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 Table of Contents  
Year : 2016  |  Volume : 7  |  Issue : 3  |  Page : 166-172

Cellular and molecular aspects at invasive tumor front in oral squamous cell carcinoma (part-I)

Department of Oral Pathology and Microbiology, Government Dental College and Hospital, Nagpur, Maharashtra, India

Date of Web Publication22-Aug-2016

Correspondence Address:
Rekha Bhaskar Chaudhari
Department of Oral Pathology and Microbiology, Government Dental College and Hospital, Nagpur - 440 003, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0976-433X.188805

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Oral squamous cell carcinoma (OSCC) is one of the leading cancers in India and Asian countries. Tumorigenesis has been linked to abnormalities in molecular regulatory machinery. Traditional factors such as tumor size, neck node status, and presence of distant metastasis staging, histological grading, and depth of invasion are currently used to predict the outcome of OSCC. However, these seem to be of limited value. Recent work indicates that morphological and molecular characteristics of tumor cells at invasive tumor front (ITF) underlie biological aggressiveness of oral cancer. Recent advances in molecular biology have facilitated analysis of the critical component of cancer progression. The degree of expression of various molecules provides reliable prognostic and predictive information. Predicting prognosis and clinical outcome of patient is very important for developing an effective therapeutic strategy. This paper provides an overview of the cellular activities and molecular interactions of the complex biology of tumor progression, invasion, and metastasis with focus on ITF.

Keywords: Invasive front, molecular biomarkers, oral squamous cell carcinoma, tumor microenvironment

How to cite this article:
Chaudhari RB. Cellular and molecular aspects at invasive tumor front in oral squamous cell carcinoma (part-I). SRM J Res Dent Sci 2016;7:166-72

How to cite this URL:
Chaudhari RB. Cellular and molecular aspects at invasive tumor front in oral squamous cell carcinoma (part-I). SRM J Res Dent Sci [serial online] 2016 [cited 2022 Aug 10];7:166-72. Available from:

  Introduction Top

Oral squamous cell carcinoma (OSCC) is the most common head and neck cancer. It is a tumor of high invasiveness and high metastatic potential and poor prognosis.[1] Current treatment regimens are guided by traditional prognostic factors such as tumor size, neck node status, and presence of distant metastasis (TNM stage), histological grade, perineural invasion, and depth of tumor invasion. However, there is an increasing evidence that this seems to be inadequate, as: (i) Clinical outcome varies dramatically in patients with OSCC with similar clinical staging and (ii) histopathological characteristics differ widely in various areas within the same tumor. It is also suggested that combined assessment of histopathology grading and clinical staging might provide a precise means for predicting outcome.[2] OSCC exhibits heterogeneous architecture. Predicting prognosis and clinical outcome of the patient is very important for the management of OSCC. In OSCC, mode of invasion and degree of cellular differentiation in invasive front has prognostic significance and represents crucial parameter.[3]

It is necessary to recognize the deleterious nature of invasive tumor front (ITF) and to look for new objective prognostic factors that might add information about biologic characteristics of cells. Cells at ITF are more aggressive in terms of metastatic potential.[4] This means that tumor cells have already reached a stage in their evolution, where they exhibit molecular events.[2] ITF was defined as the most progressed 3–6 tumor cell layers or detached tumor cell groups at advancing/leading edge of OSCC.[5] The information about invasive capacity and metastatic ability can be deduced from ITF.[2] It is thus believed that ITF is the deepest area of vital importance where several crucial molecular interactions that enhance or inhibit tumor progression occurs.[4] The complete understanding of this molecular jungle is an impossible mission. Some molecular aspects are reviewed.

A web-based PubMed search for the articles about tumor invasion in OSCC was initiated. It was restricted to the articles focusing on relevant extracellular matrix (ECM) changes, prognostic value of a wide range of molecules, cell migration, and cell adhesion, at ITF in OSCC.

This overview attempts to focus on current knowledge of cellular activities and several molecular interactions, involved in the process of invasion, progression, and metastasis of OSCC at invasive front and highlighting their possible role as prognostic factor and predictive marker.

