\r\n\tThe outcome of cancer therapy with radiation has been improving over the years due to technological progress. However, due to the biological property of cancer, current radiotherapy has limitations. Therefore, in consideration of the dynamics of tumor cells caused by radiation irradiation, attempts are being made to overcome the current drawbacks and to improve radiotherapy. It is expected that carbon ion beams, hyperthermia, oxygen effect, blood flow control, etc. will be used in the future in order to improve the treatments. This book aims to introduce research results of various radioprotective agent development research and hypoxia sensitizers.
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1. Introduction
Alginate has been extensively used for tissue engineering and regenerative medicine purposes [1]. Its ability to form hydrogels under mild gelation conditions in the presence of ions such as Ca2+, Ba2+, and Sr2+ renders it suitable for cell-based applications where exposure to harsh crosslinking buffers can lead to cell damage. When alginate is exposed to a crosslinking solution, l-guluronic residues of adjacent polysaccharide strands are connected forming a hydrogel [2, 3]. Alginate hydrogels possess the advantages of natural biomaterials such as excellent biocompatibility and abundance in nature with a low cost, properties which render it an excellent candidate for cell-based regenerative medicine applications [4]. However, the lack of alginate bioactivity requires functionalization with a wide variety of molecules promoting adhesion and modulation of stem cell fate. The purpose of this chapter is to provide an overview of the use of alginate hydrogels with mesenchymal stem cells (MSCs) which represent one of the most widely used stem cell type and the only stem cell type currently in clinical use.
2. Mesenchymal stem cells (MSCs) for tissue engineering
MSCs are multipotent stem cells with the ability to proliferate and differentiate into a variety of mature cells, mainly osteocytes, chondrocytes, and adipocytes [5].
MSCs can be isolated from a multitude of adult and fetal tissues including but not limited to the bone marrow, adipose tissue, peripheral blood, synovial tissue, placenta, Wharton’s jelly, and umbilical cord blood. Importantly, it has been shown that MSCs isolated from different tissue sources possess differential proliferation and differentiation capacity toward various lineages [6] (Figure 1). Since their description by Friedenstein et al. [7], MSCs have been evolved as the stem cell type with the most regenerative medicine applications and the only stem cell type used in clinic to date.
Figure 1.
Tissue sources and properties of mesenchymal stem cells.
MSCs represent attractive stem cell candidates for the use in tissue engineering and regenerative medicine applications for a variety of reasons. Firstly, they have the ability to proliferate and differentiate producing tissues, which are clinically relevant for regenerative medicine purposes such as musculoskeletal and neural tissues. In addition, they offer the possibility of autologous use, which can avoid adverse immune responses to allogeneic cells while also possessing an immunomodulatory capacity being able to regulate the immune environment even when implanted in an allogeneic fashion. Finally, the use of MSCs avoids the ethical shortcomings of embryonic stem cell (ESC) use and is not associated with the formation of teratomas which is a characteristic of pluripotent stem cell implantation (ESCs and induced pluripotent stem cells—iPSCs) [8, 9, 10]. Recently, protocols for the derivation of MSCs from iPSCs have also enabled the production of unlimited MSC numbers by exploiting the unlimited proliferation capacity of iPSCs prior to their differentiation to MSCs [11, 12, 13].
The use of MSCs for tissue engineering and regenerative medicine purposes requires the robust characterization of MSCs at several levels. At the moment, the International Society for Cell and Gene Therapy (ISCT) has posed the minimal criteria that need to be fulfilled so that a cell population is characterized as MSCs. These include the adherence to plastic; the presence (≥95%) of surface markers including CD73, CD90, and CD105; and the absence (≤2%) of hematopoietic markers (CD34, CD45, CD79a or CD19, CD14 or CD11b, and HLA II). Finally, cells characterized as MSCs should possess the capacity to differentiate to osteoblasts, chondroblasts, and adipocytes in vitro [14]. Other surface markers have been utilized over the years for the characterization of MSCs including Stro-1, CD271, CD146, and MSCA-1, but their use has not yet been established as a routine for MSC research [15, 16, 17, 18]. Recently, omics strategies have emerged as promising alternatives for the comprehensive evaluation of MSC quality at the undifferentiated and differentiated states [11, 19, 20, 21, 22, 23].
3. The use of alginate hydrogels and MSCs in tissue engineering and regenerative medicine applications
Due to the lack of bioactive molecules on the alginate structure, alginate hydrogels used for cell-based applications require functionalization with molecules which can aid cell adhesion, increase cellular proliferation, and/or guide stem cell differentiation toward the desired cell lineages. In an attempt to increase cell adhesion on alginate hydrogels, a wide variety of extracellular matrix proteins or protein fragments have been employed. The most commonly used molecules include collagen, gelatin (product of collagen hydrolysis), and arginylglycylaspartic acid (RGD) peptide, which is the functional adhesion sequence in several extracellular matrix (ECM) proteins. Gelatin has been widely utilized for the enhancement of cell adhesion and differentiation in alginate hydrogels [24] either mixed [25] or crosslinked with alginate [26]. It has also been shown that crosslinking of alginate with gelatin reduces gelatin leak over prolonged culture while enhancing cell adhesion and vascular endothelial growth factor (VEGF) secretion compared to natural alginate and RGD-alginate [27].
Oxidized alginate has been widely used for tissue engineering purposes. Alginate can be oxidized with the use of agents including sodium permanganate (KMnO4) and periodate, to produce two free aldehyde groups on the alginate backbone, offering enhanced in vitro and in vivo. Alginate oxidation is necessitated by the lack of natural alginate degrading enzymes in mammals, which is translated to a slower biodegradation of alginate hydrogels [28, 29]. Additionally, free aldehyde groups offer sites for possible crosslinking with amine group-containing molecules, which can be used for the robust functionalization of hydrogels used for tissue engineering [29, 30]. Similarly to natural alginate, a wide range of biomolecules have been used for the functionalization of oxidized alginate. The most commonly used are gelatin and RGD, which have been shown promote cell adhesion and viability [31] .
3.1 In vitro paradigms of alginate/MSC constructs
Culture of MSCs in alginate hydrogels has been attempted for applications ranging from the regeneration of bone, cartilage, and tendon to the repair of damaged myocardium and trachea. Most of the initial data on the use of alginate/MSC constructs have been obtained in vitro (Table 1).
Representative in vitro studies combining alginate-based hydrogels with MSCs.
Functionalization of alginate has been achieved with molecules mimicking the ECM, the most commonly used of which are RGD and gelatin. RGD has been used to increase adhesion in photo cross-linked alginate hydrogels which were found to maintain viability and promote proliferation of bone marrow MSCs [32] and muscle differentiation of umbilical cord MSCs in alginate-fibrin hydrogels [33]. Tyramine has been also cross-linked to alginate to increase MSC adhesion [34]. In hydrogels functionalized with RGD, it has been shown that high cell density favors cell-cell contact and promotes osteogenic differentiation [35] as well as increasing survival and VEGF secretion from MSC spheroids [36]. The combination of RGD with a matrix metalloproteinase cleavable peptide (proline-valine-glycine-leucine-isoleucine-glycine) in alginate has been shown to promote adhesion and allow better elongation of MSCs than RGD alginate [37]. Increased chondrogenesis has been also demonstrated with the incorporation of fucoidan (a heparan sulfate analogue) in alginate hydrogels seeded with bone marrow MSCs [38]. Glycine-histidine-lysine (GHK), a tripeptide fragment 0f osteonectin (a bone ECM protein), has been cross-linked with natural alginate and oxidized alginate achieving enhanced VEGF secretion from bone marrow MSCs [39] and increased osteogenic differentiation of umbilical cord blood MSCs compared to oxidized alginate with gelatin [20]. Finally, functionalization of alginate with RGD has been shown to promote adipose tissue MSC chondrogenesis via integrin-dependent transforming growth factor (TGF)-β3 activation [40].
