Cytokeratins 18 and 8 are poor prognostic markers in patients with squamous cell carcinoma of the oesophagus

Abstract

BACKGROUND: Cytokeratins (CKs) are structural marker proteins specific for epithelial cells. However, recent studies indicate their involvement in cancer progression. METHODS: We evaluated CK18 and its filament partner, CK8 expression, by immunohistochemistry in 210 resected specimens from patients with oesophageal squamous cell carcinoma (OSCC). We also analysed the relationship between their expression and various clinicopathological parameters including prognosis. RESULTS: Neither CK18 nor CK8 was expressed in non-cancerous squamous epithelium whereas proper oesophageal glands expressed both CKs. Ninety (42.9%) tumours were CK18 positive and 85 (40.5%) CK8 positive, and the concordance rate for immunohistochemical classification for CK18 and CK8 was 82.4%. CK18 expression correlated with poorly differentiated tumours, use of neo-adjuvant chemotherapy, and advanced stage. Prognosis of patients with CK18-positive tumours was poorer than that of patients with negative OSCC (Po0.001). A similar trend was noted for CK8 expression. Multivariate analysis identified pT (P ¼ 0.020), pN number (P ¼ 0.001), and CK18 expression (P ¼ 0.004) as independent prognostic factors. CK18 expression in 83 pretreatment biopsy specimens was detected in 47 cases (56.6%) and also correlated with prognosis (P ¼ 0.045). CONCLUSION: CK18/CK8 expression correlated with progression of OSCC. The significant correlation with prognosis and stable expression in biopsy specimen suggest usefulness of CK18 in selection of treatment strategies for OSCC.

Biological Functions of Cytokeratin 18 in Cancer

“…CK18 may modulate intracellular signaling and apoptosis via interactions with various related proteins. There is evidence to suggest that CK18 is involved in the invasive or growth properties of tumors (49,50). However, conflicting results have been obtained in vitro (58) and in vivo (51,54,55).…”

“…Patients with CK18-positive tumors had a poorer prognosis compared with patients with negative esophageal squamous cell carcinoma (49). In renal cell carcinoma, CK18 mRNA and protein levels increased with advanced stage and grade (52).…”

“…Makino and colleagues (49) reported that increased CK18 expression was correlated with poor differentiation and advanced stage in esophageal squamous cell carcinoma. Patients with CK18-positive tumors had a poorer prognosis compared with patients with negative esophageal squamous cell carcinoma (49).…”

“…CK18 has been recognized for $30 years as a structural marker protein that is specific to epithelial cells and consequently is involved in both cell motility and cancer progression (49). The expression of CK18 is associated with patient prognosis in a variety of cancers (50,51).…”

Proteomics and Esophageal Cancer

“…Keratin1 and keratin 8 ( [24], as well as our unpublished results on ESCC cell lines, [27][28][29]) and keratin 13 were observed to be overexpressed in ESCC, while keratin 4 and keratin 14 are down regulated [30] in.…”