Metallothionein expression correlates with metastatic and proliferative potential in squamous cell carcinoma of the oesophagus

Abstract

Squamous cell carcinoma (SCC) of the oesophagus is well recognized for its aggressive biological behaviour, in respect of local infiltration and metastases to regional lymph nodes and distant organs (Orrigner, 1997). Extra-oesophageal tumour spread is present in 70% of cases at the time of diagnosis, and the 5-year survival is only 3% when lymph node metastases are present, compared with 42% in lymph node negative patients (Orrigner, 1997). Patients with distant metastasis also have a poor prognosis, with a 5-year survival rate of 5% or less (Mandard et al, 1984;Orrigner, 1997).Metastasis is a multistep process involving complex associations of tumour cells with host cells or with matrix (Stracke and Liotta, 1995). Recently, genetic mechanisms underlying metastasis and pathogenesis of oesophageal SCC have been explored in several studies: int-2/hst-1 co-amplification correlated with high incidence of metastasis in distant organs (Kitagawa et al, 1991), loss of heterozygosity of the DCC gene associated with the degree of lymph node metastasis (Miyake et al, 1994), and mutation of the p53 gene in the pathogenesis (Hollstein et al, 1990;Meltzer et al, 1991) of SCC. However, there are only a limited number of reports on the prognostic indicators for invasion and metastasis of oesophageal SCC.Metallothioneins (MTs) have been described in most vertebrate and invertebrate species as low molecular weight proteins. Overexpression of MT was described in a variety of human tumours, in relation to different stages of tumour development and progression (Jasani and Schmid, 1997). MT was considered as a potential prognostic marker in invasive ductal carcinoma of the breast by Schmid et al (1993) and others (Fresno et al, 1993;Goulding et al, 1995, Oyama et al, 1996. In skin carcinoma (Zelger et al, 1994), melanoma (Zelger et al, 1993), cervical carcinoma (Lim et al, 1996) and pancreatic carcinoma (Ohshio et al, 1996), MT overexpression appears to be predominantly associated with more advanced, highly malingant tumours. To the contrary, Öfner et al (1994) reported that MT overexpression in colorectal carcinoma was associated with better clinical outcome and tumour stages. Therefore, MT overexpression may be paradoxically associated in some tumours with better clinical outcome.Tumour MT level also has been reported to correlate with resistance to anticancer reagents (Kelley et al, 1988;Kasahara et al, 1991;Chin et al, 1993;Kondo et al, 1995;Hishikawa et al, 1997). In oesophageal SCC, we already reported that MT protein expression might be a significant determinant of prognosis, in particular, associated with cisplatin resistance (Hishikawa et al, 1997). Patients with MT protein-negative tumours survived longer when treated with cisplatin than those with MT protein-positive tumours. However, the exact biological significance of the expression of MT protein and mRNA is largely unknown in the clinical setting of oesophageal SCC.Therefore, in the present study, we have investigated the expressions of both MT mRNA and its protein in...

Revisit of Field Cancerization in Squamous Cell Carcinoma of Upper Aerodigestive Tract: Better Risk Assessment with Epigenetic Markers

“…We confirmed that this approach is equivalent to the traditional risk factor method, which typically requires a comprehensive set of clinical data. The biological significance of the epigenetic approach is supported by studies investigating the pathogenesis of SCC, which find that HOXA9 protein expression is deregulated in SCC (32), that oncogenesis is triggered by silencing NEFH to activate the Akt/b-catenin pathway (33), that the prognosis of SCC is worsened by hypermethylating UCHL1 (34) that interacts with p53 through the deubiquitination pathway (35), and that overexpressing MT is associated with metastatic and proliferative activity (36). None of these 4 genes had previously been correlated with carcinogen exposure or with cancer risk prediction.…”

Estrogen receptor-associated expression of keratinocyte growth factor and its possible role in the inhibition of apoptosis in human breast cancer

“…These KGF and KGFR oligo-DNAs were haptenized by introducing T-T dimers by 12 000 J/m 2 ultraviolet irradiation, as described previously. 36,37 We performed preliminary immunodetection and dot-blot hybridization using KGF and KGFR probes as detailed previously, 37,38 and these results indicated that antisense probes were specific and had adequate sensitivity to be useful for in situ hybridization.…”

Expression of the Snurf–Snrpn IC transcript in the oocyte and its putative role in the imprinting establishment of the mouse 7C imprinting domain

“…To estimate the amount of RNA retained in the paraffin sections, methyl green-pyronin Y staining was performed before in situ hybridization (ISH), according to Shutle et al (1992). ISH was performed using digoxigenin-labeled oligonucleotide probes as previously described (Koji and Brenner 1993;Hishikawa et al 1999). Briefly, the sections were warmed at 60°C for 30 min, deparaffinized with toluene and rehydrated through decreasing concentrations of ethanol.…”