  Tumor Microenvironment-Extracellular Matrix Top

The microenvironment contributes significantly to the progression of oral cancer. Cross talk with stromal events (vascularization, fibroblast activity, myofibroblasts [MF] differentiation, and the presence of specific proteins - proteolytic enzymes, fibronectin [FN], and laminin-5 [Ln-5])[6] provides three-dimensional (3D) environment for proliferation, migration, and metastasis of transformed carcinoma cells. Along this cascade, tumor cells interact with and remodel ECM, influencing cellular processes such as adherence and motility.[7] In OSCC, fetal ECM conversion is demonstrable. As a consequence, a coordinated ECM remodeling in the carcinoma invasion front may be suggested.

  Basement Membrane Top

BM is the crucial structure in regulation of tumor invasion. Its molecular assembly is the first barrier for invasion of connective tissue.[8] Invasive growth of cancer cells is a complex process, involving interactions between tumor cells and stromal elements of ECM. BM has been proposed as one constituent of ECM.[9] Interaction of tumor cells with BM involves its attachment to surface receptor of integrin/nonintegrin variety, recognizing glycoprotein such as laminin, Type IV collagen, and FN. After establishing this attachment, neoplastic cells begin to secrete degradative enzymes (Type IV collagenase and plasminogen) causing lysis of matrix, facilitating infiltration and locomotion of neoplastic cells across BM and stroma.[10],[11] Recent study by Hagedorn et al.[12] has shown that BM components are not only degraded during tumor progression but also newly synthesized at invasive front. In addition, since there is positive correlation between amount of retained peritumoral BM and high degree of tumor cell differentiation, the amount of retained BM material seems to represent a marker for biological behavior of the tumor cell.[12]

Once installed in connective tissue, invading tumor cells may stimulate fibroblasts to increase carcinoma-associated fibroblasts/MFs (desmoplasia)[8] and recruitment of ED-B FN (oncofetal FN) messenger RNA (mRNA) + cells, which may also contribute to generation of stromal laminin/matrix milieu, influencing tumor cell behavior.[7],[8] However, ED-B FN synthesizing cells have been shown to be confined to tumor stroma and inflammatory cells, in invasive front by Kosmehl et al.[7] In OSCC, stromal fibroblasts interact with tumor cells by fibroblasts-derived cytokines, such as hepatocyte growth factor (HGF) and stromal fibroblast growth factor (FGF), thereby promoting invasion of tumor cells.[13]

Significantly increased expression of laminin, Type IV collagen, heparan sulfate proteoglycan (HS-PG) in basement membrane (BM), along tumor stroma borderline and reduced expression of decorin, vitronectin in tumor stroma at invasion site, were demonstrated in highly invasive primary tumor. At the same site, increased expression of FN, tenascin, and Ln-5/γ2 chain was also reported.[14] In addition, Kulasekara et al.[15] also asserted deposition of Type IV collagen at epithelial-biomatrix interface in the presence of fibroblast and ECM deposition of FN, in 3D in vitro, indicating enhanced BM protein expression during oral cancer progression. Further, Mishra et al.[16] showed reduced immunopositivity of perlecan (BM HS-PG) with higher grade of OSCC. They hypothesized that with increasing degree of carcinoma; perlecan gets cleaved by heparanase and releases growth factors: FGF and transforming growth factor-β (TGF-β) that promote tumor growth.

Among BM related molecules, Ln-5 and Tn-C1 seem to play certain role in OSCC.[17]