One of the most common applications of alginate/MSC constructs is for cartilage tissue engineering. It has been shown that cells differentiated to chondroblasts in alginate hydrogels produce more collagen type II than in monolayer where they predominantly produce collagen type I [41]. In addition, photocrosslinked alginate/hyaluronic acid injectable hydrogels have been shown to support the chondrogenic differentiation of bone marrow MSCs for cartilage tissue engineering [42]. Alginate hydrogels have been also combined with synovial MSCs showing chondrogenic gene expression and collagen type II deposition under the effect of bone morphogenetic protein-2 (BMP-2). However, the authors noted that full progression of chondrogenesis was not feasible [43]. Interestingly enough when applied to bone marrow MSCs in RGD-alginate hydrogels, BMP-2 has promoted osteogenic differentiation showing that it favors osteogenic differentiation [44].
Several studies have demonstrated the suitability of alginate hydrogels in combination with MSCs for bone tissue engineering. Sodium alginate (SA)/hydroxyethylcellulose (HEC)/hydroxyapatite (HA) hydrogels have been combined with bone marrow MSCs for bone tissue engineering maintaining high cell viability and proliferation [45]. Alginate-gelatin-hydroxyapatite [46] and oxidized alginate-gelatin-N-succinyl chitosan hydrogels [47] have been shown to promote the osteogenic differentiation of bone marrow MSCs. Injectable hydrogels have been also tested for the repair of bone defects such as alginate-calcium phosphate [48] and alginate-fibrin hydrogels [49] combined with umbilical cord MSCs. Such materials enable the direct injection of the hydrogel paste in a bone defect and have been shown to promote osteogenic differentiation of MSCs facilitating fracture healing. Hydroxyapatite (calcium-deficient) and RGD have also been combined with alginate for cartilage regeneration showing that placental MSCs could perform better chondrogenesis than bone marrow MSCs [50]. However, RGD-functionalized alginate has been also shown to enhance osteogenic differentiation, mineralization, and viability [51, 52]. Oxidized alginate hydrogels have been also widely utilized for bone tissue engineering. It has been cross-linked with fibrin achieving high cell viability and osteogenic differentiation of Wharton’s jelly MSCs compared to plain natural and oxidized alginate [49]. Sarker and co-workers have described the crosslinking of oxidized alginate with gelatin hydrogels for bone regeneration, demonstrating enhanced osteogenesis of adipose tissue and increase of VEGF secretion from MG-63 osteosarcoma cells compared to plain alginate and RGD-functionalized alginate [27, 53]. Other groups have also confirmed the suitability of oxidized alginate for the osteogenic differentiation of adipose-derived MSCs [53] and muscle differentiation of Wharton’s jelly MSCs [54].
Apart from bone and cartilage regeneration, alginate hydrogels have found a limited number of other applications such as the regeneration of nucleus pulposus of the intervertebral disk, the cryopreservation of MSCs, and the three-dimensional printing of cellularized structures. Specifically, alginate hydrogels outperform chitosan hydrogels in glycosaminoglycan deposition and the production of collagen type II for nucleus pulposus engineering [55]. In addition, they have been used for the cryopreservation of MSCs avoiding minimizing the effects of freezing and thawing on stem cell viability [56], and various formulations of alginate such as oxidized alginate-gelatin [57], alginate/methylcellulose [58], and alginate-gelatin-carboxymethyl chitosan [59] have been found to be suitable for 3D printing applications.
Finally, it should be mentioned that there is a constantly increasing use of dynamic bioreactor cultures for the cultivation of alginate/MSC constructs. For example, dynamic perfusion bioreactor cultures of bone marrow MSCs in alginate hydrogels have been shown to enhance early in vitro osteogenic commitment and late osteogenesis [60, 61], and dynamic cultures incorporating compression forces have been used for chondrogenic differentiation purposes [62].
Despite the encouraging in vitro results, it needs to be noted that in vitro data do not necessarily correlate to the efficiency of hydrogels in vivo. As shown by Yang et al. who performed a direct in vitro-in vivo comparison of differentiation in alginate-gelatin hydrogels with MSCs, subcutaneous implantation in mice inhibits tri-lineage differentiation despite the efficient in vitro differentiation [63]. These results highlight the fact that caution is needed when extrapolating in vitro results to the in vivo setting.
3.2 In vivo paradigms of alginate/MSC constructs
Various types of alginate hydrogels have been shown to promote bone healing in animal models (Table 2). Injectable materials such as chitosan-alginate-BMP-2 and alginate-hydroxyapatite (HA)-mineralized microsphere combinations have been used in conjunction with MSCs to promote bone healing in vivo, demonstrating the efficient formation of trabecular bone [67, 68]. When used for bone tissue engineering, alginate hydrogels are usually seeded with MSCs and are allowed to gradually obtain higher mechanical stability as a result of ECM deposition and mineralization. However, tough alginate hydrogels have been also developed in order to achieve high mechanical stability which has been shown to promote bone healing [69]. Additionally, animal experiments have shown that when RGD is used for alginate modification, faster stress relaxation of alginate hydrogels [70] and high peptide density are linked to more efficient osteogenic differentiation than low peptide density which was linked to cell migration [71]. This correlates with results showing that increasing RGD concentrations inhibit chondrogenic differentiation in vitro [72]. Rottensteiner et al. utilized oxidized alginate-gelatin-nano-Bioglass hydrogels for bone regeneration identifying evidence of in vivo vascularization without adverse reactions, despite the cytotoxic action of Bioglass in vitro [73]. Additionally, Paul et al. successfully treated critical size calvarial defects with serum-loaded oxidized alginate-gelatin-biphasic calcium phosphate hydrogels with rat BM MSCs [74]. Importantly, encapsulation of MSCs in oxidized and natural alginate hydrogels increases vascularization which is of utmost importance in bone tissue engineering and the repair of vascular lesions [75] such as hind limb ischemia [76].
Representative in vivo studies combining alginate-based hydrogels with MSCs.
The ability of alginate hydrogels with MSCs to repair cartilage defects in animal models has been demonstrated in a variety of studies with various MSC types and hydrogel formulations. Chung et al. have compared a variety of hydrogel formulations including alginate, HA, chitosan, pluronic, and combinations of them seeded with umbilical cord blood MSCs. Their results demonstrated that even though alginate mixed with pluronic and chitosan achieved a certain degree of healing in rat knee cartilage defects, it was 4% hyaluronic acid which resulted in the optimal cartilage repair with macroscopic and microscopic appearance of adjacent healthy cartilage [77]. High-quality repair of in vivo rabbit cartilage defects has been shown with the use of bone marrow MSCs and natural alginate [78]. Alginate has been also combined with polylactic acid to promote in vivo cartilage repair with bone marrow MSCs [79]. In vivo cartilage differentiation in alginate hydrogels has been also attempted for the repair of tracheal tissue with the combination of adipose tissue MSCs and chondrocytes [80]. Synovial MSCs have also been co-cultured with chondrocytes transgenic for TGF-β3 in alginate hydrogels, demonstrating that TGF-β3 release can induce synovial MSC chondrogenesis [81]. The simultaneous activation of TGF-β3 and BMP-2 genes in MSC laden alginate hydrogels showed superior chondrogenesis compared to the isolated delivery of each one of the factors where cells progressed to endochondral osteogenesis instead of chondrogenesis [82]. Interestingly, alginate was found more capable in promoting endochondral osteogenesis than chondrogenesis when compared to chitosan [83]. Finally, TGF-β1-releasing alginate hydrogels have been used to promote chondrogenesis of MSCs, demonstrating in vitro increase of chondrogenic markers and healing of articular cartilage defects in mice [84].
