REVIEW ARTICLE
Year : 2017 | Volume
: 9 | Issue : 3 | Page : 97--104
Molecular characterization of collective cell migration at invasive front in oral squamous cell carcinoma
Anjali P Ganjre1, Girija Kunjir2, Harshada Inamdar2, Suhas Pande2,
1 Department of Oral Pathology and Microbiology, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India
2 Department of Oral Medicine and Diagnostic Radiology, Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India
Correspondence Address:
Anjali P Ganjre
Dr. D. Y. Patil Dental College and Hospital, Dr. D. Y. Patil Vidyapeeth, Sant Tukaram Nagar, Pimpri Chinchwad, Pune - 411 018, Maharashtra
India
Abstract
Metastasis is the most deleterious effect associated with cancer that causes mortality. Metastasis is the migration of cells, either single cell or as collective cell migration (CCM). CCM is the migration of a group of cells attached to each other by cell junctions bounded by “tip cell” and “rear cell.” Migration of cells in oral squamous cell carcinoma (OSCC) occurs by modulation of actin cytoskeleton assembly which is under the controlled by various molecules. Rho-associated protein kinase I, II, podoplanin, paxillin, etc., are few such molecules responsible for mechanical propulsive movement. Proteolysis of extracellular matrix is carried out by matrix metalloproteinase resulting in the formation of micro and macropatterning through which cells migrate in a particular direction. Certain cells such as carcinoma-associated fibroblast are responsible for the formation of micropatterning and release of cytokines for the movement of tumor cells. This review article highlights CCM, especially in the context of OSCC, which is the most important cause of cancer-related deaths in the Indian subcontinent. Understanding the underlying pathophysiology of CCM will help us target those pathways responsible for its progression. We attempted to understand the molecular mechanism of CCM, which would enable us to design customized chemoprevention of OSCC.
How to cite this article:
Ganjre AP, Kunjir G, Inamdar H, Pande S. Molecular characterization of collective cell migration at invasive front in oral squamous cell carcinoma.J Int Oral Health 2017;9:97-104
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How to cite this URL:
Ganjre AP, Kunjir G, Inamdar H, Pande S. Molecular characterization of collective cell migration at invasive front in oral squamous cell carcinoma. J Int Oral Health [serial online] 2017 [cited 2023 Dec 9 ];9:97-104
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Full Text
Introduction
Cell migration is a broad term that is used to refer those processes that involve the translation of cells from one location to another.[1] Cell migration is crucial for synchronizing physiologic as well as pathological process of metastasis.[2] It is of two types: individual cell migration and collective cell migration (CCM).[3]
Single cell migration is a well-studied mechanism “in vivo” and has been shown to be responsible for processes such as embryogenesis, development, immune surveillance, and cancer metastasis.[2] CCM is a complex phenomenon and vital for processes such as invasion and metastasis. For local as well as distant metastasis, cells have to travel through the extracellular matrix (ECM). It is estimated that <1% of primary tumor cells complete the metastatic cycle but are responsible for >90% of cancer-related deaths.[4]
Head and neck cancer is the 5th most common malignancy worldwide and ranks 1st in the Indian Subcontinent. In spite of various treatment modalities, there is no reduction in recurrence-free survival of the patient,[5] and prognosis has not improved over the past decade because of development of distant metastasis and formation of new tumors. By unraveling the complexities of the CCM process and decoding the basic phenomenon of CCM of the tumor cells, newer modalities for the therapeutic implication can be tailored.
