. Role of placenta growth factor in cancer and inflammation. Exp. Mol. Med. 2011, 44, 10–19.
  34. Shibuya, M. Vascular Endothelial Growth Factor (VEGF) and Its Receptor (VEGFR) Signaling in Angiogenesis: A Crucial Target for Anti- and Pro-Angiogenic Therapies. Genes Cancer 2011, 2, 1097–1105.
  35. Apte, R.S.; Chen, D.S.; Ferrara, N. VEGF in Signaling and Disease: Beyond Discovery and Development. Cell 2019, 176, 1248–1264.
  36. Holmes, K.; Roberts, O.L.; Thomas, A.M.; Cross, M.J. Vascular endothelial growth factor receptor-2: Structure, function, intracellular signalling and therapeutic inhibition. Cell. Signal. 2007, 19, 2003–2012.
  37. Rizzolio, S.; Tamagnone, L. Multifaceted Role of Neuropilins in Cancer. Curr. Med. Chem. 2011, 18, 3563–3575.
  38. Ellis, L.M. The role of neuropilins in cancer. Mol. Cancer Ther. 2006, 5, 1099–1107.
  39. Wang, S.; Li, X.; Parra, M.; Verdin, E.; Bassel-Duby, R.; Olson, E.N. Control of endothelial cell proliferation and migration by VEGF signaling to histone deacetylase 7. Proc. Natl. Acad. Sci. USA 2008, 105, 7738–7743.
  40. Olsson, A.K.; Dimberg, A.; Kreuger, J.; Claesson-Welsh, L. VEGF receptor signalling—In control of vascular function. Nat. Rev. Mol. Cell Biol. 2006, 7, 359–371.
  41. Breslin, J.W.; Pappas, P.J.; Cerveira, J.J.; Hobson, R.W.; Duran, W.N. VEGF increases endothelial permeability by separate signaling pathways involving ERK-1/2 and nitric oxide. Am. J. Physiol. Heart Circ. Physiol. 2003, 284, H92–H100.
  42. Gupta, K.; Kshirsagar, S.; Li, W.; Gui, L.; Ramakrishnan, S.; Gupta, P.; Law, P.Y.; Hebbel, R.P. VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAPK/ERK and SAPK/JNK signaling. Exp. Cell Res. 1999, 247, 495–504.
  43. Reinmuth, N.; Liu, W.; Jung, Y.D.; Ahmad, S.A.; Shaheen, R.M.; Fan, F.; Bucana, C.D.; McMahon, G.; Gallick, G.E.; Ellis, L.M. Induction of VEGF in perivascular cells defines a potential paracrine mechanism for endothelial cell survival. FASEB J. 2001, 15, 1239–1241.
  44. Shigetomi, S.; Imanishi, Y.; Shibata, K.; Sakai, N.; Sakamoto, K.; Fujii, R.; Habu, N.; Otsuka, K.; Sato, Y.; Watanabe, Y.; et al. VEGF-C/Flt-4 axis in tumor cells contributes to the progression of oral squamous cell carcinoma via upregulating VEGF-C itself and contactin-1 in an autocrine manner. Am. J. Cancer Res. 2018, 8, 2046–2063.
  45. Campos, M.S.; Neiva, K.G.; Meyers, K.A.; Krishnamurthy, S.; Nör, J.E. Endothelial derived factors inhibit anoikis of head and neck cancer stem cells. Oral Oncol. 2012, 48, 26–32.
  46. Ziogas, A.C.; Gavalas, N.G.; Tsiatas, M.; Tsitsilonis, O.; Politi, E.; Terpos, E.; Rodolakis, A.; Vlahos, G.; Thomakos, N.; Haidopoulos, D.; et al. VEGF directly suppresses activation of T cells from ovarian cancer patients and healthy individuals via VEGF receptor Type 2. Int. J. Cancer 2011, 130, 857–864.
  47. Micaily, I.; Johnson, J.; Argiris, A. An update on angiogenesis targeting in head and neck squamous cell carcinoma. Cancers Head Neck 2020, 5, 5–7.
  48. Quail, D.F.; Joyce, J.A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 2013, 19, 1423–1437.
  49. Weis, S.M.; Cheresh, D.A. Tumor angiogenesis: Molecular pathways and therapeutic targets. Nat. Med. 2011, 17, 1359–1370.
  50. Curry, J.M.; Sprandio, J.; Cognetti, D.; Luginbuhl, A.; Bar-Ad, V.; Pribitkin, E.; Tuluc, M. Tumor microenvironment in head and neck squamous cell carcinoma. Semin. Oncol. 2014, 41, 217–234.
