Gene: maps to 12q13 (Yoon S.J. et al., 1994). Chromosome 12 contains several genes for type II keratins, including
keratin 8, and also the gene for keratin 18, the type I keratin that is coexpressed with keratin 8. This location of both members of a keratin pair on a single chromosome is unique among keratin genes; it is consistent with the hypothesis that keratins 8 and 18 may be closer to an ancestral gene than the keratins of more highly differentiated epithelia (Waseem A. et al., 1990). The KRT18 gene is 3,791 bp long and the keratin 18 protein is coded for by 7 exons.
mRNA: size: ~1.4 kb.
Protein: a component of
intermediate filaments.
Cell lines:
- CK18 protein expression was found to be low in highly metastatic breast cancer cell (BCC) lines and, conversely, high in weakly metastatic cell lines, suggesting that it might function as a prognostic indicator (Schaller G. et al., 1996).
- Four human BCC lines (MT-1, MaTu. MT-3 and MC4000) were established from human tumour xenografts grown in nude mice. All the lines epithelial in morphology by both light and electron microscopy and were positive for CK18. All of the new lines were shown to be
ER and
PgR negative, while using the same procedures (i.e. radioligand binding and immunohistochemical staining) the positive control cell line MCF-7 was shown to be positive (Hambly R.J. et al., 1997).
- It has been demonstated that
cytokeratin 8 (CK8) may bind plasminogen and
tissue-type plasminogen activator (tPA) and accelerate plasminogen activation on cancer cell surfaces. It appears that
CK8 may promote plasminogen activation by
tPA only when present in an oligomerized state. CK18 may participate in the oligomer, together with
CK8, based on its ability to bind
tPA (Kralovich K.R. et al., 1998).
- Two BCC lines (BrCa-MZ-01 and BrCa-MZ-02) were isolated from a solid tumor and a pleural effusion, respectively. One cell line was established from a medullary carcinoma, the other from a ductal carcinoma. These cells exhibit ultrastructural and immunohistochemical features of epithelial cells of mammary origin. Intermediate filament and cytokeratin typing showed a clear predominance of the simple-epithelial cytokeratins
CK 8, CK 18 and
CK 19, although the expression was reduced in comparison to the hormone receptor-positive reference cell lines MCF-7 and ZR-75-1 (Möbus V.J. et al., 1998).
- The phenotypic characteristics of 2 tumor cell lines (BC-H1 and BC-K1) established from bone marrow of patients with breast cancer were studied by immunocytochemistry, flow cytometry, and RT-PCR. Both cell lines expressed
E-cadherin,
vimentin, cytokeratins, alpha 5-,
alpha V-,
beta 1-, and
beta 3- integrin subunits,
ICAM-1,
MCAM, LFA-3 (CD58), and
CD44s (but not
CD44v5,
v6,
v7/8). BC-H1 also expressed
ErbB2 (not found in BC-K1), and
MAGE-4 (but not MAGE-1, -2, -3/6, -12; BC-K1 was not tested). In both cell lines, the mesenchymal cytoskeleton protein
vimentin was coexpressed with cytokeratins CK8/18 and CK8/19, indicating an epithelial to mesenchymal transition of these micrometastatic cells. The expressed molecules might be potential candidates for novel therapeutic targets (Putz E. et al., 1999).
Tumors:
- Monoclonal antibodies to CK18 stained the majority of inner cells in benign breast lesions but comparatively fewer such cells in carcinoma
in situ and invasive carcinoma (Rudland P.S. et al., 1993).
- In primary breast carcinomas, both mRNAs and proteins of
CK8 and CK18 were found to be generally expressed to a degree similar to that of normal epithelia, but a lower level of mRNA and protein of CK18 was observed in metastatic carcinomas (Su L. et al., 1996).
- By RT-PCR, CK18 was found in 5 of 7 bone marrow samples from healthy individuals, indicating the lack of specificity of this marker for the detection of micrometastases of tumor cells (Zippelius A. et al., 1997).
- Cytokeratin (CK) protein and mRNA expression were examined in malignant and benign breast tissues. Examination of cytokeratins
8, 18, and
19 revealed a consistent pattern of expression with respect to tumor grade. Only
cytokeratin 19 showed significant correlation with increasing tumor size. mRNA expression for
cytokeratin 8 was significantly higher in node-positive compared with node-negative disease. Cytokeratin 18 mRNA levels were significantly lower in both node-negative and node-positive patients when compared with benign samples. Increased levels of cytokeratin 18 mRNA showed an inverse relationship with protein expression. The results indicate that cytokeratin expression in breast cancer may be associated with tumor progression (Brotherick I. et al., 1998).
- CK18 expression was examined by immunohistochemical staining in 134 patients with breast cancer. The staining intensity was compared with clinicopathological variables and follow-up data spanning 8 years. A definitive positive staining was observed in 22 (16.4%) women. The mortality rate was 4. 5% in the CK18-positive group and 44.6% in the CK18-negative group. Multivariate analysis found CK18 expression to be an independent and significant predictor for overall survival (Schaller G. et al., 1996).
Brotherick I. et al. (1998) Cytokeratin expression in breast cancer: phenotypic changes associated with disease progression. Cytometry 32, 301-308.
Hambly R.J. et al. (1997) Establishment and characterisation of new cell lines from human breast tumours initially established as tumour xenografts in NMRI nude mice. Breast Cancer Res. Treat. 43, 247-258.
Kralovich K.R. et al. (1998) Characterization of the binding sites for plasminogen and
tissue-type plasminogen activator in
cytokeratin 8 and cytokeratin 18. J. Protein Chem. 17, 845-854.
Kulesh D.A. and Oshima R.G. (1989) Complete structure of the gene for human keratin 18. Genomics 4, 339-347.
Möbus V.J. et al. (1998) Differential characteristics of two new tumorigenic cell lines of human breast carcinoma origin. Int. J. Cancer 77, 415-423.
Putz E. et al. (1999) Phenotypic characteristics of cell lines derived from disseminated cancer cells in bone marrow of patients with solid epithelial tumors: establishment of working models for human micrometastases. Cancer Res. 59, 241-248.
Rudland P.S. et al. (1993) Immunocytochemical identification of cell types in benign and malignant breast diseases: variations in cell markers accompany the malignant state. J. Histochem. Cytochem. 41, 543-553.
Schaller G. et al. (1996) Elevated keratin 18 protein expression indicates a favorable prognosis in patients with breast cancer. Clin. Cancer Res. 2, 1879-1885.
Su L. et al. (1996) Expression of cytokeratin messenger RNA versus protein in the normal mammary gland and in breast cancer. Hum. Pathol., 800-806.
Waseem A. et al. (1990) Embryonic simple epithelial keratins 8 and 18: chromosomal location emphasizes difference from other keratin pairs. New Biologist 2, 464-478.
Yoon S.J. et al. (1994) Organization of the human keratin type II gene cluster at 12q13. Genomics 24, 502-508.
Zippelius A. et al. (1997) Limitations of reverse-transcriptase polymerase chain reaction analyses for detection of micrometastatic epithelial cancer cells in bone marrow. J. Clin. Oncol. 15, 2701-2708.