Collective Cell Migration In General
CCM is described by groups of cells that retain cell–cell adhesions for long periods of time and exhibits a high correlation in directionality between neighboring cells during migration.[6] In physiological process, collective cells consist of border cell accompanied with mobile outer cells and two centrally placed polarized cells, all moves along with the nurse cell.[2],[7] A key mechanism for cell migration for single cell involves five cyclic movements which consist of changes in cytoskeleton assembly, protrusion of leading edge in the form of lamellopodia, ECM interaction, propulsive movement, and finally shape regeneration. In CCM, the difference is only with the 5th step. When cells move in a group, the free end of these cells forms a dynamic cytoskeleton, this results in the development of multiple ruffled borders at the leading edge resulting in the formation of traction. Cells located away from leading edges generate contractile forces which result in the formation of tensile stress all over a sheet of cells. This stress is further responsible for the directional cell movement.[8] Collective migration is typically the slowest mode of cancer cell migration (0.01–0.05 mm/min); however, faster collective migration (0.2–1 mm/min) has been observed during development.[6]
In CCM, there is the formation of one unipolar leading edge, consisting of one or more tip cell or multicellular leading rows.[7] These multicellular buds are responsible for mechanical dragging of a sheet of cells in the ECM. The above mechanism involves two designated types of cells, mainly the “leader cells or pioneer cells” whose protruding edge is in contact with ECM and another one are the followers known as “rear cells.”[9] Leading edge expresses β1 and β3 integrins to mediate adhesion complexes to connect to ECM components such as fibronectin.[10] Rac 1 (Rho) is known to active selectively at the leading cell and is suppressed in other cell of cluster by E-cadherin-mediated adhesions between leader and followers. It is important to maintain junctional integrity and stability in moving CC cluster. A study demonstrated that Rac1, integrin b1, and p13k are upregulated and essential in leader cells. These molecules form a signaling pathway for leader cell. Furthermore, it has been shown that Rac1 and CD42 are important in leading endothelial cells for angiogenic sprouting at the time of development.[11] Thus, inhibition of these molecules disrupts the integrity in collectively migrating cells.[12]
CCM governs several biophysical factors within the group of cells such as distribution of tensile stress within the sheets of cells, transmission of mechanical force across cell–cell junctions, and the distribution of cell stiffness within the advancing cell sheet.[8] Maintenance of cell-to-cell contact is exhibited by specialized cell adhesion molecules which help in transmission of the signal and maintenance of polarize cell for migration.[13] Array of cadherins such as E-cadherins, P-cadherins, and N-cadherins are taken part in transmission of physical forces. Besides some other range of proteins such as β-catenin, α-catenin ZO-1, vinculin, and lima has been thought of playing important role in force transmission across the cell–cell junctions. However, a study demonstrated that the concentrations of P- and E-cadherin are good predictors of intercellular tension while adherens junctions act as proportional-derivative feedback systems to control intercellular tension.[14] CCM process has been studied “in vitro” in various models such as time-lapse microscopy, two-dimensional (2D) cultural dishes, 3D invasion assay, and most recently “in vivo.”[15]
Collective Cell Migration In Tumor Cells
The main hallmark of cancer progression is the “pattern of invasion” which is an important indicator of patient's prognosis.[16] At the time of the invasion, tumor cells acquire the capacity to detach from the primary tumor, dissociate cell-to-cell adhesion, and travel at the distant site as a single cell metastasis.[17] The same mechanism is followed by the CCM; however, the dissociation of cell junction does not take place instead they migrate to distant sites in groups.[17] To migrate in group, they need to retain and remodel their cell–cell junctions. It involves reorganization of the actin cytoskeleton (AC) and concomitant formation of F-actin-rich membrane protrusions. The F-actin protrusion consists of noninvasive and invasive protrusion.[18] These protrusions at the leading edge of mobile cells are in the form of lamellipodia, filopodia, podosomes, or invadopodia. Invadopodia contributes to the formation of an actin filament-rich core and a multimeric protein complex; enclosing the actin core is integrins and integrin-associated proteins (vinculin, talin, and paxillin). They express matrix metalloproteinases (MMPs) for ECM degradation. Invadopodia formation and function involved initiation, assembly, and maturation. Initiation is caused by growth factors. Growth factor signaling activates PI3K factor, leads to Src activation, which in turn phosphorylates multiple proteins including tyrosine kinase substrate (Tks5) which is responsible for actin polymerization. Assembly involves actin polymerization which commences by range of proteins such as cortactin (key regulator of actin polymerization), MENA (regulator of actin polymerization), and Tks. Maturation is the final stage which leads to Src kinase, integrins, and proteases recruitment. Thus, Src is a critical regulator of invadopodia.[10]
