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",isbn:"978-1-83969-048-8",printIsbn:"978-1-83969-047-1",pdfIsbn:"978-1-83969-049-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"27349927a8f626359f696ba5472bc2b2",bookSignature:"Ph.D. Shibo Ying",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10240.jpg",keywords:"Enzyme Activity, Intrinsic Disorder, Protein Structure, Transcription Factor, Cell Apoptosis, Cell Proliferation, Cellular Signal Transduction, Gene Regulation, Carcinogenesis, Diagnostic Marker, Prognostic Marker, Therapeutic Target",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 7th 2020",dateEndSecondStepPublish:"November 16th 2020",dateEndThirdStepPublish:"January 15th 2021",dateEndFourthStepPublish:"April 5th 2021",dateEndFifthStepPublish:"June 4th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"A young biological researcher in post-translational modifications with extensive overseas experience, the awardee of a Japanese government scholarship, a former research fellow of the German Cancer Research Center, Chinese Society for Cell Biology permanent member and holder of two grants from NSFC.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"306153",title:"Ph.D.",name:"Shibo",middleName:null,surname:"Ying",slug:"shibo-ying",fullName:"Shibo Ying",profilePictureURL:"https://mts.intechopen.com/storage/users/306153/images/system/306153.jpg",biography:"Dr. Shibo Ying is an associate professor in Hangzhou Medical College (China). He graduated and obtained his Ph.D. in Applied Life Sciences from Tokyo University of Agriculture and Technology (Japan) in 2011. He was awarded Japanese government scholarship and he visited University of California at Davis (UCD) as an exchange student in 2010. After his graduation, he became a research fellow at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg (Germany). Dr. Ying acts as a reviewer of many scientific journals and has authored or co-authored over 25 scientific publications. His research interests include molecular mechanisms of post-translational modification, such as SUMOylation, citrullination, and their clinical relevance in human diseases.",institutionString:"Hangzhou Medical College",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"6",title:"Biochemistry, Genetics and Molecular Biology",slug:"biochemistry-genetics-and-molecular-biology"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"259492",firstName:"Sara",lastName:"Gojević-Zrnić",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/259492/images/7469_n.png",email:"sara.p@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"42124",title:"EPS8, an Adaptor Protein Acts as an Oncoprotein in Human Cancer",doi:"10.5772/54906",slug:"eps8-an-adaptor-protein-acts-as-an-oncoprotein-in-human-cancer",body:'A spectrum of cellular activities including proliferation, differentiation and metabolism are controlled by growth factors and hormones. The effects of many growth factors are mediated and achieved via transmembrane receptor tyrosine kinases [1,2]. Following ligand binding, the intrinsic catalytic activity of the growth factor receptor tyrosine kinases (RTKs) is augmented. The autophosphorylated RTKs then transmit signals through their ability to recruit and/or phosphorylate intracellular substrates. Thus, identification and characterization of proteins that associate with and/or become tyrosyl phosphorylated by RTKs become critical to delineate RTKs-mediated signaling pathways. A variety of methodologies have been developed and applied to search for substrates of tyrosine kinases including RTKs [3-8]. Here, we focus on EGFR pathway substrate no. 8 (Eps8), a putative target of epidermal growth factor (EGF) receptor (EGFR), and discuss its biological function as well as its implication in human cancers. Given Eps8-elicited effects contribute to neoplasm, its potential as a therapeutic target for cancer treatment is anticipated.
To dissect EGFR-mediated signaling, Di Fiore’s laboratory took advantage of immuno-affinity purification of an entire set of proteins phosphorylated in EGF-treated EGFR-overexpressing cells, followed by generation of antisera against the purified protein pool. With these antisera, bacterial expression libraries were immunologically screened. Several murine cDNAs (eps clones) representing genes encoding substrates for EGFR were obtained [7,8]. One of them was designated eps8 [9,10]. The human eps8 locus was mapped to chromosome 12p12-p13 via fluorescence in situ hybridization (FISH) [11] and confirmed by a computer search of a genomic DNA database utilizing human EPS8 cDNA sequence (GeneBank accession number U12535) [12]. Similarly, the murine Eps8 genomic DNA sequences are defined on chromosome 6G1 [12]. The computer analysis also revealed three genes (designated as Eps8R1, Eps8R2, and Eps8 R3) that are highly homologous to both human and murine eps8 [12]. Due to space limitation, studies on these Eps8Rs will not be described in this review.
Proteins with molecular weights of 97 kDa and 68 kDa were recognized by Eps8 antibodies and referred to as the two Eps8 isoforms (p97Eps8 and p68Eps8) [12,13]. The exact nature (an alternatively spliced or a proteolytic product) of p68Eps8 was still elusive and remained to be established. By contrast, p97Eps8 has been well characterized and is the only isoform detected in human cancer cells so far and hereinafter is called Eps8.
Eps8 contains 821 amino acids and exhibits several features of interest: a split pleckstrin homology (PH) domain, a putative nuclear targeting sequence, an Src homology 3 (SH3) domain, several proline-rich regions, and a degenerated SH2 (dSH2) domain at the N-terminus (amino acids 55-96) (Figure 1). The proline-rich Eps8 has been demonstrated to interact with the SH3 domain of Src [13] and the SH3 of Eps8 was reported to associate with Shb [14], Shc [15], RN-tre [16], and Abi1 (also known as E3b1) [17]. The SH3 domain of Eps8 binds to a consensus sequence of proline-X-X-aspartate-tyrosine (PXXDY) instead of the canonical X-proline-X-X-proline (XPXXP) consensus, implicating the existence of a novel family of SH3-containing proteins [18]. Furthermore, two Eps8 proteins were demonstrated to form an interwound dimer with their SH3 domains being located at the interface [19]. In addition to the aforementioned Eps8-interacting proteins, Eps8 was also shown to bind directly to EGFR [20], Sos1 [21], and IRSp53 [22,23].
Structural organization of Eps8. The N-terminal split PH domain (PH*) is important for Eps8 membrane recruitment. Regions in Eps8 responsible for association with Eps8 binding partners are indicated. Green boxes indicate proline-rich regions; gray box indicates the potential nuclear localization signal. dSH2 indicates the position of a degenerated SH2.