  51. Neiva, K.G.; Zhang, Z.; Miyazawa, M.; Warner, K.A.; Karl, E.; Nör, J.E. Cross talk initiated by endothelial cells enhances migration and inhibits anoikis of squamous cell carcinoma cells through STAT3/Akt/ERK signaling. Neoplasia 2009, 11, 583–593.
  52. Lu, S.L.; Herrington, H.; Reh, D.; Weber, S.; Bornstein, S.; Wang, D.; Li, A.G.; Tang, C.-F.; Siddiqui, Y.; Nord, J.; et al. Loss of transforming growth factor-β type II receptor promotes metastatic head-and-neck squamous cell carcinoma. Genes Dev. 2006, 20, 1331–1342.
  53. Smith, B.D.; Smith, G.L.; Carter, D.; Sasaki, C.T.; Haffty, B.G. Prognostic significance of Vascular Endothelial Growth Factor protein levels in oral and oropharyngeal squamous cell carcinoma. J. Clin. Oncol. 2000, 18, 2046–2052.
  54. Mineta, H.; Miura, K.; Ogino, T.; Takebayashi, S.; Misawa, K.; Ueda, Y.; Suzuki, I.; Dictor, M.; Borg, Å.; Wennerberg, J. Prognostic value of vascular endothelial growth factor (VEGF) in head and neck squamous cell carcinomas. Br. J. Cancer 2000, 83, 775–781.
  55. Tse, G.M.; Chan, A.W.H.; Yu, K.H.; King, A.D.; Wong, K.T.; Chen, G.G.; Tsang, R.K.Y.; Chan, A.B.W. Strong immunohistochemical expression of vascular endothelial growth factor predicts overall survival in head and neck squamous cell carcinoma. Ann. Surg. Oncol. 2007, 14, 3558–3565.
  56. El-Gazzar, R.; Macluskey, M.; Williams, H.; Ogden, G.R. Vascularity and expression of vascular endothelial growth factor in oral squamous cell carcinoma, resection margins, and nodal metastases. Br. J. Oral Maxillofac. Surg. 2006, 44, 193–197.
  57. Shang, Z.J.; Li, J.R.; Li, Z.B. Circulating levels of vascular endothelial growth factor in patients with oral squamous cell carcinoma. Int. J. Oral Maxillofac. Surg. 2002, 31, 495–498.
  58. Raudenská, M.; Svobodová, M.; Gumulec, J.; Falk, M.; Masařík, M. The importance of cancer-associated fibroblasts in the pathogenesis of head and neck cancers. Klin. Onkol. 2020, 33, 39–48.
  59. Zhang, X.; Dong, Y.; Zhao, M.; Ding, L.; Yang, X.; Jing, Y.; Song, Y.; Chen, S.; Hu, Q.; Ni, Y. ITGB2-mediated metabolic switch in CAFs promotes OSCC proliferation by oxidation of NADH in mitochondrial oxidative phosphorylation system. Theranostics 2020, 10, 12044.
  60. Kumar, D.; New, J.; Vishwakarma, V.; Joshi, R.; Enders, J.; Lin, F.; Dasari, S.; Gutierrez, W.R.; Leef, G.; Ponnurangam, S.; et al. Cancer-associated fibroblasts drive glycolysis in a targetable signaling loop implicated in head and neck squamous cell carcinoma progression. Cancer Res 2018, 78, 3769–3782.
  61. Pickup, M.W.; Mouw, J.K.; Weaver, V.M. The extracellular matrix modulates the hallmarks of cancer. Embo Rep. 2014, 15, 1243–1253.
  62. Rigoglio, N.N.; Rabelo, A.C.S.; Borghesi, J.; de Sá Schiavo Matias, G.; Fratini, P.; Prazeres, P.H.D.M.; Pimentel, C.M.M.M.; Birbrair, A.; Miglino, M.A. The tumor microenvironment: Focus on extracellular matrix. In Advances in Experimental Medicine and Biology; Springer: Cham, Switzerland, 2020.
  63. Clause, K.C.; Barker, T.H. Extracellular matrix signaling in morphogenesis and repair. Curr. Opin. Biotechnol. 2013, 24, 830–833.
  64. Walker, C.; Mojares, E.; Del Río Hernández, A. Role of extracellular matrix in development and cancer progression. Int. J. Mol. Sci. 2018, 19, 3028.
  65. Provenzano, P.P.; Inman, D.R.; Eliceiri, K.W.; Knittel, J.G.; Yan, L.; Rueden, C.T.; White, J.G.; Keely, P.J. Collagen density promotes mammary tumor initiation and progression. BMC Med. 2008, 6, 11.
  66. Mammoto, T.; Jiang, A.; Jiang, E.; Panigrahy, D.; Kieran, M.W.; Mammoto, A. Role of collagen matrix in tumor angiogenesis and glioblastoma multiforme progression. Am. J. Pathol. 2013, 183, 1293–1305.