Morphologically, invadopodia consists of three parts. First part consists of “proteolytic domain” exhibits MMPs, sheddases, etc. Second part consists of “invasive domain,” present inside the invadopodia protrusion. It helps to the cell to gain mechanical forces to move forward. Third, “adhesive domain” achieves adhesive function through integrin-mediated adhesion. Invadopodia formation is the main hallmark of head and neck cancer.[10]
Moreover, some kind of biomechanical dynamics occurs within the sheet of collective cells. It was demonstrated that collective bursts of activity are present in active matter within the cells to achieve migration. It is important to note that the organization and structure of the substrate, either in the form of gel or fibrillar, has an impact on the mobility of cells. On fibrillar substrate, the final invasion velocity is the same, but the motion is different, with larger intermittent fluctuations.[19]
Collective tumor cells migrate from one location to another in search of oxygen, nutrients, and space.[20] It was thought that dynamic tumor microenvironment and genetic heterogeneity result in reactivation of developmental migratory program which results in CCM.[21] Furthermore, it was found that cells possess intrinsic motility and history-dependent polarity which is responsible for the migration of cells.[19]
Primary tumor in oral squamous cell carcinoma (OSCC) showed highly polarized locomotive cell clusters (6 of 9) in the form of “sheets” or “strands.”[13],[17] CCM consists of masses of cells with tip cells at the leading edge. It determines the direction of their cluster in a particular direction under various influences.[22] Various changes occur in the moving cells such as an alteration in apicobasal polarity and increase in epithelial plasticity. To govern the CC phenotype, certain factors such as microRNAs, miR-34, and miR-200 play a pivotal role. They exhibit collective cell phenotypic transitions in cancer cells which aid in distant metastasis.[23] Tumor epithelial cells are programed for genetic changes and adapt the ability to adjust in any kind of microenvironment. The ability of cells to adapt to environmental changes is called “plasticity.” A group of migratory cells adapts this behavior, so they can accommodate in tumor surrounding.[24] It was hypothesized that the cells which possess plasticity in CCM and the process of ectomesenchyme transition are parallel processes because cells have to govern the required plasticity to reach a particular site.[21]
CCM exhibits two patterns which were demonstrated by Friedl et al. In the first pattern, the invading cells maintain a contact with its primary site. This type of pattern is more common in OSCC and basal cell carcinoma.[7] A study of invasive front of 14 tongue OSCC showed that most invasive tumor cells are in multicellular structures of variable size.[25] While in another pattern, “cell files” detached from their parent site and migrate along the path of least resistance.[7] Cells move in the chain where the cell contacts with each other by “tip-like” junction. The single cell then “lines up” in a stromal fiber, forming “Indian file” appearance. This pattern dictates high metastatic potential and poor prognosis and mostly seen in melanomas.[26]
CCM is different in cells per unit and route of metastasis as compared with single cell movement. It is associated with an increase in cells per unit area. Route of metastasis is through blood vessels in single cell migration, while CCM prefers lymphatic route for metastasis which results in increased chance of survival of the tumor cells.[7] As it was found that clustered of cancer cell dissemination appears to be highly efficient in embolizing lymphatic or blood vessels and thus have a greater chances of cell survival in the circulation.[10] Furthermore, as compared to single cell invasion, collectively migrating cells form membrane protrusions and integrin-mediated focal adhesions that are connected to the AC. Furthermore, collectively migrating cells do not retract their cellular tails, but instead exert mechanical forces such as moving by pulling on adjacent cells that are connected by adhesion junctions. However, in spite of research work, it yet to be explored whether the single cell or CCM is important for patients prognosis.[25]
Cell migrating collectively beneficial for metastasis because of better signal interaction acts between the cells. It improves chemokine sensing through leader “exchange” or multicellular signal integration and allows collective cluster of cells to efficiently reach the circulation under the influence of chemical cues. Furthermore, it provides greater diversity when tumor cells seeding other organs. Not less than this, group of migratory cancer cells could drag cancer stem cells through the stroma and to secondary organs by allowing the cancer stem cells to nest and proliferate at metastatic sites. Finally, groups of cancer cells would provide more resistant to attack by the immune system or mechanical stress.[6]
Metastasis and migration of the tumor cells are inevitably related to each other.