Strikingly, Eps8 is an actin capper whose barbed-end capping activity resides in its C-terminal effector domain and is regulated by protein-protein interaction with Abi1 [24,25]. In addition to lamellipodia [26], Eps8 also localizes to other actin-rich structures such as PIP2-enriched vesicles, phagocytic cups and comet tails behind intracellular pathogens [25]. Two Abi1-containing complexes were reported to have multiple roles in regulating dynamic actin turnover [27]. One contains Nap1, Sra (PIR125), Hspc and WAVE, the other contains Eps8, Sos1, and the p85 subunit of PI3K. While the former may activate the Arp2/3 complex, the latter may regulate Rac activation and enable Eps8 to cap actin filament barbed ends. Of note, Eps8 turns out to be a novel capping protein capable of side-binding and bundling actin filaments [28]. The C-terminal Eps8 region (aa648-aa821) encompasses five helices (H1-H5). The N-terminal amphipathic helix (H1) is largely responsible for Eps8 capping activity, while a compact, globular domain composed of H2-H5 is critical for filament bundling. Thus, Eps8, as a bifunctional actin remodeller, regulates actin-based mobility and endomembrane cellular trafficking through its capping activity, whereas it contributes to proper structural organization of gut microvilli via its mediated actin filament bundling [28].
Known as the first identified oncoprotein, the tyrosine kinase activity of Rous sarcoma virus (RSV)-encoded v-Src is essential for its mediated transformation. Under its influence, a spectrum of proteins has their phosphotyrosine content increased and are viewed as putative v-Src substrates [3,29]. Intriguingly, some of them including Eps8 turn out to be the substrates for EGFR as well [13]. Elevated expression and tyrosyl phosphorylation of Eps8 are observed in v-Src transformed cells [13]. Overexpression of Eps8 confers the ability of fibroblasts to form foci in culture and to grow tumors in mice [30]. Consistent with its oncogenic potential [30], Eps8 attenuation retards cellular growth of fibroblasts expressing v-Src [31].
Like SH2 and SH3, PH is a common motif shared by signaling molecules, which mediates protein-protein and protein-lipid interactions. Mounting evidence indicates that via PH-mediated binding to either phospholipids [32,33] or membrane-associated proteins [34,35], the association between PH-containing molecules and plasma membrane is accelerated. The prominent examples are Akt/PKB that possesses a compact PH and PLCγ that retains a split PH. Like PLCγ, Eps8 contains a split PH (Figure 1), which does not weaken its linkage to the cell membrane. Remarkably, an intact split PH is indispensable for Eps8 membrane targeting as well as its mediated oncogenesis. In contrast, Eps8 with truncated PH fails to be recruited to plasma membrane and confers transforming ability [30].
To confirm the involvement of Eps8 in the development of cancer, the correlation between its expression and cell proliferation of various human cancer cell lines were examined [36]. In human colon cancers, there is a positive correlation between Eps8 expression and mitogenesis, implicating the importance of Eps8 in colon cancer formation. Indeed, Eps8 attenuation in high Eps8 expressing cells (i.e. SW620 and WiDr) reduces cellular growth [36]. In contrast, ectopically expressed Eps8 in low Eps8 expressing cells (i.e. SW480) or Eps8-attenuated SW620 promotes proliferation. In addition, relative to controls, there is a significant (>50%) suppression of anchorage-independent growth in eps8 siRNA-expressing SW620, and reintroduction of Eps8 rescues these defects. Concurrently, attenuation (or overexpression) of Eps8 significantly reduces (or promotes) the growth of tumors inoculated into nude mice [36]. In addition to fibroblasts and colon cancer cells, Eps8 also plays a pivotal role in cervical cancer formation. This can be supported by reduced proliferation and tumorigenesis in Eps8-attenuated SiHa and HeLa cells cultured in dishes or inoculated in mice [37].
As an adaptor, Eps8 intreracts with a variety of signaling proteins such as EGFR, Src, Abi1, RN-tre, Shb, and IRSp53 to exert its biological functions. The detail and implication of the interaction between Eps8 and each of its above-mentioned partners are described below.
Via serial deletion mutants of Eps8 and EGFR, Castagnino et al. [20] determined the minimal region of Eps8 (aa298-aa362) and EGFR (juxtamembrane region, aa648-aa688) is required for Eps8-EGFR interaction. Obviously, this interaction is not via classical pTyr-SH2 or proline-rich region-SH3 binding manner. Interestingly, the EGFR-binding region in Eps8 is rich in basic amino acids while multiple glutamic acid residues are found in the juxtamembrane region of EGFR. Although overexpression of Eps8 enhances EGF-mediated mitogenesis, the underlying mechanisms are not yet resolved. Nevertheless, the intimately correlated transforming ability of EGFR mutants and the level of tyrosyl phosphorylated Eps8 suggested the importance of tyrosyl phosphorylation of Eps8 in cellular transformation [38].
Oncogenic Src not only enhances Eps8 expression but also its tyrosyl phosphorylation [13]. In GST-pull down experiments, fusion proteins with Src SH3, but not SH2 domain directly interact with Eps8, presumably via its proline-rich sequences. Through in vitro Src kinase reactions, Eps8 was further confirmed to be directly phosphorylated by Src. Notably, simply augmenting Eps8 expression in murine C3H10T1/2 fibroblasts can not elevate its tyrosyl phosphorylation and promote cell proliferation despite these cells being tumorigenic. Given Eps8 attenuation reduced cell growth in v-Src transformed cells [31], Src-mediated Eps8 phosphorylation might be important for cell proliferation. To date, the residues on Eps8 mediated by Src are still elusive. Whether Eps8 retains the same receptor (i.e. EGFR)- and nonreceptor (i.e. Src)-mediated sites becomes an interesting issue.
ABI1 (also known as E3b1) was identified as an Eps8-binding protein by screening a human embryonic fibroblast (M426) cDNA expression library with Eps8 SH3 [17]. It contains a proline-rich sequence at its C-terminus followed by an SH3 domain. The PXXDY consensus is identified at aa389-aa393 [17]. In addition to Eps8, it also interacts with Abl tyrosine kinase and is a human homologue of previously identified murine Abl-interactor 1 (Abi1) [39]. Both Abi1 and Abl contain SH3 and proline-rich sequences. These two proteins associate through the SH3 domain of Abi1 and the proline-rich region of Abl [17,39]. Overexpression of Abi1 decreased cell proliferation in NIH3T3-based EGFR overexpressors [17] while overexpression of the murine Abi1 suppressed v-Abl transforming activity [39]. Abi1/Eps8 associate with Sos1 and enable the latter protein to act as a guanine nucleotide exchange factor (GEF) of Rac to facilitate membrane ruffling in response to the activation of Ras and PI-3 kinase [21,40]. Strikingly, PI3K was also present in this multi-protein complex containing Abi1/Eps8/Sos1 to activate Rac [41]. It is noteworthy that alternatively spliced Abi1 fused with MLL has been identified in a human acute myeloid leukemia patient, suggesting the role of Abi1 in leukemogenesis [42].
