Overexpression of Metallothionein Correlates with Chemoresistance to Cisplatin and Prognosis in Esophageal Cancer

Abstract

The aim of this study was to determine the correlation of metallothionein (MT) expression with resistance to cisplatin and to identify prognostic factors in esophageal cancer. Immunostaining for MT was performed on the specimens of squamous cell carcinoma of the esophagus resected from 68 patients with curative intent. The expression of MT was evaluated in terms of clinicopathologic variables, effect of cisplatin, and the patients’ survival. Overexpression of MT in the tumor was found in 70.6% of the patients. Stage III and IV tumors were more common in MT-positive tumors (p = 0.0282) but there was no difference in other clinicopathologic variables between MT-positive and MT-negative groups. Stage, cisplatin therapy, and tumor length were the independent prognostic indicators by multivariate analysis. Among 43 patients treated with cisplatin, the 5-year survival rate was 56% for MT-negative and 26% for MT-positive patients (p = 0.0277). In the MT-negative patients, multivariate analysis revealed that curability, stage, cisplatin therapy, and tumor length were the independent prognostic factors. These findings suggest that MT expression in squamous cell carcinoma of the esophagus is a major determinant of the chemoresistance to cisplatin and may be a predictor of poor prognosis.

Metallothionein – overexpression as a highly significant prognostic factor in melanoma: a prospective study on 1270 patients

“…In stage IV melanoma patients, anticancer drugs, as well as irradiation therapy, are known to often show only a humbled rate of clinical responses. These therapeutic failures may partially be related to an enhanced MT overexpression in tumour cells, although the involvement of MT in conferring resistance to chemotherapeutics still remains under discussion (Chin et al, 1993;Hishikawa et al, 1997;Okazaki et al, 1998;Cherian et al, 2003). As a variety of endogenous factors (e.g.…”

“…As far as we know, MT are involved in many physiological and pathophysiological processes such as the intracellular storage, transport and metabolism of heavy metal ions; they regulate essential trace metal homeostasis and play a protective role in heavy metal detoxification reactions (Miles et al, 2000;Simpkins, 2000). They can protect cells against UV-/ionic radiation (Hansen et al, 1997;Hanada et al, 1998;Reeve et al, 2000) as well as cytotoxic alkylating agents including chemotherapeutics (Chin et al, 1993;Hishikawa et al, 1997;Okazaki et al, 1998;Sunada et al, 2005), modulate oxygen free radicals and nitric oxide and inhibit apoptosis (Tsangaris and Tzortzatou-Stathopoulou, 1998). The synthesis of MT is induced by group II heavy metal ions as well as by endogenous factors such as glucocorticoids, cytokines (interleukin (IL)-1 or IL-6, interferon g (IFNg), tumour necrosis factor a (TNF-a)) or vitamin D 3 (Karin et al, 1985;Karasawa et al, 1987;Schroeder and Cousins, 1990;Sato and Sasaki, 1992;Nishimura et al, 2000).…”

The nm23-H1 gene as a predictor of sensitivity to chemotherapeutic agents in oesophageal squamous cell carcinoma

“…The results of these clinical trials suggest that it might be necessary to select the most effective therapy for each case in order to improve survival of patients with OSCC, especially advanced OSCC. Recent studies have elucidated several molecules, such as p53, GST-π and metalothionein, responsible for sensitivity to cisplatin (Timmer-Bosscha et al, 1993;Rusch et al, 1995;Hishikawa et al, 1997). More recently, nm23-H1 has been reported to correlate directly with sensitivity to cisplatin as well as other alkylating agents by transfection assay (Ferguson et al, 1996) and the expression of nm23-H1 protein has been shown to correlate inversely with prognosis of patients with ovarian carcinoma after cisplatin-based chemotherapy (Scambia et al, 1996).…”

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

“…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).…”