Certain conditions are mandatory for the collective movement of tumor cells. These are as follows:
Intact homophilic cell–cell adhesion/intercellular attachment [17]ECM-specific migration - some experiments are suggested that not only migratory genotype is sufficiently required for CCM but also surrounding ECM microenvironment plays a crucial role.[27] They provide a range of signals which determines cell shape, guidance, and its mode of migration [28]The density of tumor mass - CCM occurs spontaneously when the tumor mass exceeds that of critical amount.[22] If cells are tightly packed in compact stroma, then they restrict each. Other's abilities to move in response to stimuli.[29] A phenomenon called as contact inhibition locomotion is a process, in which colliding cells that come into contact with each other cease their migration toward their colliding partner before repolarizing and migrating away from each other. This is important process because loss of it toward healthy tissue has been established as a sign of malignancy. It can lead to invasion and metastasis in the cancer cells.[30] It occurs pronouncedly when greater density of tumor stroma is present [29] Moreover, the composition of the ECM in the form of changes from a laminin- to fibronectin-rich environment has a differential effect on the migration properties of OSCCs. It was found that in low invasive and high E-cadherin OSCC cells, fibronectin created a collective, nondirectional migration with high RhoA activity and altered cell-ECM adhesion. At the same time, the cells showed increase in Rac1 activity.[31] Other important component of ECM is collagen. Property of collagen network (e.g., fiber thickness, pore size, and mechanical properties) decides the migrating phenotype in cancer cells. Collagen type 1 was found to help the migrating cell to gain collective phenotype as compared to Matrigel [6]Chemical gradients in the form of cytokines and growth factors are responsible for the formation of the “swarm-like morphology.” It is formed by cells themselves or by nearby cells of a different type. They release chemicals into the environment. “Cell sink” is the phenomenon when cells depleting a chemical from their environment [22]Hypoxia - hypoxia of the tumor cells triggers the migration process.[32]
The Proteolytic Response Of Collective Cell Migration
Sheets of cells move through the ECM by a process called as “proteolytic migratory mode.” A Study found out that speed of the tumor cells was dependent on the cell–cell adhesiveness and MMP secretion rates. Higher cell–cell adhesion exhibits less amount of ECM degradation. Tumor cells secrete MMPs at substrate-cell interface and cleave collagen molecule, which results in the generation of the path for the following cells.[24] MMP 1, 2, 13, and 14 acts as a major proteolytic enzyme for degradation process. However, MMP 1 causes the pericellular proteolysis of collagen fiber which is thought to form physical hindrance for the tumor cells.[28] Usually, at the time of proteolysis, single cell bears ECM micropatterning (small gap) behavior, while CCM cells assume macropatterning, in which group of cells fills the preexisting tube (micro gaps). Formation of macropatterning is followed by accommodation of collective group of cells and advancement of tumor stroma.[33] Importantly, some factors are responsible for the degradation and invasion of cancer cells. It was demonstrated that high MMP secretion rate fosters collective cell invasion at high fibril densities. Thus, ECM density and organization is critical factor for deciding proteolytic and nonproteolytic degradation by CCM. Moreover, CCM requires lesser ECM degradation as compared to single cell degradation. Hence, CCM is more effective than single cell invasion. Increase in ECM density inhibits collective cell invasion because higher MMP is required for sustaining it, particularly in dense matrices. Furthermore, it was found that although increase in MMP secretion enhances both single and collective cell invasion, inhibition of MMP secretion in individually migrating cells causes a transition of single to collective cell invasion.[34]
The Role Of Junctions In Collective Cell Migration