RN-tre (Related to the N-terminal of tre) was originally identified by utilizing Eps8 SH3 as a probe to fish out its binding protein(s) in a bacterial cDNA expression library generated from NIH3T3 cells [16]. RN-tre shares a homology domain (TrH) with tre oncoprotein at its N-terminus and contains an extended proline-rich sequence at the C-terminus. The PXXDY consensus is present at aa725-aa729 (GeneBank database, accession number D13644; [16]). Overexpression of full-length RN-tre in NIH3T3 cells did not cause cell transformation [16]. However, NIH3T3 cells transfected with a plasmid encoding RN-tre C-terminal truncated mutant (lacking aa463-aa828) exhibited growth advantage in both soft agar and in low serum (1%) cultured medium [16]. The TrH domain in RN-tre possesses a Rab5 GTPase-activating protein (GAP) activity [43]. RN-tre overexpression suppressed EGF internalization via its Rab5 GAP activity [43]. Interactions with Grb2 [44] and/or Eps8 [43] are required for RN-tre inhibiting EGF receptor endocytosis. The association between RN-tre and Eps8 inhibits the ability of Eps8 to complex with Abi1 and Sos1 and attenuates EGF-mediated Rac activation [43].
Shb is an adaptor protein containing amino-terminal proline-rich sequences and a C-terminal SH2 domain [45]. Unlike Abi1 and RN-tre, there is no PXXDY consensus found in Shb sequences. Shb interacts with Eps8 SH3 domain and phosphorylated PDGFβ-receptor and FGF receptor-1 (via Shb SH2 domain) [14]. Although the role of Eps8-Shb interaction in cancer biology was not defined yet, overexpression of Shb reduced Eps8 expression [46] and induced apoptosis of NIH3T3 cells cultured in low serum [47]. Markedly, while Shb overexpression reduced tumor growth of PC3 prostate cancer cells [48], Shb attenuation sensitized SVR endothelial tumor cells to apoptotic agents such as cisplatin and staurosorine [49].
IRSp53 (Insulin/IGF-1 Receptor tyrosine kinase Substrate of 53 kDa; [50]) was also designated as brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2) [51,52]. Its interaction with Eps8 was originally observed from a GST-IRSp53 SH3 pull-down experiment [22] and confirmed by a yeast two-hybrid screening utilizing N-terminal Eps8 sequences as a bait to search for Eps8 binding partners [23]. IRSp53 contains an N-terminal I-BAR (inverse-Bin-Amphiphysin-Rev) domain, followed by a CRIB, an SH3, a WW-binding sequence (WWB), and a PDZ (post synaptic density 95, disc large, zonula occludens-1) domain. The I-BAR domain might form dimers and induce membrane curvature depending on the shape of I-BAR dimer (reviewed in [53,54]). In addition to the originally identified 53-kDa protein IRSp53S (designated IRSp53 from now on); three other IRSp53 isoforms (designated IRSp58M, IRSp53T, and IRSp53L) were identified in human cells. In contrast, only three murine homologues (i.e. mIRSp53S, mIRSp58M, and mIRSp53T) were detected [55]. Interaction between IRSp53 SH3 domain and Eps8 N-terminal proline-rich sequences (aa207-aa221) activates Rac and results in cell motility and invasion of cancer cells [22]. Interestingly, in addition to the SH3 domain, PPPDY (aa468-aa471; GeneBank accession number NP_001138360) within the IRSp53 C-terminal WWB domain also participates in the association with Eps8 SH3 [23]. The interplay between Eps8 and IRSp53 is important for Src-mediated STAT3 activation that leads to cell proliferation in cancer cells [23].
Mechanistic studies reveal that serum-induced ERK activation is involved in Eps8-mediated transformation since coexpression of dominant negative MEK1 blocks its induced oncogenesis. Consistent with the PH domain of Eps8 being critical for its oncogenic potential and membrane targeting, PH-truncated Eps8 is unable to trigger ERK activation in response to serum. These data corroborate the importance of the PH domain of Eps8 for its membrane association, ERK activation and its ability to transform cells [30].
Src becomes activated when its SH3 and/or SH2 are occupied. Given Eps8 interacts with Src SH3 in vitro [13] and the Src SH3-binding region of Eps8 resides in its multiple proline-rich containing sequences, Eps8 is thereby speculated to increase Src enzymatic activity. In agreement with the mechanism underlying Src activation, Eps8 does elevate Src activity. This can be verified by diminished Eps8, which reduces Src activation as reflected by decreased Src Pi-Y416, which can be restored by ectopically expressed Eps8 [36]. Remarkably, Eps8 also regulates the activity and the expression level of FAK. While activation of FAK can be achieved by Src-mediated phosphorylation [56], its elevated expression relies on Akt/mTOR/STAT3 Pi-S727 pathway, which also modulates cyclin D1 expression [36].
Expressing small interfering RNA of eps8 in HeLa and SiHa cells impedes G1-phase progression. In addition to cyclin D1, attenuated Eps8 also reduces expression of cyclins D3 and E, elevates accumulation of p53 and p21Waf1/Cip1, and inhibits hyperphosphorylation of Rb. Reintroduced siRNA-resistant eps8 into Eps8-attenuated HeLa and SiHa cells reverses the described alteration, indicating that the effect of Eps8 on the mentioned cell cycle modulators is specific. Eps8 facilitates p53 degradation and decreased levels of Eps8 block this process and cause p53 accumulation. Studies of the turnover rate of p53 reveal that Eps8 attenuation significantly increases the half-life of p53 in HeLa cells from ~12 min to ~40 min [37]. It is noteworthy that via accelerated degradation of p53 as well as increased activation of Src and Akt, Eps8 enables cervical cancer cells to be resistant to chemotherapeutic agents.
