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Cytokeratins in Tumor Detection

Cytokeratins (CKs, or following more recent nomenclature also simply called keratins) are intermediate filaments forming proteins that provide mechanical support and fulfill a variety of additional functions in epithelial cells. They are part of the cytoskeleton and the largest family of intermediate filament proteins.

Two types of Cytokeratins are distinguished that form heterodimers, namely acidic type I (Cytokeratins 9-23) and basic type II (Cytokeratins 1-8).

The specific nature of these heterodimers serves to distinguish different epithelial cells, in which they are expressed, and has also become important in the classification of tumor cells besides other protein tumor markers.

Mutations in most of them are now associated with specific tissue-fragility disorders, and antibodies to Cytokeratins are important markers of tissue differentiation.

Keratin - marker of tissue differentiation

Keratins are tools in diagnostic pathology, most importantly in the detection of tumors. Primary tumors and metastases of a given carcinoma share the same pattern of cytokeratins, that distinguishes them from other types of carcinomas, thereby allowing differentiation between the different tumors (Ref. 1-4).

For example, Mesotheliomas (a protective lining that covers most of the body's internal organs) and Adenocarcinomas (originating in glandular tissue) can be distinguished by detection of Keratin 5. Defects in Keratin 5 lead to inherited skin disorders such as epidermolysis bullosa simplex (EBS) or Dowling-Deogs disease (DDD) (Ref. 5-7).

Keratin 7 can be used as a tool in order to distinguish ovarian and gastrointestinal carcinomas, or transitional cell carcinomas and prostate cancer. In hepatocytes atypical expression of Keratin 7 is a marker for primary biliary cirrhosis (Ref. 8-10).

Keratin 8 and Keratin 18 have a structural role in simple epithelia. Additionally, they play a role in signaling that modulates cell attachment, protein synthesis, G1/S phase transition, and in stress adaptation. Furthermore, Keratin 18 can be applied to detect therapy-induced tumor apoptosis and necrosis (Ref. 11-14).

Squamous cell (that have protective functions to nutrition exchange) carcinomas can be diagnosed utilizing Keratin 10, Keratin 13 and Keratin 17 as biomarkers.

Because Keratin 19 is being speculated to be linked to the retention of an undifferentiated cell character it may be useful in the detection of a variety of tumors (Ref 18-22).

Below we have compiled a list that is intended to help you find what you need in your research.

Carcinoma and corresponding Keratin Marker

Carcinoma Cytokeratins Selected antibodies
Hepatocellular carcinoma 8, 18 Cytokeratin 8
Adenocarcinoma of colon, type 1 8, 18, 19 Cytokeratin 18
Adenocarcinoma of colon, type 2 8, 17, 18, 19 Cytokeratin 17
Adenocarcinoma of stomach 7, 8, 18, 19 Cytokeratin 7, 17
Adenocarcinoma of esophagus 8, 18, 19 Cytokeratin 19
Adenocarcinoma of pancreas 7, 8, 17, 18, 19 Cytokeratin 18
Ductal (adeno-) carcinoma of breast, type 1 7, 8, 18, 19 Cytokeratin 19
Basal cell epithelioma 5, 6, 8, 14, 15, 17 Cytokeratin 5, 18
Squamous cell carcinoma of skin 5, 6, 11, 14, 16, 17 Cytokeratin pan
Squamous cell carcinoma of tongue 5, 6, 14, 16, 17 Cytokeratin 14
Ductal carcinoma of breast, type 2 6, 7, 8, 11, 14, 16, 17, 18, 19 Cytokeratin 18
Undifferentiated carcinoma of bronchus (large-cell type) 6, 7, 8, 17, 18, 19 Cytokeratin 18
Solid carcinoma of maxillary sinus 5, 8, 17, 18, 19 Cytokeratin 17
Adamantinoma 4, 5, 8, 14, 15, 16, 17, 19 Cytokeratin 19
Squamous cell carcinoma of epiglottis 4, 5, 6, 8, 14, 15, 16, 17, 18, 19 Cytokeratin 18
Squamous cell carcinoma of esophagus 4, 5, 8, 14, 15, 16, 17, 19 Cytokeratin 14
Squamous cell carcinoma of rectal-anal region 4, 5, 6, 8, 10, 11, 14, 15, 16, 17, 18, 19 Cytokeratin 10
Cloacogenic carcinoma 1, 5, 6, 7, 8, 10, 11, 13, 14, 15, 17, 19 Cytokeratin 10, 13

Cytokeratin Targets

References

Lindberg, Rheinwald: "Suprabasal 40 kd keratin (K19) expression as an immunohistologic marker of premalignancy in oral epithelium." in: The American journal of pathology, Vol. 134, Issue 1, pp. 89-98, (1989) (PubMed).

Rugg, Horn, Smith, Wilson, Hill, Magee, Shemanko, Baty, Tidman, Lane: "Epidermolysis bullosa simplex in Scotland caused by a spectrum of keratin mutations." in: The Journal of investigative dermatology, Vol. 127, Issue 3, pp. 574-80, (2007) (PubMed).

Moll, Franke, Schiller, Geiger, Krepler: "The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells." in: Cell, Vol. 31, Issue 1, pp. 11-24, (1983) (PubMed).

Varadhachary, Abbruzzese, Lenzi: "Diagnostic strategies for unknown primary cancer." in: Cancer, Vol. 100, Issue 9, pp. 1776-85, (2004) (PubMed).

Gusterson, Ross, Heath, Stein: "Basal cytokeratins and their relationship to the cellular origin and functional classification of breast cancer." in: Breast cancer research : BCR, Vol. 7, Issue 4, pp. 143-8, (2006) (PubMed).