Tumor cells possess cell junctions at its periphery in CCM. These junctions play a role in the integrity of sheets of migratory cells.[35] Diverse pathways are involved in cell–cell interaction which influences the dynamic motion of the cells.[22]
Tight junctions provide a barrier for solutes and small molecules along the basolateral surface. It was demonstrated that claudin 1 increases the invasiveness of tumor cells by indirectly activating pro-MMP-2, whereas claudin 4 is associated with a decrease in invasiveness of tumor cells.[36],[37] Adherens junction provides strong mechanical cohesion through the connection to the AC.[37] Adherens junction and transmembrane protein of immunoglobulin family have been demonstrated in cohesively migrating melanoma cells.[2] Desmosomes mediate intercellular contact through intermediate filaments.[37] Research has found out that desmosomal proteins are present at the membrane surface of the cell which results in forming aggressive metastatic tumor.[36] Integrins are cell–substratum adhesion molecule and facilitate interaction between fibronectin and cytoskeleton. They help in migration of sheets of cells by confirming the attachment between ECM and tumor cells.[36] β1 integrins (α2 β1, α3 β1, and α5 β1) are responsible for the adhesion of cell-cell in sheets of tumor cells. It was proved that Activated Protein-c causes activation of β1 and β2 integrins at the time of CCM.[36] Research has shown that blocking of integrin β1 will result in loss of cadherin; single cell detachment results in amoeboid migration called as collective amoeboid transition.[2],[38] However, amoeboid to collective cell formation has been reported. In vitro study showed that single cell spontaneously accepts epithelial phenotype, acquires cell–cell contact, and upregulates α2 β1, α3 β1, and CD44 expression.[39]
Gap junctions are one of the specific types of cell junction responsible for the passage of molecules and ions. Cancer cell exhibits gap junction and help in the cell-to-cell coupling and communication.[36] The response of molecular as well as structural characteristics of tissue microenvironment and cell behavior will decide whether a cell will move in collectively or individually in tumor ECM.[39]
The Role Of Array Of Molecules In Collective Cell Migration
For migration of tumor cells, the range of molecules plays a significant role. Cadherin-like E, R, and N, consists of the cytoplasmic domain which links with β-catenin and p120. At the time of migration, they help to retain the intactness of the cell junctions thereby responsible for the multicellular coordinated movement of the cellular sheet. Experiments suggested that E-cadherin promotes anchorage-independent growth in OSCC cell line. They mediate cell–cell contact, elevate the levels of antiapoptotic proteins such as Bcl-2, and are responsible for downstream of epidermal growth factor receptor (EGFR) by activating mitogen-activated protein kinases (MAPK) signaling.[40] In fact, E-cadherin-catenin complex interact with EGFR, this interaction results in the inhibition of EGFR signaling and activation of MAPK signaling.[41]
Cadherin-11 is a mesenchymal cadherin responsible for cytoskeleton scaffolding and formation of F-actin protrusion. It regulates α-catenin at the adherens junction which is important for the remodeling of cell–cell interaction at the time of tumor cell invasion.[42]
Another important cadherin is the N-cadherin which is thought to regulate the CCM in cancer cells. Its extracellular and intracellular domain acts independently to promote the promigratory role of cancer cells. Extracellular domain interacts with the fibroblast growth factor receptor to regulate the MAPK-extracellular signal-regulated kinase pathway while intracellular domain responsible for strengthening the adhesion by regulating AC.[43]
P-cadherin is involved in CCM of epithelial as well as mesenchymal cells. In epithelia cells, they maintain stable collective cell junctions.[44] It regulates the amount of tension that a “Focal adhesion” transmits. P-cadherin functions as force transmission in monolayer. P-cadherin permits force transmission through the entire cell monolayer.[45] It has a major and specific role in the initiation of intercellular and traction forces in the cell layer. P-cadherin also specifically activates Cdc42 during CCM through the guanine nucleotide exchange factor and β-PIX. Thus, P-cadherin/β-PIX/Cdc42 axis is crucial for P-cadherin–mediated CCM.[44]