Another important application of alginate/MSC constructs is the treatment of myocardial lesions. Yu et al. combined RGD-functionalized alginate hydrogels with human bone marrow MSCs showing that they could improve left ventricular function after myocardial infarction in a rat acute myocardial infarction model [85]. Cyclic RGD in alginate hydrogels has been also shown to promote neoangiogenesis and cardiac neovascularization, improving cardiac function in animals post-myocardial infarction [86]. Finally, when alginate hydrogels are used for cardiac regeneration, it has been shown that G-type alginates possess properties suited for the regeneration of cardiac tissue [87].
MSCs have been combined with alginate hydrogels for tendon repair purposes in animal model of tendon tears. For example, rat Achilles tendon lesions have been treated with hydrogels loaded with MSCs [88] showing healing of higher quality than surgical meshes and sutures. In addition, RGD-functionalized hydrogels loaded with TGF-β3 and loaded with periodontal and gingival MSCs were found to efficiently produce tendon tissue when implanted subcutaneously in mice [89].
Alginate hydrogels have also been widely utilized as wound dressings either alone or in combination with MSCs. For this application, various types of MSCs have been used including umbilical cord MSCs [90] and bone marrow MSCs in alginate-chitosan hydrogels with antibacterial properties [66].
Finally, alginate hydrogels have been used to protect MSCs from the local immune response elicited when allogeneic cells are implanted in vivo. They have been shown to provide protection from the immune system increasing the survival of MSCs in the hostile environment of the host-releasing immunomodulatory factors [91].
4. Conclusions
In conclusion, alginate/MSC constructs have been used for a wide variety of regenerative medicine applications, ranging from musculoskeletal to cardiac tissue repair. MSCs isolated from adult and fetal tissues have been combined with alginate hydrogels functionalized with extracellular matrix components, minerals, and other natural polymers and evaluated in vitro and in vivo. In vitro studies demonstrated the ability of alginate hydrogel at different formulations to support MSC growth and differentiation toward several lineages, whereas in vivo data have shown that when alginate-based materials are combined with MSCs, they can achieve successful healing of bone and cartilage defects, myocardial tissue after myocardial infarction, tendon tears, and skin wound. Nonetheless, evaluation of safety and efficacy of the constructs is required prior to clinical use. Existing in vitro and in vivo data demonstrate the potential of alginates to play an important future role in regenerative medicine, reaching the bedside and achieving regeneration of damaged tissues.
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"alginate, mesenchymal stem cells, MSCs, in vivo, in vitro, hydrogels",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/68082.pdf",chapterXML:"https://mts.intechopen.com/source/xml/68082.xml",downloadPdfUrl:"/chapter/pdf-download/68082",previewPdfUrl:"/chapter/pdf-preview/68082",totalDownloads:508,totalViews:0,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,dateSubmitted:"March 26th 2019",dateReviewed:"June 12th 2019",datePrePublished:"July 24th 2019",datePublished:"February 5th 2020",dateFinished:"July 12th 2019",readingETA:"0",abstract:"Alginate hydrogels have been widely used in stem cell cultures due to their biocompatibility, malleable nature, high water content, enhanced mass transport properties, and their functionalization with bioactive molecules providing cues that modulate cell proliferation and differentiation. Mesenchymal stem cells (MSCs) are extensively utilized in clinical cellular therapies because of their differentiation efficiency, their immunosuppressive properties, and them not being tumorigenic when implanted in vivo. MSCs are isolated from numerous fetal and adult tissues, suitable for both autologous and allogeneic applications. Consequently, alginate hydrogels/MSCs have been applied in vivo for the treatment of a wide variety of musculoskeletal, cardiac, neural, and endocrine disorders. This chapter will review the use of alginate hydrogels (physical properties and functionalization) for MSC culture in vitro (various culture systems) and the application of alginate/MSC implants (animal models and human applications) for cellular therapy purposes in vivo.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/68082",risUrl:"/chapter/ris/68082",book:{slug:"alginates-recent-uses-of-this-natural-polymer"},signatures:"Michail E. Klontzas, Hicham Drissi and Athanasios Mantalaris",authors:[{id:"299699",title:"Dr.",name:"Michail",middleName:null,surname:"Klontzas",fullName:"Michail Klontzas",slug:"michail-klontzas",email:"miklontzas@gmail.com",position:null,institution:null},{id:"300726",title:"Dr.",name:"Athanasios",middleName:null,surname:"Mantalaris",fullName:"Athanasios Mantalaris",slug:"athanasios-mantalaris",email:"sakis.mantalaris@gatech.edu",position:null,institution:null},{id:"300736",title:"Prof.",name:"Hicham",middleName:null,surname:"Drissi",fullName:"Hicham Drissi",slug:"hicham-drissi",email:"hicham.drissi@emory.edu",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Mesenchymal stem cells (MSCs) for tissue engineering",level:"1"},{id:"sec_3",title:"3. 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Wallace H. Coulter Department of Biomedical Engineering, Biomedical Systems Engineering Laboratory, Georgia Institute of Technology, USA
School of Medicine, Winship Cancer Institute, Emory University, USA
School of Medicine, Winship Cancer Institute, Emory University, USA
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1. Introduction
Thyroid cancer is the most frequent endocrine neoplasia. The National Cancer Institute estimated that there would be 44,670 new cases of thyroid cancer (TC) with 1690 deaths in 2010, and with an overall estimate of 56,870 new cases by 2017, and its incidence has been increasing in recent decades. Compared with other adult cancers, TC tends to occur in younger people between the ages of 20 and 60. It is three times more common in women than men [1] and has the fastest rising incidence rates in women and the second fastest in men with an annual percentage change of approximately 5%, making TC the sixth most common cancer in women [2]. There are four main types of which papillary and follicular (PTC, FTC) types together account for >90% followed by medullary thyroid cancers (MTC) with 3–5% and anaplastic carcinomas (ATC) making up <3% [3]. Reasons for this trend have been attributed to improvement in imaging (ultrasound technology) that is allowing the identification of ever smaller thyroid nodules. However, with this gain in detection, determining which benign nodules (adenomas) will progress to cancer cannot be determined on the basis of histology alone, underscoring the need for genetic markers of early detection for TC. Recently, epigenetic alterations have been shown to play a role in the development and progression of thyroid cancer.
With the deepening of tumor research, it has been gradually found that epigenetics plays an important role in the occurrence and development of tumors. Mechanisms of epigenetics include, but are not limited to, DNA methylation (methylating of ciliary carbon at position 5), posttranslation modification of histone, chromatin remodeling (structural change), gene imprinting, RNA interference (noncoding RNA or gene silencing), etc. The epigenetic mechanisms of tumor cells have lost a fine regulation, and the breakdown of epigenetic patterns will lead to tumor phenotype expression. These mechanisms have been reviewed elsewhere, and here we will focus on DNA methylation in thyroid cancer.