Kanaji, Bandoh, Fujita, Ishii, Ishida, Kubo: "Compensation of type I and type II cytokeratin pools in lung cancer." in: Lung cancer (Amsterdam, Netherlands), Vol. 55, Issue 3, pp. 295-302, (2007) (PubMed).

Moll, Dhouailly, Sun: "Expression of keratin 5 as a distinctive feature of epithelial and biphasic mesotheliomas. An immunohistochemical study using monoclonal antibody AE14." in: Virchows Archiv. B, Cell pathology including molecular pathology, Vol. 58, Issue 2, pp. 129-45, (1990) (PubMed).

Betz, Planko, Eigelshoven, Hanneken, Pasternack, Bussow, Van Den Bogaert, Wenzel, Braun-Falco, Rutten, Rogers, Ruzicka, Nöthen, Magin, Kruse: "Loss-of-function mutations in the keratin 5 gene lead to Dowling-Degos disease." in: American journal of human genetics, Vol. 78, Issue 3, pp. 510-9, (2006) (PubMed).

Ramaekers, van Niekerk, Poels, Schaafsma, Huijsmans, Robben, Schaart, Vooijs: "Use of monoclonal antibodies to keratin 7 in the differential diagnosis of adenocarcinomas." in: The American journal of pathology, Vol. 136, Issue 3, pp. 641-55, (1990) (PubMed).

Yabushita, Yamamoto, Ibuki, Okano, Matsumura, Okamoto, Shimada, Tsuji: "Aberrant expression of cytokeratin 7 as a histological marker of progression in primary biliary cirrhosis." in: Liver, Vol. 21, Issue 1, pp. 50-5, (2001) (PubMed).

Chatzipantelis, Lazaris, Kafiri, Papadimitriou, Papathomas, Nonni, Patsouris: "Cytokeratin-7, cytokeratin-19, and c-Kit: Immunoreaction during the evolution stages of primary biliary cirrhosis." in: Hepatology research : the official journal of the Japan Society of Hepatology, Vol. 36, Issue 3, pp. 182-7, (2011) (PubMed).

Galarneau, Loranger, Gilbert, Marceau: "Keratins modulate hepatic cell adhesion, size and G1/S transition." in: Experimental cell research, Vol. 313, Issue 1, pp. 179-94, (2007) (PubMed).

Ku, Omary: "A disease- and phosphorylation-related nonmechanical function for keratin 8." in: The Journal of cell biology, Vol. 174, Issue 1, pp. 115-25, (2006) (PubMed).

Lau, Chiu: "The possible role of cytokeratin 8 in cadmium-induced adaptation and carcinogenesis." in: Cancer research, Vol. 67, Issue 5, pp. 2107-13, (2007) (PubMed).

Linder, Havelka, Ueno, Shoshan: "Determining tumor apoptosis and necrosis in patient serum using cytokeratin 18 as a biomarker." in: Cancer letters, Vol. 214, Issue 1, pp. 1-9, (2004) (PubMed).

van Dorst, van Muijen, Litvinov, Fleuren: "The limited difference between keratin patterns of squamous cell carcinomas and adenocarcinomas is explicable by both cell lineage and state of differentiation of tumour cells." in: Journal of clinical pathology, Vol. 51, Issue 9, pp. 679-84, (1999) (PubMed).

Maddox, Sasieni, Szarewski, Anderson, Hanby: "Differential expression of keratins 10, 17, and 19 in normal cervical epithelium, cervical intraepithelial neoplasia, and cervical carcinoma." in: Journal of clinical pathology, Vol. 52, Issue 1, pp. 41-6, (1999) (PubMed).

Toyoshima, Vairaktaris, Nkenke, Schlegel, Neukam, Ries: "Cytokeratin 17 mRNA expression has potential for diagnostic marker of oral squamous cell carcinoma." in: Journal of cancer research and clinical oncology, Vol. 134, Issue 4, pp. 515-21, (2008) (PubMed).

Deshpande, Fernandez-del Castillo, Muzikansky, Deshpande, Zukerberg, Warshaw, Lauwers: "Cytokeratin 19 is a powerful predictor of survival in pancreatic endocrine tumors." in: The American journal of surgical pathology, Vol. 28, Issue 9, pp. 1145-53, (2004) (PubMed).

Park, Kwak, Kim, Kim, Choe, Park, Jang, Park, Cho, Park: "Diagnostic value of galectin-3, HBME-1, cytokeratin 19, high molecular weight cytokeratin, cyclin D1 and p27(kip1) in the differential diagnosis of thyroid nodules." in: Journal of Korean medical science, Vol. 22, Issue 4, pp. 621-8, (2008) (PubMed).

Barroeta, Baloch, Lal, Pasha, Zhang, LiVolsi: "Diagnostic value of differential expression of CK19, Galectin-3, HBME-1, ERK, RET, and p16 in benign and malignant follicular-derived lesions of the thyroid: an immunohistochemical tissue microarray analysis." in: Endocrine pathology, Vol. 17, Issue 3, pp. 225-34, (2007) (PubMed).

Ignatiadis, Xenidis, Perraki, Apostolaki, Politaki, Kafousi, Stathopoulos, Stathopoulou, Lianidou, Chlouverakis, Sotiriou, Georgoulias, Mavroudis: "Different prognostic value of cytokeratin-19 mRNA positive circulating tumor cells according to estrogen receptor and HER2 status in early-stage breast cancer." in: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Vol. 25, Issue 33, pp. 5194-202, (2007) (PubMed).

Julian Pampel
Julian Pampel, BSc
Content Manager at antibodies-online.com

Creative mind of antibodies-online with a keen eye for details. Proficient in the field of life-science with a passion for plant biotechnology and clinical study design. Responsible for illustrated and written content at antibodies-online as well as supervision of the antibodies-online scholarship program.

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