  Laminin Top

Laminins are heterotrimeric glycoproteins of ECM.[17] Ln-332 (previously known as Ln-5) is the most important isoform which consists of α3, β3, and γ2 chains and is the major constituent of BM.[11],[17] In OSCC, Ln-332 is suggested to play an important role for tumor migration and invasion, associated with matrix remodeling.[18] OSCC progression is mediated by MFs, in association with stromal upregulation of laminin isoforms, possibly contributing to a migration promoting environment.[13] Invasion in OSCC is associated with Ln-5 synthesis, focal (Ln-5) loss from BM and its deposition in stroma, beneath invading carcinoma cells.[19] Increased expression of Ln-5 has been shown to occur in areas of direct tumor-stroma interaction.[11],[18] Especially, the α3 and γ2 chain of Ln-332 could be immunohistochemically found outside the BM in the adjacent stroma of OSCC invasive front leading to the suggestion of a Ln-332 matrix guided carcinoma invasion.[7] In addition, quantification of Ln-5 content in OSCC BM has been shown to indicate a grading dependent decrease of Ln-5 in invasive front, whereas in the reestablished BM structures nearly normal Ln-5 levels could be found.[20] Ln-5 interacts with integrin α6β4 and epithelial growth factor receptor (EGFR), thereby activating phosphatidylinositol 3-kinase (PI3K) pathway and thus promotes invasion in squamous cell carcinoma (SCC).[21]

Furthermore, stromal spot such as deposits of Ln-5/γ2 mRNA has also been observed in the vicinity of mesenchymal cells and vessel structures at ITF. Moreover, stromal Ln-5 deposits showed spatial association (relationship) with TGF-β1 as well as membrane type-1 matrix metalloproteinase (MMP) and bone morphogenetic protein. Based on these findings, Franz et al.[18] suggested that mesenchymal cells may also synthesize Ln-5/γ2 chain and contribute to promotion of tumor cell migration as well as vessel formation in OSCC by providing and organizing promigratory Ln-5 fragment. In addition, correlation between increased number of γ2 positive cells at margins of differentiated invading islands and at forefront of undifferentiated invading nests and shorter life expectancy was reported by Gasparoni et al.[22] Thus, Ln-332/γ2 chain has a key role in cancer cell migration which is the hallmark for invasion.[11],[21] These findings showed that Ln-5/γ2 may be reliable prognostic tool for OSCC.[22]

  Tenascin Top

Tenascin (Tn) is an ECM glycoprotein that modulates adhesion of cells.[19] Its isoforms are generated by alternative splicing. In physiologic adult tissue, oncofetal large Tn-C splice variant rarely occurs. Tn-C1 expression during stroma remodeling promotes tumor progression.[17] Mesenchymal cells are its major source.[23] However, carcinoma cells are also capable of synthesizing Tn-C at ITF.[23] Intracellular localization of this protein has been detected by Mori et al.[23] and Hindermann et al.[24] Its deposition in stroma perhaps contributes to enhanced tumor cell migration.[24]

Franz et al.[17] showed evidence of correlation between Tn-C1-Ln-5/γ2 colocalization in reestablished BM structures and malignancy grade in OSCC. Results of their study suggested that incorporation of this oncofetal protein (Tn-C1) in reorganized BM during ECM remodeling, serves as preinvasive structural phenomenon in OSCC during tumor progression.[17] Recently, an extracellular fibrillary co-deposition of Ln-5 with ECM molecules Tn-C (L) was found in OSCC, and functional interaction of both molecules during formation of invasion-promoting tumor microenvironment was hypothesized.[19] Colocalization of these molecules, exhibiting different patterns such as ribbon-like (subepithelial BM around well-differentiated OSCC clusters), fibrillar (in tumor stroma beneath clusters), and dot-like (at site of ruptured BM), has been shown to be biologically meaningful and reflects sequential modulation and reorganization of ECM, at tumor-stroma interface during different stages of OSCC.[19],[25]

  Syndecan Top

Syndecans are family of cell surface HS-PG, which participate in cell-matrix adhesion, modulating epithelial-mesenchymal interactions, cell migration, and proliferation.[26] These biologic effects are mediated through binding with growth factors, for example, FGF, basic FGF, vascular endothelial growth factor, and HGF. S-1, also known as CD138, is the prototype member of syndecan family, which maintains normal architecture of epithelium and is the most widely investigated member.[26] Reduced expression of S-1 seems to be valuable marker of malignancy at ITF and useful prognostic factor.[27] Loss of S-1 in tumor cells leads to decreased intercellular adhesion and increased potential for uncontrolled proliferation, disturbed differentiation, and tumor invasion.[26]