With a genome-wide screen, matrix metalloproteinase 9 (MMP9) along with the forkhead transcription factor FOXM1 and a cohort of its target genes encoding the cell cycle mediators and the chemokine ligands (i.e. CXCL5 and CXCL12) are upregulated by Eps8 through a PI3K/Akt-dependent mechanism [57]. Through degradation of extracellular matrix components as well as processing of cytokine and growth factors, Eps8-elicited MMP9 plays a critical role in the migratory and invasive phenotype of squamous cell carcinoma (SCC) [58].
It is well established that Eps8 forms a complex with Sos1 and Abi1 to transmit signals to Rac from receptor tyrosine kinases [21,26,40] and PI3K [41]. By its N-terminal region, Abi1 is recruited to the tips of filopodia and lamellipodia in motile cells [59], and associates to WAVE-1 [60], the actin regulatory protein, further supporting its importance in actin remodeling. Notably, Eps8 also interacts with RN-tre (a specific Rab5 GAP) to modulate Rab5 activity, inhibit receptor internalization and prolong receptor signaling at the cell membrane [43].
IRSp53 is an adaptor protein that plays an important role in actin cytoskeleton reorganization. By pull-down assays, Eps8 is demonstrated as an IRSp53-binding protein. Through its N-terminal proline-rich sequence, Eps8 directly associates with the SH3 domain of IRSp53. This Eps8/IRSp53 complex reinforces the formation of a trimolecular Rac-GEF complex (i.e. Eps8/Abi1/Sos1) to synergistically activate Rac and contribute to cell motility [22]. Through an independent yeast two-hybrid screening, IRSp53 was identified as an Eps8-interacting protein. In addition, its C-terminal SH3/WWB-containing domain (aa376-aa521) was essential and sufficient for Eps8 association [23]. Strikingly, Eps8 modulates IRSp53 expression in cells transformed with v-Src and attenuation of IRSp53 results in reduced cell proliferation in culture and reduced tumor formation in mice, which can be partly rescued by ectopically expressed IRSp53. Src drives the formation of Eps8/IRSp53 complex, which leads to activation of Akt, ERK, STAT3 and enhancement of cyclin D1. This signaling event not only occurs in v-Src transformed cells but also in EGF-stimulated cells. Notably, Eps8/IRSp53 is important in both cell proliferation and cell mobility [23].
As a signaling intermediate, Eps8 has been demonstrated to be critical in proliferation and control of actin dynamics that lead to increased mitogenesis and motility of various tumor cells (see below). Now, we will not only summarize the published reports regarding the role of Eps8 in human tumors, but also discuss its potential to become a novel tumor marker as well as a therapeutic target for cancer treatment.
Eps8 overexpression confers the ability of murine fibroblasts to form foci in culture and to grow tumors in mice [30]. Its oncogenic potential invites the speculation that Eps8 might be involved and contribute to development of human cancers. Indeed, following is the published reports concerning the role of Eps8 in various human tumors.
Accumulated evidence indicates that gene amplification contributes to activation of oncogenes, and is often associated with tumor progression, acquired drug resistance and poor prognosis [61]. By an integration of serial analysis of gene expression with cDNA array comparative genomic hybridization, Yao et al. [62] aimed to identify and characterize amplicons and their targets in both in situ and invasive breast carcinomas. Their characterization of the 12p13-p12 amplicon identified four putative oncogenes including Eps8. Compared with a panel of normal mammary epithelial cells, Eps8 was confirmed to be overexpressed in breast tumors with 12p13 amplification by quantitative RT-PCR as well as fluorescence in situ hybridization.
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive maliganacy and characterized by early invasion and metastasis [63]. In pancreatic ductal cells, Eps8 colocalizes to the tips of F-actin filaments, filopodia, and the leading edge of cells. Its knockdown alters actin-based cytoskeletal structures and cell shape, impairs cell-cell junctions and protrusion formation.
Studies of the expression of Eps8 in cell lines derived from various tumor stages demonstrate that the levels of Eps8 are higher in cell lines derived from metastases and ascites as compared to those from primary tumors [64]. These results suggest that Eps8 plays a critical role in the metastatic potential of PDAC.
Papillary thyroid carcinoma (PTC) is a common thyroid maligancy whose biological behavior varies widely. By studying the expression profiles of eight matched pairs of PTC and normal throid tissues, Eps8 was identified as one of the overexpressed genes in PTC [65]. Notably, Griffith et al. [66] performed a meta-review of thyroid cancer biomarkers from a large number of published studies, identified twelve candidate diagnostic biomarkers, including Eps8. Unfortunately, no follow-up study, even at the RNA level, has confirmed Eps8 upregulation in thyroid lesions. Thus, inclusion of Eps8 as a diagnostic marker for thyroid cancer requires further investigation.
Oral squamous cell carcinoma (OSCC) is a common maligancy. Its local invasion and regional lymph node metastases usually cause early death. Using expression microarrays, the eps8 gene was identified as being overexpressed in OSCC cell lines compared with normal oral keratinocytes. Despite attenuation of Eps8 in VB6, BICR56, and CA1 OSCC cells does not inhibit cell proliferation, but it does impair the cell spreading and migration toward fibronectin. Not surprisingly, Eps8 was upregulated in a subset of OSCCs where it correlated significantly with lymph node metastasis. Knockdown of Eps8 suppressed αVβ6-, and α5β1-integrin-dependent Rac1 activation and inhibited tumor cell invasion in an organotypic model of OSCC [67].
Among gynecologic cancers, ovarian cancer has the greatest motality rate due to its metastasis [68]. Not relying on the vasculature for metastasis as seen in solid tumors, ovarian maligancy is confined within the abdominal cavity and extends to adjacent organs and/or disseminate throughout the peritoneal cavity [69]. Lysophosphatidic acid (LPA), a growth factor-like phospholipid, retains migration-stimulating potential and is present at high levels in ascites of ovarian cancer patients. LPA-mediated cell motility is confirmed to play an important role in ovarian cancer metastasis, and the integrity of Sos1/Eps8/Abi1 tricomplex is essential for LPA-induced Rac activation, cell migration and metastatic colonization. Strikingly, only coexpression of the three members of the tricomplex correlates with advanced stages and shorter survival of ovarian cancer patients [70]. For ovarian cancer metastasis, these findings not only indicate the tricomplex is a reliable marker, but also suggest targeting the tricomplex can be developed as a therapeutic approach.
Colorectal cancer (CRC) is the most common gastrointestinal cancer and one of the leading causes of cancer mortality worldwide. Preferentially increased Eps8 in the advanced stage of human CRC specimens is detected. Intriguingly, simultaneous up-regulation of Eps8, Src and FAK in CRC is observed and these three proteins are positively correlated as indicated by Spearman rank correlation. This is in agreement with Eps8 modulating the expression of FAK via mTOR/STAT3 pathway [35].