Many studies have shown the role of P-cadherins in the invasive capacity of CCM. It was revealed that aberrant expression of P-cadherin was useful marker for the invasion capacity of tumor cells. Thus, P-cadherin expression is associated with cell invasiveness.[45]
Study found that the phenotypic plasticity of monolayer dynamics is more pronounced by expressing distinct combinations of cell–cell adhesion proteins. E-cadherins are not only the cadherins but also which play role in regulation of intercellular tension. Different cadherins exhibit different mechanotransduction feedback loops. Furthermore, the total protein concentration localizes at intercellular junctions is a strong determinant of intercellular tension.[14]
Cadherins were found to co-localize with podoplanin in CCM,[46] which helps to modulate AC. Its expression was increased in leading edge of the invasive front. Thus, cadherins act as a novel prognostic molecular marker for CCM.[22] Wiskott–Aldrich syndrome proteins (WASP) and WASP-family verprolin-homologous protein family proteins are cytoskeleton-modulating molecule accountable for encouraging actin remodeling through activation of actin-related protein.[47]
Another crucial molecule which is important for regulation of AC structure is Rho-associated protein kinase (ROCK I and II). It consists of twenty genes of Rho GTPase family.[24] Recently, it is recognized as a modulator of tumor cell for invasion process. The ROCKs or Rho kinase are central regulators of AC and downstream the small Rho GTPase.[48] Aberrant expression of Rho GTPase activity in cells is responsible for the cell migration and invasion. Specifically, Rnd3 gene contributes to CCM in epithelial cells.[45] Inhibition of ROCK suppresses CCM.[49] Thus, they are correlated with high grade and poor overall survival rate of the tumor. Especially in head and neck cancer, an increase in the expression of ROC is associated with progression of cancer and thus poor prognosis.[24] In tumor stroma, carcinoma-associated fibroblasts (CAF) are responsible for the deformation of ECM by an increase in ROCK-dependent myosin II-mediated contractility. They provide mechanical propulsive force to tumor cells for the invasion.[42] CAF forms macrotracks which are important for migration of collective tumor cells.[48]
Exclusively in head and neck squamous cell carcinoma, transforming growth factor-beta 1 (TGF-b1) stimulates CAF to release hepatocyte growth factor (HGF) which later on results in the invasiveness of tumor cells. Recently, recognized molecules are Src family kinase and p130 Crk-associated substrate.[50]
p130Cas was found to be associated with cell adhesion and cytoskeletal dynamic in cancer progression. Src has got two terminals: one is N-terminus and another C-terminus. Mutation in C-terminus is responsible for the increase in the kinase activity. Phosphorylation of p130Crk directly regulates AC and vice versa which is correlated with progression of cancer.[51]
Retinoblastoma (Rb) is a tumor suppressor gene. Inactivation of Rb is responsible for the collective movement of tumor cells. The study proved that suppression of Rb was responsible for lymphovascular invasion as well as hematogenous spread. Inactivation of Rb activates CD44 expression which in turn activates multiple steps in metastatic cascade which leads to CCM.[52] Certain chemokines such as stromal cell-derived factor-1 (SDF), fibroblast growth factor, TGF-β, and HGF release the signals which lead to migration of cells.[2],[47],[53] Cancer cells secrete soluble factors interleukin-1α for expression (release) of SDF-1.[53] Interaction of CXCR4 and its ligand SDF-1 is responsible for the actin polymerization and pseudopod formation. It was demonstrated that inhibiting the SDF-1 signal will result in blocking of CXCR4 signal which leads to decrease in metastasis.[54]
As the tumor grows, cells are deficient of blood supply and thus oxygen. Hypoxia augments the expression of CXCR4.[50] Further, CXCL12-CXCR4 interexchange of signaling enhances the cellular motility in head and neck squamous cell carcinoma (HNSCC) cells.[34]