DNA methylation is an important epigenetic change, which is persistent and hereditary. The methylation of promoter CpG can regulate gene expression and maintain chromosome integrity and DNA recombination. Based on 789 samples from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases, the five-CpG signature could provide a novel biomarker with useful applications in thyroid cancer (PTC, FTC, ATC, and MTC) diagnosis and the diagnostic score formula on the condition of DNA methylation data [4]. However, the methylation pattern is unstable and can be reversed by small molecules and endogenous enzymes, leading to dedifferentiation and tumor heterogeneity. Abnormal DNA methylation, including a decrease in the overall methylation level of the genome, was accompanied by hypermethylation in some gene promoter regions. The hypermethylation of tumor suppressor gene promoter can reduce its expression, while the hypomethylation of tumor suppressor gene promoter can increase its expression, leading to tumorigenesis [5, 6, 7, 8]. The following will describe the state of aberrant DNA methylation in different thyroid cancers.
2. DNA methylation in PTC
RET/PTC rearrangement and mutations in Ras and BRAF genes often occur in papillary thyroid carcinoma (PTC) [9]. In addition, many methylation of cancer suppressor genes are associated with BRAF gene mutations, such as Ras-association domain family 1A (RASSF1A), solute carrier family 5 member 8 gene (SLC5A8), retinoic acid receptor β2 (RARβ2), tissue inhibitor of metalloproteinase3 (TIMP3), phosphatase and tensin homolog deleted on chromosome ten (PTEN), metallothionein 1G (MT1G), ataxia-telangiectasia mutated (ATM), E-cadherin (ECAD), death-associated protein kinase (DAPK), multiple tumor suppressor 1 (MTS1 or P16), and mut-L homolog 1 (MLH1). Mutations of TSHR gene are not common in thyroid cancer, but high methylation and low expression of TSHR gene often occur. Recent studies have found that thyroid-specific genes (thyroid-stimulating hormone receptor and sodium/iodide symporter (TSHR and NIS), thyroid transcription factor-1 (TTF-1)) play an important role in occurrence and development of PTC. This part summarizes the related research on methylation genes in PTC in recent years (see Table 1).
Sample sources
Main method
Related gene
Methylation (high/low)
Related gene expression (high/low)
BRAF mutation (+/−)
Cell pathway
Function
References
Tumor suppressor genes
Patient tissue, normal people tissue
Western blotting analyses, RT-QPCR, fluorescent analysis
2.1 DNA methylation of cancer suppressor genes in PTC
2.1.1 Ras association domain family 1 (RASSF1A)
RASSF1A is a member of Ras superfamily, which is located at chromosome 3 (exactly on 3p21.3). Hypermethylation of CpG islands in the RASSF1A promoter region contributes to epigenetic inactivation. It is a tumor suppressor gene widely expressed in various normal organs but is often deleted in tumors. It is speculated that BRAFV600E gene mutation in PTC regulated the RASSF1A-MST1-FoxO3 signaling pathway, which led to RASSF1A hypomethylation and affected the malignant degree of thyroid cancer. It is found that the methylation rate of RASSF1A in thyroid cancer is 15–75% [10]. Studies indicated RASSF1A methylation differed in PTC compared with normal thyroid and was correlated with extracapsular invasion inversely. It suggested that RASSF1A has a potential role as a molecular marker for characterization of PTC histopathology [11, 12, 13, 14, 15]. It is shown that hypermethylation of RASSF1A promoter region is 20–32% in PTC. Hypermethylation of RASSF1A in PTC was related to the multifocal and extracapsular invasion of tumors [16].
2.1.2 Solute carrier gene family 5A, member 8 (SLC5A8)
SLC5A8 is a passive iodine transporter located in the parietal membrane of thyroid follicular cells. SLC5A8 is not regulated by thyrotropin in normal thyroid tissues but methylated in thyroid tumors. Hypermethylation often occurred in the first exon of CpG islands in SLC5A8, which results in gene silencing and restoring expression inhibiting cancer cell growth. It has been pointed out that SLC5A8 was an anti-oncogene of colon cancer [17]. SLC5A8 was also frequently hypermethylated in thyroid cancer. Its function is unclear nowadays, but its hypermethylation might play a key role in the occurrence of thyroid cancer [18]. Studies revealed that SLC5A8 gene was highly methylated in typical PTC (90%) and only 20% in other types of PTC. In addition, low expression of SLC5A8 was also associated with BRAF T1796A, suggesting that SLC5A8 methylation may be important in MAPK pathway [19].
2.1.3 Retinoic acid receptor beta2
RARβ2 is a type of nuclear receptor that is activated by both all-trans retinoic acid and 9-cis retinoic acid, which has been shown to function as a tumor suppressor gene in different types of human tumors. It has been found that RARβ2 expression was decreased or deleted in tumors. It meant that RARβ2 inactivation was related to tumorigenesis. In the treatment of metastasis and recurrence of thyroid cancer, retinoic acid therapy could restore the iodine uptake ability of metastasis and then improved the efficacy of 131-I radiotherapy. Researches indicated that the methylation rate of RARβ2 in thyroid cancer was 14%, higher than that in normal thyroid tissues (7%). RARβ2 gene methylation was associated with BRAF gene mutation in Wnt/beta catenin pathway [20]. Studies found there was RARβ2 gene hypermethylation in thyroid cancer cell lines. And after treatment with 5-azacytidine, RARβ2 expression was significantly increased, and the growth of tumors was inhibited, while the inhibition still existed after removing 5-azacytidine. RARβ2 gene methylation took part in tumorigenesis and development in PTC [21].
2.1.4 Tissue inhibitor of metalloproteinases-3 (TIMP3)
TIMP3 can bind to matrix metalloproteinases (MMPs), inhibiting the activity of MMPs effectively [20, 22]. Methylation of TIMP3 promoter has been demonstrated in many malignant tumors. It is often associated with growth, invasion, and lymph node metastasis of malignant tumors. It is pointed out that BRAF mutation caused low expression of TIMP3 in PTC, which could cause invasion and progression of tumors. It was found that 38% of TIMP3 are hypermethylated in PTC [23].
2.1.5 Phosphatase and tensin homolog deleted on chromosome 10 (PTEN)
The PTEN gene is located on chromosome 10 (especially on the region of 10q23), which could encode a specific phosphatidylinositol triphosphate 3 dephosphorylation and inhibit the activation of PI3K/Akt signaling pathway. PTEN expression alteration is crucial to the pathogenesis of cancer and other diseases. Low level of PTEN caused by homozygous deletions, frameshift, nonsense mutations or hypermethylation, or PTEN protein destability occurs frequently in various human cancers [24, 25]. It was shown that PTEN gene expression was low in thyroid cancer. One study found the methylation status of PTEN in FA, FTC, and PTC. The results indicated that PTEN methylation level was gradually increased in PTC (45.7%), FA (83.3%), and FTC (85.7%). PTEN methylation was related to mutations genes in PI3K/Akt signaling pathway, such as PIK3CA and Ras genes, suggesting that PTEN methylation and PI3K/Akt signaling pathway played an important role in the process of occurrence and development in PTC [26].
2.1.6 Metallothionein 1G (MT1G)
MT1G, a member of the metallothionein family, is a highly conserved cysteine-rich small molecule, which is mainly involved in metal-related transport. MT1G exists in normal cells; it can regulate and maintain intracellular metal ion balance, cell proliferation, and apoptosis. MT1G promoter methylation is associated with decreasing gene expression, but not complete abrogation. Studies have shown that MT1G gene has abnormal methylation in thyroid cancer, liver cancer, colon cancer, and prostate cancer. It is confirmed that restoring MT1G gene expression could inhibit tumors growth in vivo and in vitro, suggesting that MT1G gene has anticancer effect [27]. It is shown that MT1G gene was abnormally methylated in thyroid cancer (30.3% in malignant tumors and 18.8% in benign tumors). Its expression was significantly decreased, and that methylation of MT1G gene was associated with its low expression. Further studies suggested that restoring MT1G gene expression could inhibit the growth and infiltration of PTC and induced cell cycle inhibition and apoptosis. The mechanism may inhibit PI3K/AKT pathway. In addition, hypermethylation of MT1G was also associated with lymph node metastasis [28].