Downregulation of/or loss of S-1 is a common feature of OSCC.[26],[27] The expression of S-1 at ITF was evaluated immunohistochemically by Kurokawa et al.[27] They analyzed correlation between intensity of S-1 expression and histological grading of malignancy at deep invasive front and demonstrated that the patients with intermediate or strong immunoreactivity for S-1 had significantly better prognosis than those with negative or weak intensity. Statistically significant correlation between downregulation of S-1 expression and prognosis, differentiation, and pattern of invasion has also been noted at ITF.[27]

  Galectin Top

Galectins (Gas) are a family of β-galactoside-binding lectins. Gal-1 is a prototype of galectin family. These proteins participate in different cell functions such as cell cycle, adhesion, differentiation, and apoptosis as well as cancer biology (development and progression).[28] Wu et al.[29] demonstrated strong Gal-1 immunoreactivity in cells of metastatic lesions of lymph nodes and in ITF, and this was significantly associated with poor prognosis in the early stage of OSCC. Upregulation of Gal-1 in invasive front of OSCC has been demonstrated by Chiang et al.[30] and suggested that overexpression of Gal-1 at ITF might be a predictor of early metastasis in oral cancer. However, molecular mechanism is not completely understood. Gal-1 has been shown to be involved in tumor invasion and metastasis by increasing MMP-2 and MMP-9 expression and reorganizing actin cytoskeleton assembly through enhancement of the activation of Cdc42, a small GTPase, and member of Rho family. Cdc42 is a major contributor for actin remodeling. It induces increase in number and length of filopodia, lamellipodia formation on tumor cells, causing instability of intercellular adhesion leading to cell motility which is a key step in tumor progression, invasion, and metastasis [Figure 1]. Thus, Gal-1 is considered as a prognostic marker.[29]
Figure 1: Role of galectin-1, fascin, cortactin, and podoplanin (molecular pathways) in formation of cell protrusions, extracellular matrix degradation, and invasion

Click here to view

  Podoplanin Top

Podoplanin is a mucin-type transmembrane sialoglycoprotein, whose expression has been demonstrated in association with tumor invasion and lymph node metastasis.[31] It is extensively studied biomarker for predictive assessment of biologic behavior. Podoplanin is involved in remodeling of actin/cytoskeleton of tumor cells. It induces cell migration by filopodia formation via downregulation of activities of small RhoA family GTPase. Interaction between podoplanin and actin is mediated by phosphorylation of ezrin and moesin, in the presence of podoplanin overexpression. Thus, podoplanin may promote tumor cell invasion by increasing cell motility.[31],[32],[33] Its expression has been shown to be restricted to invasive front containing cancer stem cells (CSCs) and undifferentiated cells, by Kreppel et al.[31] and de Sousa et al.[32] CSCs are a heterogeneous group of cells which differ from tumor bulk and are known to be more invasive and have significant capacity of self-renewal. Expression of podoplanin by more undifferentiated cells suggests that this protein could be an indicator of tumor aggressiveness.[33]

  Fascin Top

Fascin is actin-bundling protein, involved in the formation of cell protrusions (filopodia, lamellipodia, and invadopodia). These are branched actin-rich structures associated with ECM degradation that forms invasive machinery of aggressive cancer cells. Fascin overexpression enhances cell migratory ability and appears to aid tumor cell invasion.[34],[35] Fascin is usually overexpressed in OSCC. Overexpression of fascin induces lamellipodia and filopodia formation and also showed disorganized cell–cell contacts with low E-cadherin (E-cad) and β-catenin levels in tumor cells, leading to contribute to the event of epithelial-mesenchymal transition, in early aggressiveness of OSCC.[35] Chen et al.[35] demonstrated prognostic relevance of intense immunostaining of fascin in tumor nests at ITF/or infiltrating border of tumor in OSCC. Cell motility occurs as a result of loss of intercellular adhesion and from cell to ECM interaction due to alteration of E-cad/integrin. This is followed by the reorganization of cytoskeletal actin and subsequent movement through ECM.[35] Furthermore, increased MMP-2 activity in response to fascin upregulation also contributes to invasive ability of cancer cells. It has been believed that Thrombospondin-1 induces cross-binding of fascin and actin, leading to the formation of cell protrusions [Figure 1]. Thus, fascin promotes cell progression and modulates tumor associated signaling pathway amino kinase terminal (Akt) and mitogen-activated protein kinase in OSCC. It has been shown to confer special motility and invasive properties of cancer cells.[34]

