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Cytokeratins 14 and 19 in Odontogenic Cytokeratins 14 and 19 in odontogenic cysts and tumors: a review Nieves Sabrina*, Apellaniz Delmira*, Tapia Gabriel**, Maglia Alvaro***, Mosqueda-Taylor Adalberto****, Bologna-Molina Ronell*****. Abstract All mammal cells include a cytoplasmic fiber system essential for cell mobility, the cytoskeleton, formed by three main structural units and associated proteins: microfilaments, microtubules and intermediate filaments. Cytokeratins are intermediate filaments forming a complex network which extends from the nucleus surface to the peripheral cell sector, where they are inserted into desmosomes and hemidesmosomes. Cytokeratins 14 and 19 have been used as diagnosis and prognosis markers in various tumors of epithelial origin, not only to identify a cell as epithelial, but also to identify different stages during epithelial differentiation and to characterize the tumor. There are numerous studies in biomedical literature that have exemplified the utility of cytokeratins 14 and 19 to identify odontogenic epithelium. This review analyzes the utility of their immunologic expression in the different cysts and odontogenic tumors. Keywords: Cytokeratin 14, Cytokeratin 19, Odontogenic cysts, Odontogenic tumors. * Molecular Pathology Trainee, Facultad de Odontología, UdelaR, Uruguay ** Assistant Professor, Grade 3, Department of Histology, Facultad de Odontología, UdelaR, Uruguay *** Associate Professor, Grade 5, Department of Histology, Facultad de Odontología, UdelaR, Uruguay **** Specialist in Pathology and Oral Medicine, Full-time Research Professor, Health Care Department, Universidad Autónoma Metro- politana, Mexico ***** Specialist in Pathology and Oral Medicine, Doctor in Biological Sciences (Molecular Pathology), Full-time Associate Professor, Grade 5, Molecular Pathology, Facultad de Odontología, UdelaR, Uruguay Received on: 08.05.14 - Accepted on: 01.09.14 Odontoestomatología / Vol. XVI. Nº 24 / November 2014 45 What are cytokeratins? epithelial keratins with variable molecular weights within the 40-70 kDa range, and sub- All mammal cells include a cytoplasmic fiber sequently an additional keratin was identified: system essential for cell mobility: the cytoskel- CK20. They can be divided into low versus eton. If we try to explain it in a simple and high molecular weight, and into acid or basic colloquial way, we could compare it to the according to their isoelectric points (2). steel rods that support the structure of a build- CKs 14 and 19 are type I keratins: CK 19 is ing: the cytoskeleton plays a key role as it sup- the smallest one and it is exceptional because, ports the plasma membrane and presents paths unlike other cytokeratins, it lacks the typical along which organelles and other cytosol ele- domain (no alpha helix) (5). CK14 is found in ments can move. However, unlike the passive the keratinocytes of stratified squamous epi- frame of a building, the cytoskeleton is con- thelium, both in the epidermis and the nonke- stantly restructured, which allows for move- ratinized mucosa (4), while CK19 is expressed ment (1). The cytoskeleton is formed by three in most simple epithelia, in various ductal main structural units and associated proteins: epithelia, in intestinal epithelia, in the gastric microfilaments, microtubules and intermedi- foveolar epithelium, and in the mesothelium. ate filaments. Intermediate filaments are divid- Besides, it is present in most pseudostratified ed into six types according to their molecular epithelia and urothelial cells, as well as in basal characteristics. Cytokeratins (CK) are type I cells of nonkeratinized stratified squamous and type II intermediate filaments (2, 3). epithelium (4). Moll et al. (4) classified a total of 19 human Fig. 1. Epithelial cells. Disposition of cytokeratins from the cytoplasmic plaque toward the nuclear periphery. 46 Nieves Sabrina, Apellaniz Delmira, Tapia Gabriel, Maglia Alvaro, Mosqueda-Taylor Adalberto, Bologna-Molina Ronell Which are their functions? Utility of cytokeratins as markers Cytokeratins form a complex network which Not all keratins are synthesized simultane- extends from the nucleus surface to the pe- ously by a cell, but rather different subsets of ripheral cell sector, where they are inserted keratins are expressed during terminal differ- into desmosomes and hemidesmosomes. entiation in different stages of development, (Figure 1). As they connect the nucleus sur- as well as in different epithelia. Therefore, all face with the plasma membrane, they provide epithelia (simple and complex) can be clas- a permanent link that can have important sified according to cytokeratin expression. implications for cytoplasm organization, cell Simple or monostratified epithelia generally communication, and perhaps for the