2.1.7 Ataxia-telangiectasia mutated
ATM belongs to the PI3/PI4 enzyme family. Although there is emerging evidence for a role of ATM in promoting tumorigenesis, ATM signaling provides a barrier to activated oncogenes and tumor progression, rather than promoting cancer early in tumorigenesis. ATM is ubiquitous in human and other higher animal tissues and cells, such as testicular tissue. And a study showed that ATM was hypermethylated in PTC (50%) and 0% in normal thyroid tissue [29].
2.1.8 E-cadherin
ECAD is a family of transmembrane glycoproteins responsible for calcium-dependent cell adhesion. It is the key structural components of adherens junctions. It is reported that ECAD may also act as a gene transcriptional regulator. Two main mechanisms including hypermethylation of the promoter and microRNA imbalance have been widely studied under the ECAD regulation in head and neck tumors. The methylation of ECAD promoter region was accounted for 39.3% in PTC, and ECAD expression decreased in the early stage of tumorigenesis. The experiment data showed that methylation level of ECAD in thyroid cancer increased to 56% (18/32) and 0% (0/27) in normal thyroid tissue. Further studies found that there was no significant correlation between ECAD methylation and T stage of lymph node metastasis in thyroid cancer. After 2.6 years of follow-up, the recurrence of thyroid cancer associated with ECAD methylation has no correlation [8].
2.1.9 Death-associated protein kinase
DAPK is a calmodulin-regulated ATK, which has an important role in the process of apoptosis. DAPK mechanism is largely due to promoter hypermethylation, leading to gene silencing. DAPK is ubiquitous in normal tissues. When the promoter of DAPK is methylated, it will cause an abnormal gene expression. Abnormal expression of DAPK can hinder the normal process of apoptosis and bring about tumorigenesis. And its low expression or deletion is one of the important mechanisms of cell carcinogenesis. It has been found that methylation of CpG island in the promoter region in DAPK is an important reason for expression silencing. The loss of DAPK protein in sporadic colorectal cancer is caused by the promoter hypermethylation. It existed in very small tumors. Therefore, the loss of DAPK gene plays an important role in the early stage of tumor formation. It is reported that DAPK promoter methylation accounts for 51% in PTC and abnormal methylation and DAPK gene silencing existed in many kinds of cancer cells [30]. It is pointed out that the high methylation level of DAPK gene was associated with tumor size and multiple lesions [31].
2.1.10 Multiple tumor suppressor 1 (MTS1 or P16)
MTS1 is hereafter called p16. It is an anti-oncogene in many tumors. The 5′-CpG fragment in the promoter region of P16 gene is the most susceptible to methylation, inhibiting its expression products. Abnormal expression of P16 gene can over-activate cyclin-dependent protein kinase 4 and stimulate abnormal cell proliferation, leading to tumorigenesis. Aberrant methylation of promoter region in P16 gene is the main cause for P16 gene inactivation [32]. Some scholars reported that the P16 gene was hypermethylated (35.9%) in PTC [33].
2.1.11 Mut-L homolog 1
MLH1 is one of the DNA mismatch repair genes located on the 3p21 region in chromosome 3. A correlation between MLH1 promoter methylation, specifically the ‘C’ region stops in MLH1 protein formation, can prevent the normal activation of DNA repair gene. Low expression of MLH1 gene was associated with BRAFV600E mutation and RET/PTC rearrangement. Hypermethylation of MLH1 promoter was found in colon cancer as well. A study indicated that abnormal methylation of MLH1 was significantly correlated with lymph node metastasis of PTC, suggesting that MLH1 might be a molecular marker of lymph node metastasis in PTC [34]. Another study found that there were abnormal methylation and low expression of MLH1 in thyroid cancer and MLH1 expression is associated with BRAF, IDH1, and NRAS gene mutations [35].
2.2 DNA methylation of thyroid-specific genes in PTC
2.2.1 Thyroid-stimulating hormone receptor and sodium/iodide symporter
On the other hand, methylation of thyroid-specific genes is also one of the causes for occurrence and development of PTC. Thyroid-specific genes mainly include TSHR, NIS, thyroglobulin (Tg), and thyroid peroxidase (TPO), which participate in thyroid iodine uptake and maintenance of normal thyroid function. Under normal conditions, TSH stimulates TSHR on thyroid follicular epithelial cells and activates NIS to ingest iodine into cells. TSH is produced by the pituitary thyrotrophs and stimulates thyroid functions using TSHR. The iodine ingested synthesizes thyroid hormones catalyzed by TPO and is stored in Tg. It is found that abnormal expression of these molecules is related to iodine metabolism in PTC. Studies have shown that the expression of TSHR, NIS, Tg, and TPO with BRAF mutated in thyroid cancer is decreased [36]. In PTC, both TSHR and NIS are abnormally methylated, and their expression is decreased. Low expression of TSHR and NIS may be related to the occurrence and development of tumors. It also reduces the uptake of iodine capacity in tumor cells. Scholars found TSHR and NIS become an important cause for PTC in 131-I radiotherapy [37, 38]. In human and rabbit thyroid cancer cells, BRAFV600E mutant, a carcinogenic homolog of murine sarcomatous virulent bacterium, could cause activation of BRAF/MEK/MAPK signaling pathway and expression silencing of thyroid-specific genes including TPO, Tg, TSHR, and NIS. At last, it resulted in the reduction of iodine uptake in PTC.
2.2.2 Thyroid transcription factor-1
TTF-1 is known as thyroid-specific enhancer-binding protein (T/EBP). It is a transcription factor with homologous domains in the thyroid, lung, and central nervous system. TTF-1 gene is located in region 14q13.3 on chromosome 14. It is comprised of three exons and two introns. Under physiological conditions, TTF-1 is stable positive in thyroid tissue. TTF-1 can regulate the expression of thyroid-related genes such as TG, TPO, TSHR, and NIS. Thus it acts a pivotal part in regulating growth, development, and function of thyroid. It showed hNIS mRNA expression loss might be related to methylation of thyroid-specific transcription factor genes. Abnormal methylation caused loss of transcription factor expression with indirect loss of hNIS mRNA expression through the KAT-5 and KAT-10 responses to 5-azacytidine treatment with acquisition of parallel TTF-1 and hNIS mRNA expression. It was found that insufficient expression of TTF-1 and Pax-8 may result in the decrease of activity of thyroglobulin gene promoter in thyroid cancer cells. Some confirmed that TTF-1 gene was expressed lowly in thyroid cancer [39]. Other researchers studied the methylation status of TTF-1 in thyroid cancer and found that TTF-1 gene was highly methylated and lowly expressed in thyroid cancer cell lines, but not in normal thyroid [40].
2.3 DNA methylation of oncogene gene in PTC
At present, BRAF gene mutation has been found in melanoma, ovarian serous tumor, colorectal cancer, glioma, liver cancer, and leukemia. A large number of studies also showed that BRAF gene mutation in PTC is closely related to methylation of tumor suppressor. BRAF gene is an important transducer for Ras/Raf/MEK/ERK/MAPK pathways. About 90% of T1799A point mutation in BRAFV600E happen in PTC, which can increase BRAF activity. The BRAF gene plays its biological role by activating MEK/ERK signaling pathway. The result showed that PTC with BRAF gene mutation had strong tissue invasiveness and was easy to infiltrate tissues around thyroid gland [41]. Methylation of TIMP3 gene, SLC5A8 gene, and DAPK gene, which are tumor suppressor genes, are related to BRAF gene mutation and PTC invasion. The overexpression of BRAFV600E gene could lead to silencing of some thyroid-specific genes (like NIS, TG, TPO) in the activation state of BRAF/MEK/MAPK pathway. It could cause iodine uptake activity decrease and ineffectiveness of radioiodine therapy. Therefore, it could affect thyroid cancer progression.