  67. Provenzano, P.P.; Hingorani, S.R. Hyaluronan, fluid pressure, and stromal resistance in pancreas cancer. Br. J. Cancer 2013, 108, 1–8.
  68. Cox, T.R.; Erler, J.T. Remodeling and homeostasis of the extracellular matrix: Implications for fibrotic diseases and cancer. Dis. Model. Mech. 2011, 4, 165–178.
  69. Sala, M.; Ros, M.; Saltel, F. A Complex and Evolutive Character: Two Face Aspects of ECM in Tumor Progression. Front. Oncol. 2020, 10, 1620.
  70. Le, Q.T.; Harris, J.; Magliocco, A.M.; Kong, C.S.; Diaz, R.; Shin, B.; Cao, H.; Trotti, A.; Erler, J.T.; Chung, C.H.; et al. Validation of lysyl oxidase as a prognostic marker for metastasis and survival in head and neck squamous cell carcinoma: Radiation Therapy Oncology Group trial 90-03. J. Clin. Oncol. 2009, 27, 4281–4286.
  71. Kass, L.; Erler, J.T.; Dembo, M.; Weaver, V.M. Mammary epithelial cell: Influence of extracellular matrix composition and organization during development and tumorigenesis. Cell Biol. 2007, 39, 1987–1994.
  72. Huang, J.; Zhang, L.; Wan, D.; Zhou, L.; Zheng, S.; Lin, S.; Qiao, Y. Extracellular matrix and its therapeutic potential for cancer treatment. Signal Transduct. Target. Ther. 2021, 6, 153.
  73. Saint, A.; Van Obberghen-Schillinga, E. The role of the tumor matrix environment in progression of head and neck cancer. Curr. Opin. Oncol. 2021, 33, 168–174.
  74. Hynes, R.O. The extracellular matrix: Not just pretty fibrils. Science 2009, 326, 1216–1219.
  75. Puram, S.V.; Tirosh, I.; Parikh, A.S.; Patel, A.P.; Yizhak, K.; Gillespie, S.; Rodman, C.; Luo, C.L.; Mroz, E.A.; Emerick, K.S.; et al. Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Head and Neck Cancer. Cell 2017, 171, 1611–1624.e24.
  76. Peltanova, B.; Raudenska, M.; Masarik, M. Effect of tumor microenvironment on pathogenesis of the head and neck squamous cell carcinoma: A systematic review. Mol. Cancer 2019, 18, 63.
  77. Gong, Y.; Bao, L.; Xu, T.; Yi, X.; Chen, J.; Wang, S.; Pan, Z.; Huang, P.; Ge, M. The tumor ecosystem in head and neck squamous cell carcinoma and advances in ecotherapy. Mol. Cancer 2023, 22, 68.
  78. Naba, A.; Clauser, K.R.; Ding, H.; Whittaker, C.A.; Carr, S.A.; Hynes, R.O. The extracellular matrix: Tools and insights for the “omics” era. Matrix Biol. 2016, 49, 10–24.
  79. Gopal, S.; Veracini, L.; Grall, D.; Butori, C.; Schaub, S.; Audebert, S.; Camoin, L.; Baudelet, E.; Radwanska, A.; Beghelli-de la Forest Divonne, S.; et al. Fibronectin-guided migration of carcinoma collectives. Nat. Commun. 2017, 8, 14105.
  80. Tian, C.; Clauser, K.R.; Öhlund, D.; Rickelt, S.; Huang, Y.; Gupta, M.; Mani, D.R.; Carr, S.A.; Tuveson, D.A.; Hynes, R.O. Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells. Proc. Natl. Acad. Sci. USA 2019, 116, 19609–19618.
  81. Acerbi, I.; Cassereau, L.; Dean, I.; Shi, Q.; Au, A.; Park, C.; Chen, Y.Y.; Liphardt, J.; Hwang, E.S.; Weaver, V.M. Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integr. Biol. 2015, 7, 1120–1134.
  82. Maller, O.; Drain, A.P.; Barrett, A.S.; Borgquist, S.; Ruffell, B.; Zakharevich, I.; Pham, T.T.; Gruosso, T.; Kuasne, H.; Lakins, J.N.; et al. Tumour-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression. Nat. Mater. 2020, 20, 548–559.
  83. Provenzano, P.P.; Eliceiri, K.W.; Campbell, J.M.; Inman, D.R.; White, J.G.; Keely, P.J. Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med. 2006, 4, 38.
  84. Lai, S.L.; Tan, M.L.; Hollows, R.J.; Robinson, M.; Ibrahim, M.; Margielewska, S.; Parkinson, E.K.; Ramanathan, A.; Zain, R.B.; Mehanna, H.; et al. Collagen induces a more proliferative, migratory and chemoresistant phenotype in head and neck cancer via DDR1. Cancers 2019, 11, 1766.
