Aberrant expression of minichromosome maintenance proteins 2 and 5, and Ki-67 in dysplastic squamous oesophageal epithelium and Barrett's mucosa

Abstract

Background: Minichromosome maintenance (Mcm) proteins are essential for eukaryotic DNA replication, and their expression implies potential for cell proliferation. Expression is dysregulated in dysplastic states but data for oesophageal squamous mucosa and Barrett's mucosa have not been published. Aim: To test the hypothesis that Mcm proteins are downregulated together with the proliferation marker Ki-67 in differentiating epithelial compartments of non-dysplastic squamous and Barrett's epithelium, and that this process does not occur in dysplastic mucosae. Methods and cases: Forty five patients with Barrett's oesophagus included 20 with glandular dysplasia (10 low grade, eight high grade, two both, and four with invasive adenocarcinoma). Twenty five other patients included 12 with oesophageal squamous dysplasia (three low grade, six high grade, three both, and four with invasive squamous carcinoma). Formalin fixed paraffin embedded tissue sections from biopsy series and resections were immunostained using antibodies to Mcm2, Mcm5, and Ki-67. Percentage of nuclei positive for Mcm2, Mcm5, and Ki-67 was estimated and scored from 0 to 6 as: 0, none +; 1, <10%+; 2, 10-30%+; 3, 30-70%+; 4, 70-90%+; 5, >90%+; 6, all+. Four separate epithelial strata were scored: in squamous epithelium the basal layer and thirds to the surface, in Barrett's mucosa the luminal surface, upper and lower crypt, and deep glands. Results: In non-dysplastic squamous epithelium and Barrett's mucosa, high level expression of Mcm2, Mcm5, and Ki-67 proteins was largely confined to the proliferative compartments and downregulated in differentiated compartments. Expression persisted up to the mucosal surface in dysplastic squamous epithelium and Barrett's mucosa. Conclusions: Persistent expression of Mcm2, Mcm5, and Ki-67 proteins in luminal compartments of dysplastic oesophageal squamous epithelium and dysplastic Barrett's mucosa may be diagnostic markers and imply disruption of cell cycle control and differentiation in these dysplastic epithelia.

Minichromosome maintenance protein 6, a proliferation marker superior to Ki-67 and independent predictor of survival in patients with mantle cell lymphoma

“…With the development of (Meng et al, 2001;Padmanabhan et al, 2004) and ovarian serous neoplasms (Scott et al, 2004) chondrosarcoma (Helfenstein et al, 2004), oligodendroglial tumours (Wharton et al, 2001(Wharton et al, , 2004, oesophageal neoplasm (Going et al, 2002), renal cell carcinoma (Dudderidge et al, 2005), breast cancer (Gonzalez et al, 2004), endometrial carcinoma (Li et al, 2005) and thyroid carcinoma (Guida et al, 2005).…”

“…The clinical relevance of MCM proteins as proliferation markers has been investigated immunohistochemically in several different malignant tumours (Freeman et al, 1999), for example, non-smallcell lung cancer (Ramnath et al, 2001), prostate cancer (Meng et al, 2001;Padmanabhan et al, 2004), oral squamous cell carcinoma (Kodani et al, 2003), chondrosarcoma (Helfenstein et al, 2004), oligodendroglial tumours (Wharton et al, 2001(Wharton et al, , 2004, oesophageal neoplasm (Going et al, 2002), renal cell carcinoma (Dudderidge et al, 2005), breast cancer (Gonzalez et al, 2004), endometrial carcinoma (Li et al, 2005) and thyroid carcinoma (Guida et al, 2005). Most of these studies focused on the detection of MCM2 (Freeman et al, 1999;Chatrath et al, 2003;Davidson et al, 2003;Kodani et al, 2003;Scott et al, 2004).…”

The cell cycle and cancer

“…Identification of MCM proteins in pathological specimens using immunodetection methods has been shown to be an accurate and simple method for determining the growth fraction in dynamic tumour cell populations [39,[68][69][70] ( Figure 1B). Moreover, Mcm2-7 expression levels are powerful prognostic indicators in diverse tumour types, including cancers of the lung, breast, kidney, bladder, prostate and ovary [71][72][73][74][75][76][77].…”

“…Notably, the arrested differentiation that characterizes cancer, particularly in high-grade tumours, is associated with failure to down-regulate the replication initiation proteins. (B) Spatial organization of Mcm2-7 protein expression in normal oesophageal squamous epithelium and non-dysplastic Barrett's mucosa and disruption of this highly organized spatial arrangement in premalignant dysplasia and invasive cancer [69,96]. In normal squamous epithelium, high expression levels of Mcm2 above a well-defined basal layer fall to undetectable levels in the upper third.…”

“…These early, non-invasive lesions are characterized by the emergence of cytologically abnormal cells, abrogation of the normal differentiation programme with loss of epithelial polarity, and an increase in the size of the proliferative compartment. Intriguingly, the switch to the dysplastic state is associated with a failure to downregulate the licensing system, resulting in high MCM protein expression in all epithelial layers, including the surface cells [3,39,68,69]. This expression pattern indicates that the majority of cells in premalignant lesions are locked into the cell division cycle.…”