  Cortactin Top

Cortactin-a filament (F)-actin binding protein has emerged as crucial regulator of actin dynamics. It is a key player in aggressive cancer.[36] Cortactin stimulates cell migration/motility, invasion, and metastasis.[37] Yamada et al.[36] reported that cortactin overexpression occurs more frequently in tumors with high TNM classification and invasive pattern. Its amplification has been shown to be associated with aggressive phenotype and poor prognosis. However, exact underlying mechanism seems to be unclear. Cortactin – Src kinase substrate has central role in the development and maturation of invadopodia in invasive cancer cells. Cortactin binds with (F)-actin and activates Arp2/3 complex, thereby promotes actin polymerization.[36],[37] This cooperative action allows invadopodia formation and directs cell migration through degradation of ECM by increased MMP-2,-9, and-14 activity [Figure 1]. Cortactin promotes MMP secretion. Thus, coupling of dynamic actin assembly with secretory machinery produces enhanced ECM degradation, subsequently leading to increased invasive capacity and metastatic potential of aggressive cancer cells.[37]

  Glucose Transporter-1 Top

Malignant cells need an increased glucose uptake which is facilitated by transmembranous glucose transporter proteins (GLUTs). During tumor development, cells are exposed to a hypoxic microenvironment due to insufficient blood and oxygen supplies. Tumor hypoxia induces an overexpression of certain genes such as GLUT.[38] GLUT-1 is an important hypoxia-inducing factor target gene that mediates one of the most important mechanisms for increasing cellular glucose influx. GLUT-1 upregulation is widely recognized response to hypoxia. Ohba et al.[38] reported high GLUT-1 expression at ITF to be associated with biologic significance tumor progression and aggressiveness. A significant association of GLUT-1 with regard to depth of tumor was also observed in their study. It was demonstrated that cancer cells in deep invasive areas with hypoxia needed much glucose as an energy source in comparison with wide and shallow invasive areas.[38] Overexpression of GLUT-1 is a common feature in head and neck carcinoma and is associated with enhanced tumor aggressiveness and poor survival.[39] It is possible that increased GLUT-1 expression may be responsible for protection of cells from hypoxia-induced apoptosis. Hence, GLUT-1 is considered as a negative biomarker of prognosis and overall survival in patients with OSCC.[39]

  Adhesion Molecules Top

During invasion, SCC cells migrate through surrounding tissues with simultaneous remodeling at their intercellular adhesion.[40] To acquire invasive potential neoplastic cells have to fulfill the necessary bioactivities including loss of cell adhesion molecule, increased motility, proliferation, and degradation of BM. SCC cells express receptors that mediate cell–cell adhesion (cadherins) and ECM adhesion (integrins). Both receptor families participate in signal transduction process that is capable of promoting survival and proliferation.[40] These and other molecules such as intercellular adhesion molecule-1, CD44, dystroglycans, selectins, and vitronectins are involved and undergo alteration in carcinoma.[41] Cell adhesion molecules regulate the growth and differentiation of epithelial cells and play pivotal role in maintaining the structural integrity.[42]

  E-Cadherin Top

E-cad-a glycoprotein is a key molecule that plays a critical role in cell–cell adhesion via homotypic calcium-dependent interactions.[42] The adhesive function of E-cad crucially depends on its association with cytoplasmic proteins, termed “catenin” (α-, β-, and γ-catenins) that link E-cad to the actin cytoskeleton. Several reports have shown loss of E-cad expression in OSCC.[42],[43],[44] Increased motility and invasiveness are associated with decreased cell–cell adhesion, degradation of BM, and stroma and enhanced local growth of tumor cells. Some of these properties are linked to downregulation of E-cad and upregulation of MMPs. Both processes can be mediated by PI3K/Akt pathway activation.[45] The absence of β- and γ-catenin was considered to be a hallmark of aggressive biological behavior. A decreased expression of γ-catenin has been observed at invasive front of carcinoma, suggesting a more aggressive biological behavior.[46]