Proto-oncogene c-src is responsible for modulating signal pathway that regulates adhesion and motility. Research has shown that high expression of Src is related with metastasis of tumor cells. To migrate collectively, Src plays a vital role. HNSCC tumor cells constitutively secreted high level of Src expression which localizes at cellular junctions.[55] Invadopodia which is a form at the leading edge of the tumor cell is dependent on the Src activity. Vesicles that secret MMP-1 and MMP-9 are present in invadopodia which are responsible for degradation and remodeling of ECM. Expression of MMP 9 requires PI3K activity.[41] Suppression of Src kinase activity inhibits invadopodia formation, motility, and invasion by tumor cells.[56] It was found that Src plays an important role in stabilizing intercellular adhesion in E-cadherin-positive HNSCC and this regulatory function is important for collective strategies of tumor cell invasion.[55]
Alpha-catulin is a molecule associated with increased in migratory movements of the tumor cells. It acts as a scaffold for Rho signaling which contains a binding site for AC. Thus, acting as a cytoskeletal linker protein to regulate cell migration, ablation in gene expression which is responsible for the migration of the tumor cells.[56],[57] In ECM, certain intrinsic matrix molecules such as tenascin-C and laminin are present which are associated with the promigratory movements of the tumor cells.[47] Laminin-5 γ2 chain is cleaved by MT-1MMP and active MMP-2. These cleaved molecules bind with EGFR on cancer cell surface and transmit intracellular signals which promote cell motility.[36]
For migration of tumor cells, invadopodia is the essential structure. Paxillin phosphorylation is responsible for the activity of invadopodia by modulating AC. Phosphorylation of paxillin modulates AC which is responsible for the action of invadopodia. Depletion of protein results in the inhibition of invasion, transendothelial migration, and thus failure in metastasis.[58]
As it was thought that decrease in oxygen is responsible for the migratory movement of cells. Hypoxia-inducible factor-1 engages itself in stimulating the migratory process of cells.[20]
Tumor suppressor protein p53 was found to be associated with tumor cell migration and invasion. It regulates proteins responsible for AC dynamic and ECM modulation. Signals associated with changes in the cytoskeleton are controlled by P53 which then unite with Rho family of small GTPases. GTPase proteins control the AC dynamic and are essential for cytoskeletal changes [32] [Table 1].{Table 1}
Swiprosin-1 (also known as EF-hand domain containing 2) was initially identified in human CD8+ lymphocytes. An association was found between Swiprosin-1 and F-actin reorganization which is responsible for CCM. Swiprosin-1 was characterized as an actin-binding protein and induced F-actin bundling in the presence of Ca2+. Thus, it was direct interactions between Swiprosin-1 and F-actin which found to modulate membrane dynamics by lamellipodia formation. Overexpression of it is correlated with an increase in migration of tumor cells.[59]
Fascin is not present in healthy epithelium but found to upregulated in aggressive and metastatic cancers of epithelial origin. It is present in invading edges of tumor cell and associated with poor survival rate.[18]
Myosin X is present in invadopodia. Upregulation is related with invadopodia formation and invasion in cancer cells. Myosin-X causes cell invasion by transporting integrin receptors to the tips of invadopodia to bind with the ECM. Myosin-X gene expression is induced by gain-of-functional mutation of P53. It drives the cell for cancer invasion.[18]
