An Overview of Cytokeratin,
 

 

Uploaded: 2007-11-06, Updated: 2007-11-06
 
Distribution and Pairing Cytokeratins in Human Tissues
 
Type II / A, Neutral-basic
Type I / B, Acidic
Keratin
MW (kD)
Keratin
MW (kD)
Keratinized squamous epidermis
1
67
9
10
64
56.5
Epithelium, all locations
2
65
11
56
Cornea
3
63
12
55
Non-cornifying stratified epithelium
4
59
13
51
Basal cells of squamous and glandular epithelia, mesothelium, myoepthelium
Squamous epithelium
5
58
14
15
50
50
Fast turnover squamous epithelium
6
56
16
48
Ductal or simple epithelium
7
54
17
46
Basal cells of glandular epithelia, myoepithelium
Simple epithelium, Basal cells of glandular and squamous epithelia
Simple gastric and intestinal epithelia, Merkel cells
8
52
18
19
20
45
40
46
  • The keratin intermediate filaments comprise 20 different keratin polypeptides of the approximately 30 keratin polypeptides. They are resolved with two-dimensional gel electrophoresis into acidic (pI <5.7) type and basic (pI >6.0) type. Acidic type keratins are also called type I, type B or low-molecular-weight (LMW) cytokeratins, and comprise 12 keratins; Basic type keratins are also called type II, type A or high-molecular-weight (LMW) cytokeratins, and comprise 8 keratins. Usually the type II cytokeratins are 8kD larger than the type I proteins.
  • Cytokeratins are usually expressed in pairs comprising a type I and a type II cytokeratin. The primary cytokeratins (#5, #14, #8 & #18) are present in all cell types: cytokeratins (8/18) in simple epithelia and (5/14) in basal cells of stratified epithelium. In complex epithelia, such as prostate, the inner (luminal) cell layer expresses simple primary cytokeratins (8/18) and the outer layer expresses squamous primary cytokeratins (5/14). The other cytokeratins are secondary cytokeratins.
  • Simple epithelium, including cuboidal, columnar epithelium or one-layered epithelium, directly contacts with the basement membrane and has a free luminal surface at the apical side of the cell, and it primarily expresses cytokeratins 8 and 18 and often cytokeratins 7, 19 and 20.
  • Stratified epithelia are subdivided into the keratinizing, the non-keratinizing and transitional type. The keratinizing and non-keratinizing epithelia have a basal cell layer which invariably expresses cytokeratins 5 and 14. The suprabasal cell layers express cytokeratins 4 and 13 in noncornifying epithelia and cytokeratins 1 and 10 in cornifying epithelia. The transitional epithelium of the urinary bladder expresses cytokeratins 4 and 13 together with the cytokeratins of the simple epithelia, including cytokeratins 7, 8, 18, 19 and 20.
  • Combined epithelia are composed of a basal cell layer and a layer of columnar cells both in contact with the basement membrane. The basal cells express cytokeratins 5, 14 and 17, while the luminal cells can express different combinations of cytokeratins 7, 8, 18 and 19.
 
AE1/AE3
  • Mouse monoclonal, AE1, is reactive to the acidic cytokeratin and AE3 has reaction to the basic cytokeratin antibody.
  • The mixture of these two antibodies produces positive staining most of the epithelia.
  
Cytokeratin 1 is specifically expressed in the spinous and granular layers of the epidermis. Mutations are associated with bullous congenital ichthyosiform erythroderma.
 
Cytokeratin 5 & 6 antibody stains basal cells and part of the stratum spinosum in normal squamous epithelium, and part of the basal layer of prostate gland epithelium. It does not stain other normal simple layer glandular epithelium. Positive: simple epithelia of intestine, liver, nonkeratinizing stratified squamous epithelia, epithelia of trachea, apocrine and sweat glands of skin, epidermis, hair follicles, and mammary glands.
 
Cytokeratin 6 and 16 are expressed in keratinocytes, which are undergoing rapid turnover in the suprabasal region (also known as hyperproliferation related keratins). Expression of CK6 is particularly associated with differentiation. Keratin 6 is found in hair follicles, suprabasal cells of a variety of internal stratified epithelia, in epidermis, in both normal and hyperproliferative situations. Epidermal injury results in activation of keratinocytes which express CK6 and CK16. CK6 is strongly expressed in about 75% of head and neck squamous cell carcinomas.
 