2.4 Other potentially aberrant methylation genes in PTC
In recent years, DNA methylation has become a new research hotspot. Many genes have been studied as potential abnormal methylation sites, including Ras association domain family 2 (RASSF2), Ras-association domain family 10 (RASSF10), disheveled-binding antagonist of beta-catenin 2 (DACT2), retinoblastoma protein-interacting zinc finger gene 1 (RIZ1), 14-3-3 protein family (14-3-3 sigma), and other signaling pathways such as JAK-STAT pathway, NF-kappa B pathway, HIF1 alpha pathway, and Notch pathway in thyroid cancer [42, 43, 44, 45]. However, there are relatively few reports on these genes and pathways in thyroid cancer. Most of the mechanisms are not clear at present and need further study.
3. DNA methylation in FTC
DNA methylation analysis revealed 2130 and 19 differentially methylated CpGs in PTC and follicular thyroid carcinoma (FTC), respectively [46]. Aberrant DNA methylation of tumor suppressor genes is common in FTC and ATC. Certain specific tumor suppressor genes are mainly PTEN, RASSF1A, Rap1-GTPase activating protein, and thyroid-specific gene TRSH in FTC. This part summarizes the related research on methylation genes in FTC in recent years (see Table 2).
3.1 DNA methylation of tumor suppressor genes in FTC
3.1.1 PTEN
PTEN negatively regulates AKT/PKB signaling pathway. It is involved in regulation of cell cycle, cell growth inhibition, and rapid division [47]. Aberrant DNA methylation in this gene is also mostly reported in FTC. It confirmed that PTEN promoter hypermethylation was detected in six of seven (85%) FTC and five of six (83.3%) follicular adenomas. The results showed a high frequency of PTEN promoter hypermethylation, especially in follicular tumors. It means that it has a possible role in thyroid cancer [25]. Studies found methylation status of PTEN in FA and FTC. And PTEN methylation level was gradually increased in FA (83.3%) and FTC (85.7%). Authors have shown that methylation of PTEN promoter plays an important role in FTC [48].
3.1.2 RASSF1A
Differential expression of RASSF1A gene is related to occurrence of thyroid cancer. Aberrant DNA methylation is an important mechanism of RASSF1A gene inactivation. Studies found 44% benign adenomas, 75% follicular thyroid cancers tumors, and 20% PTC tumors harbored promoter methylation in greater than or equal to 25% of RASSF1A alleles by real-time quantitative methylation-specific PCR [39, 40, 41, 42]. Methylation frequency was higher in invasive thyroid cancer. It was found to be 70% of the RASSF1A methylation rate in FTC, 80% in MTC, and 78% in UTC compared with benign PTC [14]. Inactivation of RASSF1A in different stages of thyroid cancer was detected by tumor metastasis classification, and compared with FTC, only a small part of RASSF1A methylation in PTC is abnormal. These studies indicated follicular cell-derived thyroid tumorigenesis may be an early step [15, 49].
3.1.3 Rap1-GTPase-activating protein
RAP1GAP gene encodes a type of GTPase-activating protein that downregulates Ras-related protein activity. Ras oncoproteins are very important for both development and maintenance of many tumor types. RAP1GAP is involved in the regulation of mitosis and carcinogenesis in thyroid cells. Researchers aimed to determine the global patterns of aberrant DNA methylation in thyroid cancer using DNA methylation arrays [50]. And the study identified 262 and 352 hypermethylated and 13 and 21 hypomethylated genes in PTC and FTC, respectively. In addition, 86 and 131 hypermethylated genes were identified. Among these genes, four potential oncogenes (INSL4, DPPA2, TCL1B, and NOTCH4) were frequently regulated by aberrant methylation in primary thyroid tumors [51].
3.1.4 Mammary serine protease inhibitor (Maspin)
Besides, a member of the serine protease inhibitor superfamily named Maspin is a unique tumor suppressor gene encoding SERPINB5 gene. Epigenetic changes of Maspin expression occurred in the 5′ regulatory region of Maspin gene and involved cytosine methylation, histone deacetylation, and chromatin accessibility. The epigenetic deregulation frequently participates in tumorigenesis by inactivation of tumor suppressor genes. The association of promoter hypermethylation and gene silencing is an established oncogenic process in cancer. Promoter methylation of Maspin gene could lead to gene silencing in thyroid cancer, breast cancer, skin cancer, and colon cancer. Studies have indicated that overexpression of Maspin in gastric cancer, pancreatic cancer, and ovarian cancers resulted from CpG promoter of Maspin demethylation. A study detected DNA methylation status in Maspin promoter region, indicating that overexpression of the gene was the result of DNA hypomethylation [52]. It was closely related to the morphological dedifferentiation of thyroid cancer. Another study found 100% Maspin hypermethylation was closely associated with morphological dedifferentiation in thyroid cancers [52, 53].
3.2 DNA methylation of thyroid-specific genes in FTC
In addition to tumor suppressor genes and oncogenes, hypermethylation could lead to NIS and TSHR gene silencing in FTC, too. NIS methylation is of great significance in treatment of thyroid cancer. Therefore, abnormal methylation of these genes may be the pathogenesis or progression factor in FTC [54, 55]. Aberrant promoter methylation was examined in 24 tumor suppressor genes using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) assay and methylation-specific PCR (MSP). In thyroid cancers, CASP8 (caspase-8), RASSF1, and NIS were methylated in 9/13, 10/13, and 7/13, respectively [56]. Some researches also found combination gene panels TPO and UCHL1 (ROC = 0.607, sensitivity 78%) discriminated FTC from FA and RASSF1 and TPO (ROC = 0.881, sensitivity 78%) discriminated FTC from normal. Methylation of TSHR distinguished PTC from FTC (ROC = 0.701, sensitivity 84%) and PTC from FA (ROC = 0.685, sensitivity 70%) [57]. And the six-gene panel of TIMP3, RARβ2, SERPINB5, RASSF1, TPO, and TSHR, which differentiates PTC from normal thyroid, had the best combination sensitivity (91%) and specificity (81%) of the panels addressing discrimination of cancer tissue by quantitative methylation-specific polymerase chain reaction (QMSP) in a retrospective cohort of 329 patients [58, 59].
3.3 Other abnormal methylation genes in FTC
Nowadays, there are a few studies on methylation of FTC genes. However, many genes still have been studied as potential abnormal methylation sites in FTC. For example, one of the ZIC families called ZIC1 (C2H2-type zinc finger proteins) is frequently hypermethylated in FTCs [60]. Moreover, 3564 differentially methylated CpGs (DMCpG) were detected in FTC and 84% hypermethylated with respect to normal controls. It is suggested that perturbed DNA methylation, in particular hypermethylation, is a component of the molecular mechanisms leading to FTC formation and that DNA methylation profiling might help in differentiating FTCs from their benign counterpart [61]. Also, others identified the presence of RASAL1 mutations, with a prevalence of 4.88% (n = 2 of 41) in FTC and 16.67% (n = 5 of 30) in ATC [62]. Studies found a more detailed analysis showing that 53.9% of the hypermethylated and 81.5% of the hypomethylated CpG sites identified in differentiated primary tumors (PTCs and FTCs) were also present in differentiated thyroid carcinoma-derived cancer cell [61]. Aside from that, COL4A2 was hypermethylated in 56% of the FTC samples by array measurement in the discovery series [57, 63]. Another study indicated that RASSF10 was frequently hypermethylated in thyroid cancer. It showed 50% of methylation frequency of RASSF10 in FTC and the highest (100%) in MTCs [64].