Cervical carcinoma evolves slowly from intraepithelial neoplasia to invasive carcinoma and is the second most common malignancy among women [68]. Through clinicopathologic examination and immunohistochemical staining, an intimate correlation between Eps8 abundance and the aggressiveness (local lymph node metastasis or parametrium invasion) of early-stage cervical cancer is established. Concurrently, Eps8 expression inversely correlates with the survival rate of cervical cancer patients [36].
A thorough analysis of both esophageal squamous cell carcinoma and esophageal adenocarcinoma revealed 4-6 fold increase in expression of Eps8 in esophageal cancers compared to adjacent normal tissues. Notably, unlike colon cancer, higher Eps8 expression in tumors as compared to their nearby normal tissue was independent of grade of esophageal cancer [72].
Comprising some of the most common intracranial neoplasms, pituitary tumors can either be detected clinically (i.e. acromegaly and amenorrhea) or become clinically silent such as those of the gonadotrope lineage [73]. By DNA microarrays, eps8 is identified as an overexpressed transcript (5.9-fold) in pituitary tumors compared with normal controls. Xu et al. [74] demonstrated that overexpression of Eps8 in gonadotrope pituitary cells results in activation of ERK and Akt, which provide proliferative stimulation and antiapoptotic protection respectively. Remarkably, the above mentioned signaling components are upregulated in human pituitary tumor tissues suggesting a functional significance of Eps8 in human pituitary tumorigenesis.
Accumulated evidence revealed the significance of Eps8 in tumor development and metastasis. According to the elucidated mechanisms underlying Eps8-mediated transformation, suppressed expression of Eps8 as well as disruption of the Eps8-containing signaling complex become two promising strategies to inhibit tumorigenesis.
Considering Eps8 is an oncoprotein whose overexpression is closely linked to tumor formation, suppressing its expression might provide a means to treat and eradicate tumors. Strategies published to decrease Eps8 expression are described below.
2.2.1.1. Histone deacetylase inhibitors
Epigenetic modulation of gene expression is implicated in cancer development. Emerging evidences indicate the acetylation status of histones controls the acess of transcription factors to DNA and influences gene expression. Histone acetylation and deacetylation are mediated by histone acetyl transferases (HATs) and histone deacetylases (HDACs) respectively. HDAC inhibitors are well documented to promote differentiation, growth arrest and apoptosis of cancer cells with minimal effects on normal tissues. Notably, HDAC inhibitors not only decompact histone/DNA complex, but also influence acetylation status and function of nonhistone proteins [75]. A number of HDAC inhibitors have entered preclinical and early clinical studies. Although these compounds were chosen for their ability to inhibit histone deacetylation, they still had widely varying potency and HDAC isoenzyme specificity as well as different effects on acetylation of nonhistone proteins. To date, the prominent targets of HDAC inhibitors include HDACs, p21WAF1/CIP1, p53, death receptor proteins (i.e. TNF-α, Fas and TRAIL receptors), HIF-1α, and VEGFR [75].
Trichostatin A (TSA), an antifungal agent, is a HDAC inhibitor. The reversal of v-Src-mediated transformation by TSA is attributable to its suppression of Eps8 expression. RT-PCR and Northern analyses reveal the significant decrease of eps8 transcripts in TSA-treated v-Src-expressing cells relative to control cells [31]. Similar reduction of Eps8 is also obtained when butyrate, another well known HDAC inhibitor is applied (unpublished result). These data indicate Eps8 can be added to the growing list of HDAC inhibitor targets and its downregulation contributes to the antineoplastic effects of HDAC inhibitors.
2.2.1.2. Mithramycin
Mithramycin (MIT, also known as mithracin, aureolic acid and plicamycin), a polyketide produced by various soil bacteria of the genus streptomyces, is an inhibitor that blocks the binding of the Sp-family transcription factors to the GC box [76]. To date, expression of several proto-oncoproteins such as Met, Myb, Myc, Ras and Src can be suppressed by MIT. Interestingly, in several cancer cell lines, MIT also reduces the protein and mRNA levels of Eps8 in dose- and time-dependent manners [77]. Considering the mechanistic action exerted by MIT, the promoter composition and the transcriptional regulation of eps8 gene warrant further investigation.
2.2.1.3. Small interference RNA or short hairpin RNA methodology
Expressing either small interference RNA (siRNA) [31,36,37] or short hairpin RNA (shRNA) of eps8 [58] in tumor cells efficiently inhibits the expression of Eps8. Decreased levels of Eps8 alters the behavior of cancer cells such as (1) suppressed v-Src-mediated transformation in fibroblasts [31], (2) reduced colonocyte proliferation and motility in colon cancer cells [36], (3) retarded cell cycle and decreased chemoresistance in cervical cancer cells [37], (4) impaired tumorigenicity of HNSCC cells in xenograft assays [58]. Hence, using siRNA (or shRNA) methodology to suppress Eps8 expression in tumor cells might block their progression, invasion and increase their chemosensitivity to anti-cancer drugs.
Eps8 exerts its effects through the formation of various complexes. The well-studied ones are Sos1/Eps8/Abi1 and Eps8/IRSp53. Formation of both complexes results in Rac activation and promotes cell proliferation and cell motility.
2.2.2.1. Disruption of Sos1/Eps8/Abi1 complex formation
Sos1/Eps8/Abi1 tricomplex is well established to mediate Rac activation and whose integrity is required for LPA-stimulated cell motility and metastatic colonization in ovarian cancer cells. Given coexpression of Sos1, Eps8 and Abi1, but not any one alone, correlates with advanced stages as well as shorter survival of ovarian cancer patients [70], silencing any member of Sos1/Eps8/Abi1 tricomplex and/or targeting this tricomplex can be developed as a therapeutic approach for tumor metastasis.