  85. Itoh, Y. Discoidin domain receptors: Microenvironment sensors that promote cellular migration and invasion. Cell Adhes. Migr. 2018, 12, 378–385.
  86. Leitinger, B. Discoidin domain receptor functions in physiological and pathological conditions. Int. Rev. Cell Mol. Biol. 2014, 310, 39–87.
  87. Hidalgo-Carcedo, C.; Hooper, S.; Chaudhry, S.I.; Williamson, P.; Harrington, K.; Leitinger, B.; Sahai, E. Collective cell migration requires suppression of actomyosin at cell-cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6. Nat. Cell Biol. 2010, 13, 49–59.
  88. Cox, T.R.; Gartland, A.; Erler, J.T. Lysyl oxidase, a targetable secreted molecule involved in cancer metastasis. Cancer Res 2016, 76, 188–192.
  89. Mayorca-Guiliani, A.; Erler, J.T. The potential for targeting extracellular LOX proteins in human malignancy. OncoTargets Ther. 2013, 6, 1729–1735.
  90. Sanada, T.; Islam, A.; Kaminota, T.; Kirino, Y.; Tanimoto, R.; Yoshimitsu, H.; Yano, H.; Mizuno, Y.; Okada, M.; Mitani, S.; et al. Elevated exosomal lysyl oxidase like 2 is a potential biomarker for head and neck squamous cell carcinoma. Laryngoscope 2019, 130, E327–E334.
  91. Mayorca-Guiliani, A.E.; Yano, H.; Nakashiro, K.I.; Hamakawa, H.; Tanaka, J. Premetastatic vasculogenesis in oral squamous cell carcinoma xenograft-draining lymph nodes. Oral Oncol. 2012, 48, 663–670.
  92. Zhou, W.H.; Du, W.D.; Li, Y.F.; Al-Aroomi, M.A.; Yan, C.; Wang, Y.; Zhang, Z.Y.; Liu, F.Y.; Sun, C.F. The Overexpression of Fibronectin 1 Promotes Cancer Progression and Associated with M2 Macrophages Polarization in Head and Neck Squamous Cell Carcinoma Patients. Int. J. Gen. Med. 2022, 15, 5027–5042.
  93. Marzeda, A.M.; Midwood, K.S. Internal Affairs: Tenascin-C as a Clinically Relevant, Endogenous Driver of Innate Immunity. J. Histochem. Cytochem. 2018, 66, 289–304.
  94. Phillips, G.R.; Krushel, L.A.; Crossin, K.L. Domains of tenascin involved in glioma migration. J. Cell Sci. 1998, 111, 1095–1104.
  95. Schenk, S.; Chiquet-Ehrismann, R.; Battegay, E.J. The fibrinogen globe of tenascin-C promotes basic fibroblast growth factor-induced endothelial cell elongation. Mol. Biol. Cell 1999, 10, 2933–2943.
  96. Tremble, P.; Chiquet-Ehrismann, R.; Werb, Z. The extracellular matrix ligands fibronectin and tenascin collaborate in regulating collagenase gene expression in fibroblasts. Mol. Biol. Cell 1994, 5, 439–453.
  97. Sternlicht, M.D.; Lochtest, A.; Sympson, C.J.; Huey, B.; Rougier, J.P.; Gray, J.W.; Pinkel, D.; Bissell, M.J.; Werb, Z. The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell 1999, 98, 137–146.
  98. Spenle, C.; Loustau, T.; Murdamoothoo, D.; Erne, W.; Beghelli-De la Forest Divonne, S.; Veber, R.; Petti, L.; Bourdely, P.; Mörgelin, M.; Brauchle, E.-M.; et al. Tenascin-C orchestrates an immune-suppressive tumor microenvironment in oral squamous cell carcinoma. Cancer Immunol. Res. 2020, 8, 1122–1138.
  99. Marangon Junior, H.; Rocha, V.N.; Leite, C.F.; de Aguiar, M.C.F.; Souza, P.E.A.; Horta, M.C.R. Laminin-5 gamma 2 chain expression is associated with intensity of tumor budding and density of stromal myofibroblasts in oral squamous cell carcinoma. J. Oral Pathol. Med. 2013, 43, 199–204.
  100. Leitinger, B. Transmembrane collagen receptors. Annu. Rev. Cell Dev. Biol. 2011, 27, 265–290.
  101. Beaulieu, J.F. Integrin α6β4 in colorectal cancer: Expression, regulation, functional alterations and use as a biomarker. Cancers 2020, 12, 41.
  102. Li, H.X.; Zheng, J.H.; Fan, H.X.; Li, H.P.; Gao, Z.X.; Chen, D. Expression of αvβ6 integrin and collagen fibre in oral squamous cell carcinoma: Association with clinical outcomes and prognostic implications. J. Oral Pathol. Med. 2013, 42, 547–556.