4. DNA methylation in ATC
Promoter methylation of PTEN is also common in anaplastic thyroid cancer (ATC) [65]. PTEN methylation is related to gene changes of PI3K Akt pathway in thyroid tumors, including PTEN mutations, various subtypes of Ras mutations, PIK3CA mutations, and amplification [66, 67]. One study analyzed 24 genetic alterations in the major genes of MAPK and PI3K-AKT pathways in 48 ATC samples and found that the majority of (81%) samples that harbored genetic alterations could be likely activated in both pathways [68]. Accordingly, another DNA methylation pan-cancer study focused on promoters found that thyroid carcinoma exhibited one of the lowest frequencies in both hypomethylation and hypermethylation events. And ATC exhibits a high frequency of DNA methylation alterations (tenfold higher than PTC) [69, 70]. A recent pan-cancer analysis on whole exome sequencing revealed that the mutation frequency in PTC was one of the lowest (approximately 1 change/Mb across the entire exome) among solid tumors, while the mutation frequency in ATC was at the opposite extreme and was closer to that in melanoma and lung cancer, exceeding 100 changes/Mb [71, 72].
In addition, solute carrier family 26, member 4 (SLC26A4) gene, encodes a transmembrane protein named pendrin with up to 15 predicted membrane spanning domains and affects the flow of iodine into follicular lumen. The following were reported: 71% of ATC, 44% of benign tumors, 46% of FTC, and 71% of PTC, with abnormal SLC26A4 gene methylation in 64 cases of primary thyroid tumors and 6 cases of thyroid tumor cell lines [18, 73]. In addition, 81.5% of hypermethylated genes and 89% of hypomethylated genes were also present in nondifferentiated primary tumors (MTCs and ATCs) and nondifferentiated thyroid carcinoma-derived cancer cell lines [74], while Ras protein activator like-1 gene (RASAL1) displayed MAPK- and PI3K-suppressing and thyroid tumor-suppressing activities, which can be impaired by the mutations. Hypermethylation and mutations of RASAL1 were found in 33.33% (n = 10 of 30) of ATCs and in 0 of 20 (0%) of benign thyroid tumors [62]. However, ATC showed more hypomethylation than hypermethylation events, indicating that hypomethylation is related to dedifferentiation [70]. The authors validated four genes (NOTCH4 and TCL1B in ATCs, INSL4 and DPPA2 in MTCs) that become aberrantly hypomethylated in nondifferentiated thyroid tumors. All of them have been proposed to have an oncogenic role in cancer. And NOTCH4 (a member of the Notch family of transmembrane receptors) is frequently overexpressed in thyroid tumors [75, 76].
This part summarizes the related research on methylation genes in ATC in recent years (see Table 3).
Medullary thyroid cancer is a neuroendocrine tumor originating from parafollicular C cells, and it is highly resistant to chemo- and radiotherapy [77]. Spry1 is a candidate tumor-suppressor gene in MTC. The hyper-activation of PI3K/Akt/mTOR cascade has a relevant role in the pathogenesis and progression of MTC. In fact, most of pro-oncogenic effects of RET and Ras mutations are modulated by the activation of PI3K/Akt/mTOR pathway [78, 79]. For patients with metastatic disease, standard treatment modalities include local treatments (radiofrequency ablation, radiation therapy, embolization) and systemic treatment chemotherapy and more recently tyrosine kinase inhibitors (TKIs) targeting RET protein. As experience has been limited to case reports or case series, response rates (RR) ranged from 0 to 25% for periods of up to a few months. In nondifferentiated thyroid tumors, INSL4 and DPPA2 become aberrantly hypomethylated, both of which have been proposed to have an oncogenic role in MTC.
5.1 Sprouty1 (Spry1)
Sprouty (Spry) family of genes is composed of four members in mammals (Spry1–4). The Spry1 promoter is frequently methylated in MTC, and that Spry1 expression is consequently decreased. These findings identify Spry1 as a candidate tumor-suppressor gene in MTC. In mammals, the situation is more complicated as Spry proteins have been shown to be activators or inhibitors of receptor tyrosine kinase signaling depending on the cellular context or the receptor tyrosine kinase analyzed [80, 81]. Spry family members have been proposed to function as tumor-suppressor genes in a growing list of cancerous malignancies, including prostate and hepatocellular carcinoma, B-cell lymphoma, or neuroblastoma [82]. Finally, the authors found that SPRY1 promoter is frequently methylated and its expression decreased in human MTC. The mRNA levels of Spry1 are detected in murine C cells of thyroid with real-time RT-PCR. In situ hybridization showed expression of Spry1 mRNA in the fourth pharyngeal pouch, where thyroid C-cells originate and beta-galactosidase staining of thyroids from 1-month-old Spry1LacZ/þ mice. One study used the hypomethylating agent 5′-aza-deoxycytidine (5′-Aza-dC) to confirm a causal relationship between promoter methylation and Spry1 expression [83]. As expected, TT cells treated with 5′-aza-dC showed an increase of approximately sixfold in the levels of Spry1 mRNA when compared to vehicle-treated cells. 5′-Aza-deoxycytidine (AZA), a demethylating agent, is in combination with the mTOR inhibitor everolimus in MTC cells (MZ-CRC-1 and TT). An innovative bioinformatic pipeline identified four potential molecular pathways implicated in the synergy between AZA and everolimus: PI3K-Akt signaling, the neurotrophin pathway, ECM-receptor interaction, and focal adhesion. Among these, the neurotrophin signaling pathway was most directly involved in apoptosis, through NGFR and Bax gene overexpression. Increased expression of genes involved in the NGFR-MAPK10-TP53-Bax/Bcl2 pathway during incubation with AZA plus everolimus was validated by western blotting in MZ-CRC-1 cells [84].
5.2 Insulin-like 4 (INSL4)
INSL4 (pro-EPIL) belongs to the insulin and insulin-like growth factor family and is expressed strongly during the first trimester of pregnancy by the differentiated syncytiotrophoblast [85]. It has been shown to be overexpressed in breast tumors with an aggressive phenotype [86], but the underlying mechanisms are still unknown. The aberrant overexpression of INSL4 in breast tumors, together with the aberrant promoter hypomethylation reported in this study, suggests that promoter demethylation might be a frequent mechanism of activation of INSL4 oncogene activation in cancer.
DPPA2 is expressed early in the embryo’s development [87] but also in some tumor types [88]. Although the underlying molecular mechanism has not been reported yet, the authors’ data indicated that promoter hypomethylation might play an important role. The frequent promoter hypomethylation observed in nondifferentiated tumors might be relevant for treatment with demethylating drugs [51, 88].