2.2.2.2. Disruption of Eps8/IRSp53 complex formation
Eps8/IRSp53 complex, occurs at the leading edge of motile cells, augments Sos1/Eps8/Abi1 trimolecular complex formation, and synergistically activates Rac. Inhibiting its formation reduces the mobility and invasiveness of fibrosarcoma cells [22]. Strikingly, elevated activity of Akt, ERK, STAT3, and augmented expression of cyclin D1 are also dictated by Eps8/IRSp53 that can be reduced by SU6656, an inhibitor of Src family kinases [23]. Of note, through activation of Src, EGF induces the formation of Eps8/IRSp53 and activation of STAT3 in HeLa cells [23]. Since the association between Eps8 and IRSp53 is Src-dependent and might be a physiological event in relaying EGF signaling, strategies that interrupt the interaction between Eps8 and IRSp53 can be developed and applied for cancer treatment. Specifically designed peptides, naturally occurring or artificially synthesized chemicals that block the association between Eps8 and IRSp53 might fulfill the purpose and become novel cancer therapeutics.
Considering a spectrum of proteins bind to Eps8 and play important roles in cell proliferation and migration (Figure 2), Eps8 upregulation is thus expected to cause human carcinogenesis. Indeed, aberrant overexpression of Eps8 is closely linked to many types of human cancer. Although Eps8-mediated signal transduction is gradually being resolved, several important questions still remain unanswered. For instance, tyrosyl phosphorylation of Eps8 mediated by either Src or EGFR is not addressed yet. Where are these tyrosine residues located? How does their phosphorylation contribute to abnormal cell proliferation and motility in cancer cells? In addition, Eps8 possesses a nuclear localization signal (Figure 1). However, to date there are no reports regarding the role of nuclear Eps8 and how the nuclear localization of Eps8 is regulated? Tremendous work needs to be done before these questions get answers.
The signals transmitted by Eps8. Active EGFR and Src phosphorylate Eps8 and induce Eps8-IRSp53 interaction that facilitates Src-mediated STAT3 Pi-Y705 and dimerization, resulting in the increased transcription of Cyclin D1 and FAK and in cell cycle progression. By binding to RN-tre, Eps8 reduces Rab5 activity and hinders EGFR endocytosis. In addition to its actin-capping activity, Eps8 interacts with proteins listed in the square box, activates Rac, promotes membrane actin polymerization, and increases motility. Nu: nucleus.
This study is supported in part by grants from National Health Research Institute (NHRI-EX101-1013BI to T.-H.L.), National Science Council (NSC101-2325-B-006-010 to T.-H.L; NSC98-2311-B-039-002-MY3 to M.-C. M), Comprehensive Cancer Center in Southern Taiwan (DOH100-TD-C-111-003 to T.-H. L.), Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH101-TD-B-111-004 to M.-C.M.) and China Medical University (CMU97-193 to M.-C.M.).
LASER, an abbreviation of light amplification by stimulated emission of radiation, was first established by Maiman in 1960 [1], a scientist of the Hughes Aircraft Company. Based on the theory originally proposed by Albert Einstein, Maiman used the ruby crystal that produces a coherent radiant light when activated by energy. Goldman et al. [2], a dermatologist experimenting laser for tattoo removal, showed painless surface crazing of enamel after focusing two pulses of red light beam from ruby crystal. Following experiments by Stern and Sognnaes [3], pendulum shifted from ruby laser to CO2 and Nd:YAG lasers for better interactions with dental hard tissues. The 1970s and 1980s sought use of lasers for soft tissue surgical procedures, and Lenz et al. [4] were among the pioneers to report oral surgical application of CO2 laser, together with Frame [5], Pecaro [6], and Pick [7] who used the same for oral soft tissue lesions and periodontal procedures. Myers and Myers [8] described the use of modified ophthalmic Nd:YAG laser for removal of dental caries and received the US FDA’s permission for selling Nd:YAG laser device in 1989 [9]. After Myers’s suggested use in soft tissue surgery [10], Nd:YAG laser was eventually used in periodontal procedures [11, 12], and since then lasers have been used largely by researchers and clinical periodontal practitioners.
Lasers can be used in a focused beam (for excisions and incisions) and in an unfocused beam (for ablation and coagulation). Some evidence suggests that lasers used as an adjunct to scaling and root planning (SRP) may provide additional benefits [13]. It had been shown that using lasers in periodontal treatment had a beneficial role in controlling of bacteremia, bacterial reduction, effective subgingival calculus elimination (using Er:YAG lasers), improved eradication of the pocket epithelium in pockets involving teeth, and enhancement of periodontal regeneration in humans and animals without a destructive effect on the neighboring pulp tissues and bone [14, 15, 16, 17, 18, 19, 20, 21]. In India the capability of using laser device at laboratories and institutes offers a huge chance to the researchers and scientists concerned in the field of free electron lasers, semiconductor lasers, solid-state lasers, and gas lasers [22]. So because of the importance of the subject and the wide use of laser in India, this chapter focuses on the most important types of laser used in the India as well as in Iraq.
In dental field, lasers can be categorized by different ways: according to the type of the affected tissue, soft tissue and hard tissue lasers; according to the medium of laser used, like solid laser and gas laser; and finally according to wavelength of laser that is being used.
The neodymium yttrium aluminum garnet laser (Nd:YAG) wavelength is strongly absorbed by the pigmented tissue. There has been research on using the Nd:YAG laser for nonsurgical sulcular debridement in periodontal disease control [23]. Neodymium yttrium aluminum garnet laser is a very effective surgical laser for coagulating and cutting periodontal soft tissues, with good hemostasis [24]. In addition Nd:YAG laser is used in laser-assisted new attachment procedure (LANAP) [25].
The CO2 laser has the advantage of rapid soft tissue elimination and hemostasis with a very shallow depth of penetration, and this advantage is due to its wavelength which has a great affinity for water. Carbon dioxide laser has the highest absorbance of any laser [26], but it is associated with several disadvantages including its high cost, relative large size, and its interactive destruction to the hard tissue.
Diode wavelengths are absorbed mainly by hemoglobin and pigmented tissue (melanin). On the other hand, they are poorly absorbed by the enamel and hydroxyapatite. Laser wavelengths, ranging from 810 to 980 nm, are produced from the active medium of the diode laser which is a solid-state semiconductor made of gallium, aluminum, arsenide, and infrequently indium. Diode laser is used in particular procedures including soft tissue crown lengthening, aesthetic gingival (gingivoplasty), removal of inflamed soft tissue, exposure of soft tissue impacted teeth, frenectomies, and photostimulation of the herpetic and aphthous lesions [27].