Cytokeratin 7 is a 54kD intermediate filament protein found in most glandular and transitional epithelia. Keratin 7 is often co-expressed with keratin 19. Positive in columnar and glandular epithelium of the lung, cervix, breast, bile/pancreatic ducts and larger collecting ducts of the kidney.
Present in the transitional epithelium of bladder as well as ovarian and lung epithelia.  Cytokeratin 7 is not expressed by epithelial cells of the gastrointestinal tract, colon or prostate, and it does not react with stratified squamous epithelia.
 
Cytokeratin 8 belongs to the type A (basic) type of high molecular weight keratins and exists in combination with cytokeratin 18.
Primarily found in the non squamous epithelia and is present in majority of adenocarcinomas and ductal carcinomas. It is absent in squamous cell carcinomas. Monoclonal antibody reacts specifically with a wide variety of human simple and complex epithelia (e.g., liver, intestine, pancreas, urinary bladder, salivary gland,thyroid, prostate, mesothelium, and placenta). It does not react with stratified squamous epithelia. Hepatocellular carcinomas are defined by the use of antibodies that recognize only cytokeratin polypeptides 8 and 18.
 
Cytokeratin 14 is usually found paired with keratin 5, a type II keratin. Mutations in the genes for these keratins are associated with epidermolysis bullosa simplex. Keratin 14 has been studied as a prognostic marker in breast cancer. CK14 also identifies oncocytes of oncocytic neoplasms.
 
Cytokeratin 15 is a type I keratin without a defined type II partner. Keratin 15 is expressed primarily in the basal keratinocytes of stratified tissues. Expression of keratin 15 is downregulated in some hyperproliferating situations, such as psoriasis and hypertrophic scars.
 
Cytokeratin 6 and 16, are expressed when keratincytes are undergoing rapid turnover in various pathological states, wound healing, psoriasis and some carcinomas.  Keratin 16 is expressed in keratinocytes that are undergoing rapid turnover in the suprabasal region (also known as hyperproliferation-related keratins). Keratin 16 is absent in normal breast tissue and in noninvasive breast carcinomas. Only 10% of the invasive breast carcinomas show diffuse or focal positivity. Reportedly, a relatively high concordance was found between the carcinomas immunostaining with the basal cell and the hyperproliferation-related keratins, but not between these markers and the proliferation marker Ki-67. This supports the conclusion that basal cells in breast cancer may show extensive proliferation, and that absence of Ki-67 staining does not mean that (tumor) cells are not proliferating.

Cytokeratin 17 is expressed only in the basal cells of a group of complex epithelia: glandular epithelium with myoepithelial component, transitional and pseudostratified epithelia. Immunolocalization of keratin 17 provides evidence that the expression of this keratin strongly depends on the cell position within epithelial structures. The topographical character of the keratin expression suggests that these proteins may be implicated in the generation of spatial organization of epithelial tissues.
 
Cytokeratin 18 is an acidic keratin which is found primarily in non squamous epithelia. Cytokeratin 18 exists in combination with cytokeratin 8, a basic keratin. Present in a majority of adenocarcinomas and ductal carcinomas but not in squamous cell carcinomas. Hepatocellular carcinomas have been reportedly defined by the use of antibodies that recognize only cytokeratins 8 and 18.
 
Cytokeratin 19 is a simple epithelial cytokeratin, and it is also expressed in the squamous basal layer. Keratin 19 is often co-expressed with keratin Keratin 19 is not expressed in hepatocytes, and antibody to keratin 19 is useful in the identification of liver metastasis. The degree of keratin 19 positivity in breast cancer distinguishes malignant from benign tumors.
 
Cytokeratin 20 is a major cellular protein of mature enterocytes and goblet cells and is specifically expressed in the gastric and intestinal mucosa. It is also expressed in adenocarcinomas of the colon, stomach, pancreas and the bile system and is present in mucinous ovarian tumors, transitional-cell and Merkel-cell carcinomas. Notably, the squamous cell carcinomas and adenocarcinomas of the breast, lung, and endometrium, non-mucinous tumors of the ovary, and small cell carcinomas lack cytokeratin 20. This monoclonal antibody is useful in distinguishing colon adenocarcinoma from non-mucinous ovarian adenocarcinoma. The antibody consistently stains Merkel cell carcinoma and can be used to differentiate this carcinoma from metastatic small cell carcinoma of the skin.
REFERENCES
 
  • Diagnostic immunohistochemistry. David Dabbs.2006, 2nd edition.