Loss of E-cad and β-catenin and increased EGFR at the most invasive part of carcinoma with significant statistical correlation between later and tumor front score have been found by Bánkfalvi et al.[42] Wang et al.[43] noted a statistical relation of downregulation of E-cad at ITF to invasive front grading score, pathology primary tumor and tumor thickness, and poor survival of OSCC. This indicated that cells at ITF can dissociate easily and altered E-cad expression may promote invasion and metastasis. Methylation of E-cad gene promoter was shown to have caused reduction in E-cad expression in the tumor, resulting in acquisition of invasive phenotype.[44] E-cad is a complex molecule with both structural and signaling role in cell architecture and in intercellular invasion. Loss of its function is accompanied by the gain of mesenchymal cadherin expression, i.e. N-cad which interacts with membrane of FGFR family, thereby inducing promigratory and invasive signaling cascade. The process of metastatic spread involves invasive malignant phenotype by tumor cells.[47]

  Integrins Top

Integrins are family of heterodimericcation-dependent cell membrane adhesion molecules, which can interact with ECM and having role in cell proliferation, growth, differentiation, and migration.[48] Integrins are composed of α and β chains. Integrins have been implicated in neoplasia and tumor progression and metastasis.[48] Process of SCC invasion and dissemination requires active cell migration through ECM. Integrins are clearly important in invasion process.[40]

Its expression and functions are altered in malignant cells.[48] Ohara et al.[49] evaluated the relationship between α3, α6, and β1 integrin expression in cancer cells at ITF and clinical/pathological characteristics of OSCC and concluded that patients with higher expression levels had significantly better prognosis than those with low expression levels. Furthermore, overexpression of FN receptor αvβ6 in malignant keratinocytes has been shown to result in enhanced motility by triggering upregulation of MMP-9 and MMP-2 expression and thus promoting invasion in OSCC.[50] Roy et al.[51] also demonstrated the presence of α9 integrin in islands of infiltrating tumor cells, suggesting its role in tumorigenesis. A statistically significant marked expression of α2, α3, and α5 integrin was found to be associated with mode of tumor invasion and nodal involvement by Shinohara et al.[52]

  Cd44 Top

CD44 is a ubiquitous multistructural, multifunctional cell surface glycoprotein adhesion molecule.[53] Interaction with hyaluronan activates essential characteristics of tumor progression, for example, cell proliferation, survival, migration, and invasion at invasive front.[54] Carcinoma cells often show abnormal pattern of expression along their stromal surface and this may be important in epithelial-connective tissue interaction, in the metastatic cascade.[53] At invasive front, a striking accumulation of CD44s, V3 and V4 and V9 has been detected by Bánkfalvi et al.,[55] whereas loss of V4, V5, V7, and V8 has been shown to be associated with invasion and metastatic potential of carcinoma and correlated with poor prognosis in patients with SCC.[53],[55],[56] Wang et al.[57] have shown high levels of expression of V3 variant exons, linked to metastasis. Reports on role of CD44 are contradictory. However, it may be considered as valuable factor for predicting progression of OSCC.

  Conclusion and Perspectives Top

OSCC exhibits heterogeneous population with different biological properties. In invasive front, the cells are less differentiated compared to superficial areas of the tumor. This review summarized some of the most promising tumor molecular factors that may exert influence on tumor progression and correlated with outcome. These molecules could be considered complementary to conventional prognostic factors. Understanding of cellular and molecular interactions at ITF has ignited the hope for developing additional new therapeutic and preventive strategies for improved management of OSCC and to facilitate better survival. However, it seems important that the most putative relevant biomarkers need to be validated before its actual implementation in clinical practice.

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1 Focal adhesion kinases in head and neck squamous cell carcinoma
Anacláudia P. C. Flores,Kelly B. Dias,Laura Campos Hildebrand,Márcia Gaiger Oliveira,Marcelo Lazzaron Lamers,Manoel SantæAna Filho
Journal of Oral Pathology & Medicine. 2018;
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