  103. Regezi, J.A.; Ramos, D.M.; Pytela, R.; Dekker, N.P.; Jordan, R.C.K. Tenascin and β6 integrin are overexpressed in floor of mouth in situ carcinomas and invasive squamous cell carcinomas. Oral Oncol. 2002, 38, 332–336.
  104. Fan, Q.C.; Tian, H.; Wang, Y.; Liu, X.B. Integrin-α5 promoted the progression of oral squamous cell carcinoma and modulated PI3K/AKT signaling pathway. Arch. Oral Biol. 2019, 101, 85–91.
  105. Niu, J.; Li, Z. The roles of integrin αvβ6 in cancer. Cancer Lett. 2017, 403, 128–137.
  106. Xiong, H.; Hong, J.; Du, W.; Lin, Y.W.; Ren, L.L.; Wang, Y.C.; Su, W.Y.; Wang, J.L.; Cui, Y.; Wang, Z.H.; et al. Roles of STAT3 and ZEB1 proteins in E-cadherin down-regulation and human colorectal cancer epithelial-mesenchymal transition. J. Biol. Chem. 2012, 287, 5819–5832.
  107. Gómez-Herrera, Z.; Molina-Frechero, N.; Damián-Matsumura, P.; Bologna-Molina, R. Proteoglycans as potential biomarkers in odontogenic tumors. J. Oral Maxillofac. Pathol. 2018, 22, 98–103.
  108. Gubbiotti, M.A.; Neill, T.; Iozzo, R.V. A current view of perlecan in physiology and pathology: A mosaic of functions. Matrix Biol. 2017, 57–58, 285–298.
  109. Theocharis, A.D.; Karamanos, N.K. Proteoglycans remodeling in cancer: Underlying molecular mechanisms. Matrix Biol. 2019, 75–76, 220–259.
  110. Pereira, B.A.; Vennin, C.; Papanicolaou, M.; Chambers, C.R.; Herrmann, D.; Morton, J.P.; Cox, T.R.; Timpson, P. CAF Subpopulations: A New Reservoir of Stromal Targets in Pancreatic Cancer. Trends Cancer 2019, 5, 724–741.
  111. Netti, P.A.; Berk, D.A.; Swartz, M.A.; Grodzinsky, A.J.; Jain, R.K. Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res. 2000, 60, 2497–2503.
  112. Graham, K.; Unger, E. Overcoming tumor hypoxia as a barrier to radiotherapy, chemotherapy and immunotherapy in cancer treatment. Int. J. Nanomed. 2018, 13, 6049–6058.
  113. Hodi, F.S.; Chiarion-Sileni, V.; Gonzalez, R.; Grob, J.J.; Rutkowski, P.; Cowey, C.L.; Lao, C.D.; Schadendorf, D.; Wagstaff, J.; Dummer, R.; et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018, 19, 1480–1492.
  114. Raavé, R.; van Kuppevelt, T.H.; Daamen, W.F. Chemotherapeutic drug delivery by tumoral extracellular matrix targeting. J. Control. Release 2018, 274, 1–8.
  115. Najafi, M.; Farhood, B.; Mortezaee, K. Extracellular matrix (ECM) stiffness and degradation as cancer drivers. J. Cell. Biochem. 2018, 120, 2782–2790.
  116. Piersma, B.; Hayward, M.K.; Weaver, V.M. Fibrosis and cancer: A strained relationship. Biochim. Biophys. Acta Rev. Cancer 2020, 1873, 188356.
  117. Henke, E.; Nandigama, R.; Ergün, S. Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy. Front. Mol. Biosci. 2020, 6, 160.
  118. Hallmann, R.; Zhang, X.; Di Russo, J.; Li, L.; Song, J.; Hannocks, M.J.; Sorokin, L. The regulation of immune cell trafficking by the extracellular matrix. Curr. Opin. Cell Biol. 2015, 36, 54–61.
  119. Wei, J.; Wu, A.; Kong, L.Y.; Wang, Y.; Fuller, G.; Fokt, I.; Melillo, G.; Priebe, W.; Heimberger, A.B. Hypoxia potentiates glioma-mediated immunosuppression. PLoS ONE 2011, 6, e16195.
  120. Schaaf, M.B.; Garg, A.D.; Agostinis, P. Defining the role of the tumor vasculature in antitumor immunity and immunotherapy article. Cell Death Disease 2018, 9, 115.
  121. Ostroukhova, M.; Qi, Z.; Oriss, T.B.; Dixon-McCarthy, B.; Ray, P.; Ray, A. Treg-mediated immunosuppression involves activation of the Notch-HES1 axis by membrane-bound TGF-β. J. Clin. Investig. 2006, 116, 996–1004.
