Immunohistochemical and clinicopathological correlation of the metastasis-associated gene 1 (MTA1) expression in benign and malignant pancreatic endocrine tumors.

Pancreatic endocrine tumors are rare tumors with unpredictable clinical behavior. No histological features or immunohistochemical markers reliably predict malignant progression and the molecular basis of progression of pancreatic endocrine tumors remains unknown. The metastasis-associated gene 1 is thought to play a role in transcription repression and estrogen receptor interaction and is overexpressed in several human cancers, including endocrine neoplasms. The purpose of this study was to analyze the expression of metastasis-associated gene 1 in pancreatic endocrine tumors for its possible role in malignant progression. Twenty-seven pancreatic endocrine tumors were identified from our archive. The mean age at presentation was 57 years (range 28-86); the male/female ratio was 1.25 to 1, and the mean size was 4.5 cm (0.1-18 cm). The clinical follow-up data were examined and tumors were classified according to the 2004 World Health Organization criteria as benign behavior (WHO 1.1), uncertain behavior (WHO 1.2), well-differentiated endocrine carcinoma (WHO 2), and poorly differentiated endocrine carcinoma (WHO 3). Histopathological and immunohistochemical stains were evaluated and metastasis-associated gene 1 expression scored semiquantitatively as absent (1+), weak (2+), moderate (3+), or strong (4+). Statistical analysis was performed using Kruskal-Wallis nonparametric analysis of variance with a significance level of 0.05. Metastasis-associated gene 1 expression was significantly higher in malignant tumors (n=17) with a mean staining intensity of 3.8 compared with 2.9 in benign tumors (n=10, P=0.046). The expression levels were significantly associated with WHO class (P=0.028), as well as size of tumor (P=0.029), and mitotic rate (P=0.035). Metastasis-associated gene 1 expression was associated with local invasion with borderline significance (0.062). We show that metastasis-associated gene 1 expression is significantly associated with malignant behavior in pancreatic endocrine tumors. This may suggest a potential role for metastasis-associated gene 1 in the malignant progression and metastasis and its use as biomarker for malignant pancreatic endocrine tumors.

Immunohistochemical analysis of cyclooxygenase (COX)-2 expression in pancreatic endocrine tumors: association with tumor progression and proliferation.

An immunohistochemical study of cyclooxygenase (COX)-2 expression in pancreatic endocrine tumors (PET) was carried out, and the expression of COX-2 was compared with pathological features, the expression of several markers (hormones, vascular endothelial growth factor, single-stranded DNA, and the Ki-67 labeling index [LI]). Twenty PET, including 10 metastasizing cases (tumor size: 3-8 cm) and 10 non-metastasizing cases (tumor size: 0.3-8 cm) were studied. Tumors with a high level of COX-2 expression were placed in the H group, and the remaining tumors were placed in the L group. The H group was comprised of 13 tumors: all 10 of the metastasizing cases and three of the non-metastasizing cases. There were significant differences in tumor size between the two groups (H group 46.5 mm; L group 0.9 mm). There were significant differences in the presence of the following histological criteria for malignancy: pleomorphism (H group 13/13; L group 1/7), mitotic activity (H group 2.9; L group 0) and/or angioinvasion (H group 13/13; L group 1/7); and there were also significant differences in the number of cases that expressed ectopic hormones (gastrin, vasoactive intestinal peptide, serotonin and calcitonin; H group 12/13; L group 2/7) and in the Ki-67 LI (H group 8.3%; L group 0.4%). The distribution of COX-2-positive cells tended to be similar to the distribution of Ki-67-positive cells. Our data show that COX-2 is frequently upregulated in malignant PET and that there is a close relationship between COX-2 expression and tumor progression/proliferative activity.

Differential regulation of telomerase activity and telomerase RNA during multi-stage tumorigenesis.

Telomeres consist of short repeated sequences that are synthesized by telomerase, a ribonucleo-protein DNA polymerase. Telomerase activity is present in many tumours and not detected in many normal tissues. Telomere shortening in human and mouse tissues and primary cell cultures may be due to the absence of telomerase activity. To determine when telomerase is activated during tumour development and progression, we examined telomerase activity and expression of the recently cloned mouse telomerase RNA component (mTR) in two different transgenic mouse models of multi-stage tumorigenesis. These mouse models allow examination of many independent tumours from genetically identical individuals. These mice reproducibly develop pancreatic islet cell carcinoma and squamous cell carcinoma of the skin. In both carcinoma types, we detected telomerase activity only in late-stage tumours; in contrast, we found mTR levels were upregulated in the early preneoplastic stages, and further increased during progression. Surprisingly, mTR levels did not parallel the amount of telomerase activity detected and a subset of tumours lacked telomerase activity and yet expressed telomerase RNA. Regulation of telomerase activity may therefore be separable from expression of its RNA component. These results clearly demonstrate telomerase is activated in late stages of tumour progression, and show for the first time that the initial up regulation of telomerase RNA is an early event, concurrent with the hyperproliferation elicited by viral oncogenes.