trans- express keratins 7, 18, 19 and 20, while com- portation of information inside and outside plex (stratified) epithelia express keratins 5, the nucleus (2, 4). Additionally, as they are 6, 10, 14 and 15. When an epithelium un- inserted into desmosomes and hemidesmo- dergoes malignant transformation, its keratin somes, they contribute not only to the stabil- profile usually remains constant (2). There- ity of epithelial cells, but to their union with fore, patterns of keratin expression allow us the basal membrane and the underlying con- not only to identify a cell as epithelial, but nective tissue (4, 6). also to determine the phases of epithelial dif- In recent years there has been agreement re- ferentiation and to characterize the tumor. garding the fact that keratins have two funda- This is why antibodies against several keratins mental roles in epithelial cells: are used routinely at immunohistochemistry a) structural support, without which physical labs to diagnose carcinoma, especially unclear trauma leads to loss of integrity, and b) regulation of metabolic processes and their metastases (4). growth, proliferation, migration and apopto- Another clinical application is the detection of sis. protein fragments of CK8, CK18 and CK19 These two general roles involve regulated in- in the bloodstream of cancer patients. These teractions with a diverse group of fragments are increasingly used to monitor proteins (2, 7), which include signaling mol- tumor burden and the progression of the dis- ecules such as 14-3-3 proteins, apoptosis-re- ease in certain carcinomas such as lung cancer lated proteins, kinases and phosphatases (8). (15, 16). Besides, it has been observed that Oriolo et al. (9) say that they can also have a over 95% of lung carcinoma squamous cells role in epithelial polarity and membrane traf- are positive for CK14 (13, 17). fic. CK19 is one of the most frequently studied Cytokeratins have also been linked to wound immunohistochemical markers in thyroid pa- healing, as they provide a more pliable cyto- thology, which could make it a useful diagno- skeleton to the cell, which favors the migra- sis and prognosis tool, as it can be determined tion of keratinocytes for wound closure (10). before the therapeutic procedure in cytologic As for CK14, mutations in the CK genes are findings (14). responsible for epidermolysis bullosa simplex Immunohistochemical staining for CK19 (11, 12), a hereditary disease, considered im- facilitates the differential diagnosis between portant for the physical stability of the epi- papillary carcinoma, which presents strong dermis (4). In turn, CKs 15 and 20 have been and diffuse staining, and other thyroid can- used as diagnosis and prognosis markers in cers, which present weak and focal staining. various tumors of epithelial origin (13, 14). It has also been suggested that it could be a Cytokeratins 14 and 19 in odontogenic cysts and tumors: a review 47 useful predictor of the progression of thyroid nign or malignant myoepithelioma, adenoid carcinoma (14). cystic carcinoma and pleomorphic adenoma Tsuruba et al. (18) showed that CK8 and (13, 26, 27). CK14 can be useful to diagnose tumors in skin appendices. In general, the following tu- Cytokeratins and odontogenesis mors test negative for CK8 and positive for CK14: epidermis, sebaceous glands and hair Patterns of expression of cytokeratins in the follicles, while tumors derived from eccrine odontogenic epithelium have been described glands and apocrine sweat glands are CK8 in a very general way. Domingues et al. (28), positive and CK14 negative. in their immunohistochemical study, showed Squamous cells carcinoma, as well as malig- that epithelial cells of the tooth germ and in nant mesothelioma, show a strong expression the remnants of the dental lamina are posi- of CK14, while adenocarcinomas show none tive for CK14 and CK19 with slight changes or very little (2, 4, 19). Studies have suggested in their expression pattern, depending on the that the expression of certain keratins of sim- phase of odontogenesis. For example, they ple epithelia (like CK19) in squamous cells state that at the inner epithelium of the enam- carcinomas may indicate a poorly differenti- el organ the expression of CK14 and CK19 ated carcinoma (4). CK19 is detected in the varies in the follicle and bell stages (early bell epithelium near squamous cells carcinomas, stage according to the author). They observed which suggests that it could be used as a fun- a strong positive for CK14 while CK 19 had damental biological agent of the malignant weak staining, which was the opposite at the progression (20). Clearly these findings can late bell or follicle stage. CK19 has a strong be applied in the case of oral cavity squamous positive, while the expression of CK14 de- cells,
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