  122. Zhang, F.; Wang, H.; Wang, X.; Jiang, G.; Liu, H.; Zhang, G.; Wang, H.; Fang, R.; Bu, X.; Cai, S.; et al. TGF-β induces M2-like macrophage polarization via SNAILmediated suppression of a pro-inflammatory phenotype. Oncotarget 2016, 7, 52294–52306.
  123. Shibue, T.; Weinberg, R.A. EMT, CSCs, and drug resistance: The mechanistic link and clinical implications. Nat. Rev. Clin. Oncol. 2017, 14, 611–629.
  124. Fischer, K.R.; Durrans, A.; Lee, S.; Sheng, J.; Choi, H.; Li, F.; Wong, S.; Altorki, N.K.; Mittal, V.; Gao, D. Abstract 4721: Epithelial to mesenchymal transition is not required for breast to lung metastasis but contributes to chemoresistance. Cancer Res. 2015, 75 (Suppl. S15), 4721.
  125. Poltavets, V.; Kochetkova, M.; Pitson, S.M.; Samuel, M.S. The role of the extracellular matrix and its molecular and cellular regulators in cancer cell plasticity. Front. Oncol. 2018, 8, 431.
  126. Branch, K.M.; Hoshino, D.; Weaver, A.M. Adhesion rings surround invadopodia and promote maturation. Biol. Open 2012, 1, 711–722.
  127. Hu, C.; Zhang, Y.; Wu, C.; Huang, Q. Heterogeneity of cancer-associated fibroblasts in head and neck squamous cell carcinoma: Opportunities and challenges. Cell Death Discov. 2023, 9, 124.
  128. Leong, H.S.; Robertson, A.E.; Stoletov, K.; Leith, S.J.; Chin, C.A.; Chien, A.E.; Hague, M.N.; Ablack, A.; Carmine-Simmen, K.; McPherson, V.A.; et al. Invadopodia Are Required for Cancer Cell Extravasation and Are a Therapeutic Target for Metastasis. Cell Rep. 2014, 8, 1558–1570.
  129. Paz, H.; Pathak, N.; Yang, J. Invading one step at a time: The role of invadopodia in tumor metastasis. Oncogene 2014, 33, 4193–4202.
  130. Kumar, K.V.; Hema, K.N. Extracellular matrix in invasion and metastasis of oral squamous cell carcinoma. J. Oral Maxillofac. Pathol. 2019, 23, 10–16.
  131. Culhaci, N.; Metin, K.; Copcu, E.; Dikicioglu, E. Elevated expression of MMP-13 and TIMP-1 in head and neck squamous cell carcinomas may reflect increased tumor invasiveness. BMC Cancer 2004, 4, 42.
  132. Niland, S.; Riscanevo, A.X.; Eble, J.A. Matrix metalloproteinases shape the tumor microenvironment in cancer progression. Int. J. Mol. Sci. 2022, 23, 146.
  133. Zhang, Y.; Dong, P.; Yang, L. The role of nanotherapy in head and neck squamous cell carcinoma by targeting tumor microenvironment. Front. Immunol. 2023, 14, 1189323.
  134. Bates, A.M.; Hernandez, M.P.G.; Lanzel, E.A.; Qian, F.; Brogden, K.A. Matrix metalloproteinase (MMP) and immunosuppressive biomarker profiles of seven head and neck squamous cell carcinoma (HNSCC) cell lines. Transl. Cancer Res. 2018, 7, 533.
  135. Ginos, M.A.; Page, G.P.; Michalowicz, B.S.; Patel, K.J.; Volker, S.E.; Pambuccian, S.E.; Ondrey, F.G.; Adams, G.L.; Gaffney, P.M. Identification of a Gene Expression Signature Associated with Recurrent Disease in Squamous Cell Carcinoma of the Head and Neck. Cancer Res 2004, 64, 55–63.
  136. Liu, M.; Huang, L.; Liu, Y.; Yang, S.; Rao, Y.; Chen, X.; Nie, M.; Liu, X. Identification of the MMP family as therapeutic targets and prognostic biomarkers in the microenvironment of head and neck squamous cell carcinoma. J. Transl. Med. 2023, 21, 208.
  137. Peng, C.H.; Liao, C.T.; Peng, S.C.; Chen, Y.J.; Cheng, A.J.; Juang, J.L.; Tsai, C.Y.; Chen, T.C.; Chuang, Y.J.; Tang, C.Y.; et al. A novel molecular signature identified by systems genetics approach predicts prognosis in oral squamous cell carcinoma. PLoS ONE 2011, 6, e23452.