6. Conclusion
More and more researches have realized that the occurrence of tumors is not only entirely determined by genes but also epigenetics. The changes of epigenetics in thyroid cancer are mainly manifested in the aberrant methylation of tumor suppressor genes and thyroid-related genes. Numerous studies on DNA methylation in thyroid cancer have improved our understanding of thyroid carcinogenesis. Some of the recent findings, including the huge catalog of DNA methylation alterations, the association of DNA hypomethylation with cancer progression and dedifferentiation, the existence of different methylomes related to different clinical and molecular phenotypes, and the influence of immune-infiltrating cells in tumor DNA methylation patterns, are most likely to lead the direction of future research in the field of DNA methylation in thyroid cancer. A large number of studies confirmed the importance of DNA methylation as a source of novel biomarkers for early diagnosis, therapeutic perspective, and prognosis evaluation in thyroid cancer. In addition, the design of specific target demethylation drugs, which reactivate the function of tumor suppressor genes, is expected to become a new scheme for cancer treatment. Therefore, further functional experiments in vitro and in vivo are necessary for better understanding of the meaning and potential mechanism of DNA methylation changes in thyroid cancer as well as the evaluation of candidate biomarkers through case-control studies and prospective trials.
\n',keywords:"thyroid carcinoma, DNA methylation, epigenetic inheritance, tumor suppressor genes, oncogene genes, thyroid-specific genes",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/71481.pdf",chapterXML:"https://mts.intechopen.com/source/xml/71481.xml",downloadPdfUrl:"/chapter/pdf-download/71481",previewPdfUrl:"/chapter/pdf-preview/71481",totalDownloads:352,totalViews:0,totalCrossrefCites:0,dateSubmitted:"August 12th 2019",dateReviewed:"January 8th 2020",datePrePublished:"March 18th 2020",datePublished:"July 1st 2020",dateFinished:"March 18th 2020",readingETA:"0",abstract:"We have summarized increasing data from all kinds of experiment results of papers in recent years, which are associated with tumor suppressor genes, oncogenes, and thyroid-specific genes and attempt to elucidate the importance of epigenetic modifications and the mechanisms of aberrant DNA methylation in thyroid cancer in this review. The results showed that current articles have revealed the importance of epigenetic modifications and the different types of mechanisms in thyroid cancer. The mechanisms of DNA methylation related to thyroid cancer demonstrate that acquired epigenetic abnormalities together with genetic changes play an important role in alteration of gene expression patterns. Aberrant DNA methylation has been well known in the CpG regions. Among the genes identified, we have shown the status of DNA promoter methylation in papillary, follicular, medullary, and anaplastic thyroid cancer. It suggested that thyroid cancer subtypes present differential promoter methylation signatures, which will encourage potential thyroid cancer detection in its early stages, assessment of prognosis, and targeted cancer treatment.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/71481",risUrl:"/chapter/ris/71481",signatures:"Zhu Gaohong and Xie Lijun",book:{id:"8176",title:"DNA Methylation Mechanism",subtitle:null,fullTitle:"DNA Methylation Mechanism",slug:"dna-methylation-mechanism",publishedDate:"July 1st 2020",bookSignature:"Metin Budak and Mustafa Yıldız",coverURL:"https://cdn.intechopen.com/books/images_new/8176.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"226275",title:"Ph.D.",name:"Metin",middleName:null,surname:"Budak",slug:"metin-budak",fullName:"Metin Budak"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. DNA methylation in PTC",level:"1"},{id:"sec_2_2",title:"2.1 DNA methylation of cancer suppressor genes in PTC",level:"2"},{id:"sec_2_3",title:"2.1.1 Ras association domain family 1 (RASSF1A)",level:"3"},{id:"sec_3_3",title:"2.1.2 Solute carrier gene family 5A, member 8 (SLC5A8)",level:"3"},{id:"sec_4_3",title:"2.1.3 Retinoic acid receptor beta2",level:"3"},{id:"sec_5_3",title:"2.1.4 Tissue inhibitor of metalloproteinases-3 (TIMP3)",level:"3"},{id:"sec_6_3",title:"2.1.5 Phosphatase and tensin homolog deleted on chromosome 10 (PTEN)",level:"3"},{id:"sec_7_3",title:"2.1.6 Metallothionein 1G (MT1G)",level:"3"},{id:"sec_8_3",title:"2.1.7 Ataxia-telangiectasia mutated",level:"3"},{id:"sec_9_3",title:"2.1.8 E-cadherin",level:"3"},{id:"sec_10_3",title:"2.1.9 Death-associated protein kinase",level:"3"},{id:"sec_11_3",title:"2.1.10 Multiple tumor suppressor 1 (MTS1 or P16)",level:"3"},{id:"sec_12_3",title:"2.1.11 Mut-L homolog 1",level:"3"},{id:"sec_14_2",title:"2.2 DNA methylation of thyroid-specific genes in PTC",level:"2"},{id:"sec_14_3",title:"2.2.1 Thyroid-stimulating hormone receptor and sodium/iodide symporter",level:"3"},{id:"sec_15_3",title:"2.2.2 Thyroid transcription factor-1",level:"3"},{id:"sec_17_2",title:"2.3 DNA methylation of oncogene gene in PTC",level:"2"},{id:"sec_18_2",title:"2.4 Other potentially aberrant methylation genes in PTC",level:"2"},{id:"sec_20",title:"3. DNA methylation in FTC",level:"1"},{id:"sec_20_2",title:"3.1 DNA methylation of tumor suppressor genes in FTC",level:"2"},{id:"sec_20_3",title:"3.1.1 PTEN",level:"3"},{id:"sec_21_3",title:"3.1.2 RASSF1A",level:"3"},{id:"sec_22_3",title:"3.1.3 Rap1-GTPase-activating protein",level:"3"},{id:"sec_23_3",title:"3.1.4 Mammary serine protease inhibitor (Maspin)",level:"3"},{id:"sec_25_2",title:"3.2 DNA methylation of thyroid-specific genes in FTC",level:"2"},{id:"sec_26_2",title:"3.3 Other abnormal methylation genes in FTC",level:"2"},{id:"sec_28",title:"4. DNA methylation in ATC",level:"1"},{id:"sec_29",title:"5. DNA methylation in MTC",level:"1"},{id:"sec_29_2",title:"5.1 Sprouty1 (Spry1)",level:"2"},{id:"sec_30_2",title:"5.2 Insulin-like 4 (INSL4)",level:"2"},{id:"sec_31_2",title:"5.3 Developmental pluripotency-associated 2 (DPPA2)",level:"2"},{id:"sec_33",title:"6. 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DOI: 10.1677/JOE-09-0110'},{id:"B81",body:'Cerrato A, De Falco V, Santoro M. Molecular genetics of medullary thyroid carcinoma: The quest for novel therapeutic targets. Journal of Molecular Endocrinology. 2009;43(4):143-155. DOI: 10.1677/JME-09-0024'},{id:"B82",body:'Ishida M, Ichihara M, Mii S, Jijiwa M, Asai N, Enomoto A, et al. Sprouty2 regulates growth and differentiation of human neuroblastoma cells through RET tyrosine kinase. Cancer Science. 2007;98(6):815-821. DOI: 10.1111/j.1349-7006.2007.00457.x'},{id:"B83",body:'Macià A, Gallel P, Vaquero M, Gou-Fabregas M, Santacana M, Robledo AMM, et al. Sprouty1 is a candidate tumor-suppressor gene in medullary thyroid carcinoma. Oncogene. 2012;31(35):3961-3972. DOI: 10.1038/onc.2011.556'},{id:"B84",body:'Vitale G, Dicitore A, Pepe D, Gentilini D, Grassi ES, Borghi MO, et al. Synergistic activity of everolimus and 5-aza-2′-deoxycytidine in medullary thyroid carcinoma cell lines. Molecular Oncology. 2017;11(8):1007-1022. 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Department of Nuclear Medicine, First Affiliated Hospital of Kunming Medical University, Kunming, China
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Open Access Funding
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To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at oapf@intechopen.com for further details or assistance.
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For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
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Visibility on the world's strongest OA platform
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