The erbium wavelengths have the highest absorption of water in any dental laser wavelengths and have a great affinity for hydroxyapatite. Two distinct wavelengths of erbium lasers had been developed, including Er:YAG (yttrium aluminum garnet) lasers and Er,Cr:YSGG (yttrium scandium gallium garnet) lasers. Because of its great affinity for hydroxyapatite, it is the laser of choice for dealing with dental hard tissues [28], and because of its high absorption of water, erbium lasers can be used for periodontal soft tissue ablation, as dental soft tissue is composed of a high proportion of water [29].
Soft tissue surgical applications
Removal of the pocket epithelium
Laser root conditioning
Bacterial reduction
Implant therapy
Lasers such as diode, CO2,Nd:YAG, Er:YAG, and Er,Cr:YSGG are being extensively used in periodontal treatments including gingival soft tissue procedures such as gingivoplasty, gingivectomy, frenectomy, benign tumors or epulis elimination [30], irradiation of aphthous ulcers, gingival depigmentation, coagulation of free graft donor sites, second-stage exposure of dental implants [13], and crown lengthening procedures [30]. This diversity of laser use is due to its superior properties over conventional scalpel procedures which include bacteremia reduction, ease of soft tissue ablation, hemostasis [30], slight wound contraction and slight scarring, immediate sterilization, edema reduction, mechanical trauma reduction, no or little operative and postoperative pain [13, 31, 32], improved patient acceptance [13], more rapid healing, little need for suturing, much easier technique, and necessitating no topical anesthesia [33].
The penetration depth of lasers differs, and therefore their performance differs, and lasers possibly cause a hazardous effect on the underlying tissues by thermal injury. Laser light is absorbed in the superficial layers in Er:YAG,CO2 and Er,Cr:YSGG lasers, and hence it has the advantage of being simple and rapidly vaporized from soft tissues, while other type of laser such as diode lasers and deeply penetrating Nd:YAG associate with more thermal influences, which consequently lead to formation of thick coagulation zone on the treated surface [21, 29, 30] and hence used similar to electrosurgical procedures [30]. Finkbeiner [34] has suggested the usefulness of argon laser in soft tissue welding and soldering compared to conventional tissue closure method. Epithelial exclusion using CO2 laser had been suggested to retard its downward growth, and studies have shown effective removal of epithelium from gingival tissues without damaging the underlying connective tissues [35, 36].
Lasers are also used for soft tissue periodontal applications. The Nd:YAG was the first laser wavelength to be compared to the scalpel for treating periodontal pockets [16] and controlling bacteremia and gingival bleeding [16, 18]. The probing pocket depth and bleeding index scores were reduced using the pulsed Nd:YAG laser. Furthermore, clinical evaluation of soft tissue biopsies taken from human subjects using the Nd:YAG laser versus a curette presented a complete removal of the epithelium of the pocket after use of the pulsed Nd:YAG laser compared to the curette [15]. Similar effects presented in pig jaws (in vitro) after the use of a 980 nm diode laser with 2–4 W power settings and continuous wave compared to the conventional curette [37]. There are advantages in the postsurgical outcomes with the removal of pocket epithelium. A recent clinical study in India showed that the modified Widman flap with removal of the pocket epithelium was more effective in reducing mean probing depth than access flap with intrasulcular incision. It showed greater gain of clinical attachment and demonstrated less gingival recession [38]. When deep periodontal pockets are present, removal of the pocket epithelium using a fiber-optic glass laser offers benefits. With or without flap elevation and a conventional periodontal access flap procedure, the pocket epithelium will be removed from the inner and the outer part of the pocket. Depending on how the patient heals, the epithelium can later be ablated every 7–10 days from the outer part of the pocket, usually under the use of topical anesthesia, in order to control apical migration. This can result in long-term, stable connective tissue attachment, without gingival recession. The principle underlying this approach is guided tissue regeneration; it has been called “laser-assisted guided tissue regeneration” [39]. This approach should be evaluated in different prospective clinical studies involving many patients and following exactly the same protocol in order to establish that it is a technological improvement that should be incorporated routinely in daily practice. Both clinical case series and clinical research have shown the potential of this application using the CO2 laser, since the noncontact handpiece is able to ablate tissues very quickly, controlling the epithelial cell proliferation and further apical migration of a long junctional epithelium. Israel et al. [20] were able to demonstrate histologically the effects of this de-epithelialization technique in humans. The technique involves using the CO2 laser to remove (ablate) the inner part of flap after conventional periodontal flap elevation and then using the same method in the outer part of the flap to achieve epithelial retardation. Case series in patients with generalized advanced periodontal disease have shown that the laser de-epithelialization technique leads to good results without the need for multiple membrane therapy [40, 41].
The use of CO2 lasers to decontaminate root surfaces has been investigated, providing more information about the exact power settings and parameters required to avoid root damage. Barone et al. [42] showed that a defocused, pulsed CO2 laser is able to create smooth and clean root surfaces compared to a focused, continuous wave; the latter leads to melting and root surface damage. Later studies using the same parameters for CO2 lasers reported root conditioning with a better fibroblastic activity, cellular proliferation, and greater fibroblast attachment [43]. Different clinical case reports have demonstrated these advantages of CO2 laser de-epithelialization [44]. This technique has also been used in clinical studies and has shown that coronal flap advancement in conjunction with CO2 laser root conditioning leads to improvements in clinical parameters and long-term tissue stability after 15 years, compared to the modified Widman periodontal flap procedure [45]. The authors concluded that this laser technique seemed to have greater effects and should be used in treating deep periodontal pockets (more than 7 mm deep).
A laser application that has been especially promoted in the past is for the reduction of bacteria in pockets, due to the high absorption of specific laser wavelengths by the chromophores. Initially, the use of an Nd:YAG laser was shown to reduce the load of Porphyromonas gingivalis and Prevotella intermedia [46]. A study by Assaf et al. [47] is of special interest. Using a diode laser in conjunction with ultrasonic scaling for treatment of gingivitis, they were able to show a significantly lower incidence of bacteremia in the diode + ultrasonic group (36%) than the ultrasonic only group (68%). They suggested that diode lasers should be used to prevent bacteremia, especially in immunocompromised patients. Using a 980 nm diode laser to reduce periodonto-pathogenic bacteria in patients with aggressive periodontitis has also been investigated. Kamma et al. [48] confirmed that it was possible to reduce the total bacterial load in pockets without the use of any systemic antibiotic therapy. Clinical case series with 10 patients using in the same patient (in a randomized protocol) SRP in conjunction with 980 nm diode laser, SRP and an Nd:YAG laser, and SRP with photodynamic therapy (PDT) showed that the PDT was able to reduce significantly the bacteria in the pockets and provide a predictable clinical outcome for 3 months. In contrast to that, the use of Nd:YAG laser was not very beneficial and was similar to the control (SRP) group [49]. Due to the bacteria reduction and the reduced bleeding on probing provided by the PDT, the PDT was recommended for periodontal patients especially for the maintenance appointments.