  138. Ye, H.; Yu, T.; Temam, S.; Ziober, B.L.; Wang, J.; Schwartz, J.L.; Mao, L.; Wong, D.T.; Zhou, X. Transcriptomic dissection of tongue squamous cell carcinoma. BMC Genom. 2008, 9, 69.
  139. Rosenthal, E.L.; Matrisian, L.M. Matrix metalloproteases in head and neck cancer. Head Neck 2006, 28, 639–648.
  140. Koontongkaew, S.; Amornphimoltham, P.; Monthanpisut, P.; Saensuk, T.; Leelakriangsak, M. Fibroblasts and extracellular matrix differently modulate MMP activation by primary and metastatic head and neck cancer cells. Med Oncol. 2011, 29, 690–703.
  141. Noda, Y.; Ishida, M.; Yamaka, R.; Ueno, Y.; Sakagami, T.; Fujisawa, T.; Iwai, H.; Tsuta, K. MMP14 expression levels accurately predict the presence of extranodal extensions in oral squamous cell carcinoma: A retrospective cohort study. BMC Cancer 2023, 23, 142.
  142. Yang, Q.; Liu, Y.; Huang, Y.; Huang, D.; Li, Y.; Wu, J.; Duan, M. Expression of COX-2, CD44v6 and CD147 and Relationship with Invasion and Lymph Node Metastasis in Hypopharyngeal Squamous Cell Carcinoma. PLoS ONE 2013, 8, e71048.
  143. Su, C.W.; Su, B.F.; Chiang, W.L.; Yang, S.F.; Chen, M.K.; Lin, C.W. Plasma levels of the tissue inhibitor matrix metalloproteinase-3 as a potential biomarker in oral cancer progression. Int. J. Med. Sci. 2017, 14, 37.
  144. Kudo, Y.; Kitajima, S.; Ogawa, I.; Hiraoka, M.; Sargolzaei, S.; Keikhaee, M.R.; Sato, S.; Miyauchi, M.; Takata, T. Invasion and metastasis of oral cancer cells require methylation of E-cadherin and/or degradation of membranous β-catenin. Clin. Cancer Res. 2004, 10, 5455–5463.
  145. Costanza, B.; Umelo, I.A.; Bellier, J.; Castronovo, V.; Turtoi, A. Stromal modulators of TGF-β in cancer. J. Clin. Med. 2017, 6, 7.
  146. Chen, J.M.; Chen, P.Y.; Lin, C.C.; Hsieh, M.C.; Lin, J.T. Antimetastatic effects of sesamin on human head and neck squamous cell Carcinoma through regulation of matrix metalloproteinase-2. Molecules 2020, 25, 2248.
  147. Utispan, K.; Niyomtham, N.; Yingyongnarongkul, B.E.; Koontongkaew, S. Ethanolic Extract of Ocimum sanctum Leaves Reduced Invasion and Matrix Metalloproteinase Activity of Head and Neck Cancer Cell Lines. Asian Pac. J. Cancer Prev. 2020, 21, 363.
  148. Juin, A.; Billotteta, C.; Moreau, V.; Destaing, O.; Albiges-Rizo, C.; Rosenbaum, J.; Génot, E.; Saltel, F. Physiological type I collagen organization induces the formation of a novel class of linear invadosomes. Mol. Biol. Cell 2012, 23, 297–309.
  149. Zhong, C.; Tao, B.; Tang, F.; Yang, X.; Peng, T.; You, J.; Xia, K.; Xia, X.; Chen, L.; Peng, L. Remodeling cancer stemness by collagen/fibronectin via the AKT and CDC42 signaling pathway crosstalk in glioma. Theranostics 2021, 11, 1991–2005.
  150. Hayashido, Y.; Kitano, H.; Sakaue, T.; Fujii, T.; Suematsu, M.; Sakurai, S.; Okamoto, T. Overexpression of integrin αv facilitates proliferation and invasion of oral squamous cell carcinoma cells via mek/erk signaling pathway that is activated by interaction of integrin αvβ8 with type I collagen. Int. J. Oncol. 2014, 45, 1875–1882.
  151. Ray, A.; Provenzano, P.P. Aligned forces: Origins and mechanisms of cancer dissemination guided by extracellular matrix architecture. Curr. Opin. Cell Biol. 2021, 72, 63–71.
  152. Levental, K.R.; Yu, H.; Kass, L.; Lakins, J.N.; Egeblad, M.; Erler, J.T.; Fong, S.F.T.; Csiszar, K.; Giaccia, A.; Weninger, W.; et al. Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling. Cell 2009, 139, 891–906.
  153. Prabhudesai, S.A.; Carvalho, K.; Dhupar, A.; Spadigam, A. Elastin remodeling: Does it play a role in priming the malignant phenotype of oral mucosa? Indian J. Pathol. Microbiol. 2023, 66, 332.