Tetraspanins, also called the transmembrane 4 superfamily, are a family of small transmembrane proteins. They regulate integrins and other adhesion- and motility-related proteins and found as key regulators of cell adhesion and migration in cancer. Aberrant expression of tetraspanins, especially CD151, CD9, CD82, CO-029, and CD63, is detected in metastatic tumors and has been linked to cancer progression. CD151 found to promote CCM and metastasis in tongue squamous cell carcinoma by regulating α3 β1 and α6 β4 integrin-dependent cell adhesion and migration and by moderating Rho A signaling.[60],[61] It promotes the maintenance of organized cell–cell junctions and controls collective migration. The loss of CD151-α3 β1 integrin co-distribution is a feature of invading OSCCs.[61] TSPAN1 is another important family of tetraspanin and found to be key regulators of cancer cell migration, invasion, and metastasis in squamous cell carcinoma of head and neck region.[60]
Therapeutic Relevance
CCM is a unique process in its own way and is very common in oral cancer. OSCC invades as a small group of cells and has a greater tendency to metastasize.[62] In spite of a number of studies on metastasis, CCM is still a largely unexplored phenomenon in OSCC. It is an early cause which decides the prognosis of the disease and will be more beneficial if the therapeutic implication will be targeted in inhibiting the motility of tumor cells.
Various approaches could be implicated in arresting the distant metastasis. First, suppression of action of the molecules which are responsible for modulating AC. Disorganization of AC does not allow the cell to gain its shape for motility which is called as an antimotility approach. Antimotility molecule such as decorin- or small leucine-rich proteoglycans is a novel target molecule for stopping the migratory mode of the tumor cells. Research has found out that decrease in expression of antimotility molecule leads to the cessation of invasive capacity of tumor cells.[47] Second, one can stop forming “tip guiding” cells. Hence, this will help in stopping the navigation of the tumor island to the distant site.
Targeting specific components of ECM provides achievable cessation which results in metastasis and invasion. In certain cancers, it was found that targeted depletion of fibronectin amends CCM and makes cancer cells more sensitive for ionizing radiation.[31]
Another therapeutic approach is focusing on cessation of cell–cell interaction or by stopping the formation of swarms of cells. However, amoeboid movement (single cell movement) to collective migration was also reported in certain cancers, which are more drug resistant and irradiation.[26]
Interestingly, blocking the signals which promote growth factor stimuli such as inhibiting the expression of TGF-β could help in arresting CCM in cancer cells.[21] Protease inhibitors which inhibit the activity of MMPs will provide hindrance for movement of tumor cells and will result in accomplishing an anti-invasive approach.[27],[33]
Genes responsible for signal transduction has to be ablated. One of such novel drugs which is responsible for Src gene protein inhibitor is Saracatinib. Saracatinib is designed to disrupt Src kinase activity. Its anti-invasive activity helps in the cessation of movement of tumor cells in ECM matrix.[56]
The invasive behavior of OSCC not only relies on intrinsic factors (i.e., mutations and abnormal expression of proteins) but also on extrinsic factors (such as the ECM composition), which could help to understand the failure of some tumor therapies and contribute to the development of new antitumorigenic approaches.
Conclusion
Head and neck cancer is a daunting and dreadful disease. One of the major features is its high invasiveness and metastatic potential. In oral cancer, CCM is the most effective way of transmigration of tumor cells at a distant location, and it is critical for enhancing the detrimental effect of cancer in the form of prognosis. It is a challenge for the practitioner to overcome the metastatic movement of CCM. By appreciating the details of the collective tumor cell movements, as it is associated with a diversity of molecules, it will be possible to target the collective tumor cell movement and thus provide an inroad for the novel therapeutic approaches for stopping and prevented further dissemination of the tumor cells. It is important to aim combination of a therapeutic regimen for the migration of cells which will control cell behavior and thus overall patient's survival.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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