In the previous years the important role of laser in dental implant treatment has been discussed widely [50]. Because of the lack of comparable test and control sites, it is difficult nowadays to know if lasers, with their different types, can be used to treat peri-implantitis using randomized clinical trials [51]. Removal of peri-implant soft tissues and bacterial reduction, uses of laser in second-stage surgery [52], and decontamination of failing implants [53] are the most important applications for lasers in implant dentistry. However there are a lot of limitations of using laser in implant dentistry including the serious alarms about the overheating of the implant and the concern about the melting of the implant surface [54, 55], as well as the fears regarding missing of the re-osseointegration after peri-implantitis treatment with lasers. In recent years a lot of reviews have concentrated on these limitations and gave additional facts about re-stabilization and re-osseointegration of the implants subsequent to the laser decontamination of the implant surface [56]. Deppe et al. [57] showed that CO2 laser decontamination of the surface of implants placed in dogs allowed new bone to grow and be in contact with the implant surface (re-osseointegration). In vitro studies of osteoblasts have confirmed these effects for CO2 and Er,Cr:YSGG lasers [58]. Previous clinical case series were able to demonstrate new bone fill and long-term success of failing implants that were decontaminated with a CO2 laser [59, 60]. The main advantage of using CO2 laser irradiation on implant surfaces is that this wavelength does not pose the risk of overheating [61], unlike other wavelengths, such as that of diode, Nd:YAG, and Er:YAG lasers [62, 63]. A significant increase of the implant surface temperature has been demonstrated when irradiating implant surfaces with a diode laser in vitro for more than 10 s [62, 63, 64]. It is possible that authors have presented unsuccessful and nonpredictable clinical results from their studies because of overheating resulting from inconsistent power settings [65]. Limited facts available regarding laser-assisted decontamination of implant surfaces, with a limited number of included studies, as well as the great heterogeneity of the results had been pointed out by a recent systematic review. Nevertheless, even though data is incomplete regarding the clinical use of CO2 (10.6 nm) lasers in the surgical treatment of peri-implantitis, its use appears promising [66].
The following summary of advantages and disadvantages of using lasers for periodontal therapy is based on the literature and the author’s experience.
Less pain. Less need for anesthetics (an advantage for medically compromised patients). No risk of bacteremia. Excellent wound healing. No scar tissue formation. Bleeding control (dependent on the wavelength and power settings). Usually no need for sutures. Use of fewer instruments and materials and no need for autoclaving (economic advantages). Ability to remove both hard and soft tissues. Lasers can be used in combination with scalpels (however, the laser is a tool and not a panacea) [67].
Relatively high cost of the devices. A need for additional education (especially in basic physics). Lasers do not eliminate the need for anesthesia. Every wavelength has different properties. The need for implementation of safety measures (i.e., goggle use, etc.) [68].
Despite apparent benefits of lasers regarding patient compliance and clinical observation, there are no enough data to support that laser is associated with reduced scarring, which itself appears to be different according to the wavelength and extremely related to the energy density, and there are no enough data to support quicker healing associated with laser therapy [13]. Limited experimental animal studies [68, 69] involving CO2,Nd:YAG, diode lasers, or Er:YAG have evaluated the histological and immunohistochemical patterns of periodontal tissue healing following surgical and nonsurgical periodontal therapy. Sculean et al. [70] and Yukna et al. [71] reported healing response of intrabony defects after open flap surgery or treatment using a laser-assisted new attachment procedure in humans using Er:YAG and Nd:YAG lasers, respectively. Lippert et al. [72] claimed that CO2 laser-induced wounds in oral and oropharyngeal mucosa healed significantly faster (in 32.8 ± 9.2 days) than those created by Nd:YAG laser (in 40.4 ± 9.2). However, in contrast to conventional scalpel surgery, the histological findings showed that the beginning of wound healing was delayed after laser surgery, and it depends on the size of the initial defect. Due to the more pronounced zone of necrosis at the base of the wound ground, this effect is more evident using the Nd:YAG laser [72]. Although, as compared to conventional treatment, overall [72] as well as initial periodontal wound healing laser application [73] has been shown to be delayed, few studies have reported that laser-induced wounds show a reduced propensity of contraction of the scar in comparison to the usual surgeries of scalpel [13]. Low-level laser treatment by GaAIAs radiation in milliwatt range has been shown to be effective in recent studies, as it absolutely affects proliferation of fibroblasts in gingiva or periodontal ligament, so it consequently maintains peri-implant and periodontal wound healing [73].
Waterlase® system is a revolutionary dental device that uses laser-energized water to cut or ablate soft and hard tissues and provide periodontists with the opportunity to perform more procedures in fewer appointments with less need for anesthesia, scalpels, and drill [74]. Periowave™, a photodynamic disinfection system, utilizes nontoxic dye (photosensitizer) in combination with a low-intensity laser, enabling singlet oxygen molecules to destroy bacteria [75]. After applying a light-sensitive drug (photosensitizer), low-intensity laser is directed on the area treated with the drug resulting in phototoxic reactions. Although the use of photosensitizers for complete suppression of the anaerobic perio-pathogens has been suggested, the same is not true for facultative anaerobes [76].
Laser safety officer (LSO) is an elected, well-trained individual who guides safety of laser performs and confirms a harmless surroundings for exhausting it, as an important part of giving dental treatment with laser device is protection and safety. All clinicians must be aware and take care of the prevention of accidental and hazardous irradiation. The patient, clinician, and assistant must wear a protective eyewear particular for the wavelength and the type of laser in use. Additionally, the clinician should follow laser safety rules and join certificate courses by dental laser organizations; however the size and the cost of laser device still create a difficulty and a struggle for its practical application [77].
Lasers have been suggested as an adjunctive or alternative to conventional techniques for various periodontal procedures and considered superior in respect to easy ablation, decontamination, and hemostasis besides less postoperative pain and less operative pain. Application of lasers with their different types in implant dentistry and the recent laser practical modalities had revolutionized the outcome of periodontal therapy with patient acceptance. But, procedural cost and patient risk should be kept in mind and completely assumed before laser use.
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