  154. Von Au, A.; Vasel, M.; Kraft, S.; Sens, C.; Hackl, N.; Marx, A.; Stroebel, P.; Hennenlotter, J.; Todenhöfer, T.; Stenzl, A.; et al. Circulating fibronectin controls tumor growth. Neoplasia 2013, 15, 925–938.
  155. Zhang, Y.; Lu, H.; Dazin, P.; Kapila, Y. Squamous cell carcinoma cell aggregates escape suspension-induced, p53-mediated anoikis: Fibronectin and integrin αv mediate survival signals through focal adhesion kinase. J. Biol. Chem. 2004, 279, 48342–48349.
  156. Degen, M.; Natarajan, E.; Barron, P.; Widlund, H.R.; Rheinwald, J.G. MAPK/ERK-dependent translation factor hyperactivation and dysregulated laminin γ2 expression in oral dysplasia and squamous cell carcinoma. Am. J. Pathol. 2012, 180, 2462–2478.
  157. Bourguignon, L.Y.W.; Earle, C.; Shiina, M. Activation of matrix Hyaluronan-Mediated CD44 signaling, epigenetic regulation and chemoresistance in head and neck cancer stem cells. Int. J. Mol. Sci. 2017, 18, 1849.
  158. O’Connell, J.T.; Sugimoto, H.; Cooke, V.G.; MacDonald, B.A.; Mehta, A.I.; LeBleu, V.S.; Dewar, R.; Rocha, R.M.; Brentani, R.R.; Resnick, M.B.; et al. VEGF-A and Tenascin-C produced by S100A4 + stromal cells are important for metastatic colonization. Proc. Natl. Acad. Sci. USA 2011, 108, 16002–16007.
  159. Miller, S.E.; Veale, R.B. Environmental modulation of αv, α2 and β1 integrin subunit expression in human oesophageal squamous cell carcinomas. Cell Biol. Int. 2001, 25, 61–69.
  160. Xuan, S.H.; Zhou, Y.G.; Pan, J.Q.; Zhu, W.; Xu, P. Overexpression of integrin αv in the human nasopharyngeal carcinoma associated with metastasis and progression. Cancer Biomark. 2013, 13, 323–328.
  161. Ou, J.; Luan, W.; Deng, J.; Sa, R.; Liang, H. αV integrin induces multicellular radioresistance in human nasopharyngeal carcinoma via activating SAPK/JNK pathway. PLoS ONE 2012, 7, e38737.
  162. Terry, S.Y.A.; Abiraj, K.; Frielink, C.; Van Dijk, L.K.; Bussink, J.; Oyen, W.J.; Boerman, O.C. Imaging integrin αvβ3 on blood vessels with 111In-RGD2 in head and neck tumor xenografts. J. Nucl. Med. 2014, 55, 281–286.
  163. Zhang, W.; Liu, Y.; Wang, C.W. S100A4 promotes squamous cell laryngeal cancer Hep-2 cell invasion via NF-kB/MMP-9 signal. Eur. Rev. Med. Pharmacol. Sci. 2014, 18, 1361–1367.
  164. Vilen, S.T.; Salo, T.; Sorsa, T.; Nyberg, P. Fluctuating roles of matrix metalloproteinase-9 in oral squamous cell carcinoma. Sci. World J. 2013, 2013, 920595.
  165. Kudo, Y.; Iizuka, S.; Yoshida, M.; Tsunematsu, T.; Kondo, T.; Subarnbhesaj, A.; Deraz, E.M.; Siriwardena, S.B.S.M.; Tahara, H.; Ishimaru, N.; et al. Matrix metalloproteinase-13 (MMP-13) directly and indirectly promotes tumor angiogenesis. J. Biol. Chem. 2012, 287, 38716–38728.
  166. Yan, X.; Cao, N.; Chen, Y.; Lan, H.Y.; Cha, J.H.; Yang, W.H.; Yang, M.H. MT4-MMP promotes invadopodia formation and cell motility in FaDu head and neck cancer cells. Biochem. Biophys. Res. Commun. 2020, 522, 1009–1014.
  167. Aseervatham, J.; Ogbureke, K.U.E. Effects of DSPP and MMP20 silencing on adhesion, metastasis, angiogenesis, and epithelial-mesenchymal transition proteins in oral squamous cell carcinoma cells. Int. J. Mol. Sci. 2020, 21, 4734.
  168. Kawahara, R.; Granato, D.C.; Carnielli, C.M.; Cervigne, N.K.; Oliveria, C.E.; Martinez, C.A.R.; Yokoo, S.; Fonseca, F.P.; Lopes, M.; Santos-Silva, A.R.; et al. Agrin and perlecan mediate tumorigenic processes in oral squamous cell carcinoma. PLoS ONE 2014, 9, e115004.
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