To clarify kinetics in ulcerative colitis (UC)-associated lesions, cell proliferation, apoptosis, and expression of apoptosis-inhibitory proteins were studied. Ki-67 labeling and survivin and bcl-2 expression were examined immunohistochemically in 22 low-grade dysplasias (LGDs), 25 high-grade dysplasias (HGDs), and 13 adenocarcinomas associated with UC, and for comparison in 21 sporadic adenomas with LGD, 22 sporadic adenomas with HGD, and 21 invasive adenocarcinomas. Apoptosis was studied with nick-end labeling and immunohistochemical analysis of single-stranded DNA. In UC-associated LGDs, Ki-67--positive cells were more frequent in the lower than the upper half of the crypt, related to bcl-2 expression, while in sporadic adenomas such cells were more common in the upper half. No difference in apoptosis was found between UC-associated LGDs and sporadic adenomas with LGD or between UC-associated HGDs and sporadic adenomas with HGD. However, UC-associated carcinomas exhibited a lower apoptotic count than their sporadic invasive counterparts. This seemed related to higher survivin expression without a significant difference between the 2 types of invasive lesions regarding bcl-2 levels. Apoptosis is less frequent in UC-associated than in sporadic invasive colon carcinomas, this being linked to elevated survivin expression. The control of apoptosis may be different in the 2 types of tumorigenesis.

We comparatively assessed 41 mucinous colorectal carcinomas (MUCs) and 620 non-MUC (well-, moderately, and poorly differentiated adenocarcinoma) cases for clinicopathologic findings; and 41 MUCs and 115 randomly selected non-MUCs also were studied for the following: (1) apoptotic activity and Ki-67 immunoreactivity; (2) immunohistochemical expression of p21(WAF1/CIP1), p27Kip1, p53, and bcl-2; and (3) c-Ki-ras mutations. The rates for lymph node involvement and peritoneal dissemination were higher in MUCs than in non-MUCs. Multivariate analysis showed MUCs to have a worse prognosis than well-differentiated adenocarcinomas. The Ki-67 labeling for MUCs was significantly lower than that for non-MUCs, whereas the apoptotic index was significantly higher than for the well-differentiated type. The labeling for p21(WAF1/CIP1) and p27Kip1 was lower in MUCs (2.7% and 35.3%, respectively) than in well-differentiated adenocarcinomas (4.2% and 48.6%, respectively). MUCs can be considered a different tumor from the well-differentiated type, with a poor prognosis owing to frequent lymph node metastasis and peritoneal dissemination, and characterized by high apoptotic and low proliferative activities associated with low p21(WAF1/CIP1) and p27Kip1 expression.

Ovarian hormones are considered to be capable of regulating expression of β β β β-catenins. A possible role of β β β β-catenin in alteration of cell morphology has been proposed, but little is known about β β β β-catenin expression during changes in the tumor morphology of endometrial carcinomas induced by progesterone therapy. To clarify changes in expression of β β β β-catenin and their relation to morphological alteration, expression of hormone receptors and several cell kinetic markers, sequential biopsy and hysterectomy specimens of 23 endometrial carcinoma and 6 complex hyperplasia with atypia (atypical hyperplasia) cases receiving progesterone therapy were investigated. In vitro assay was also conducted using two endometrial carcinoma cell lines (HEC265 and Ishikawa) expressing progesterone receptors (PRs). An increase of nuclear β β β β-catenin accumulation was evident during progesterone therapy in endometrial carcinomas and atypical hyperplasias. he most successful approach to the treatment of endometrial carcinoma is hysterectomy with bilateral salpingooophorectomy, combined with cytotoxic chemotherapy and radiation therapy employed for advanced or recurrent tumors. Hormone therapy on the basis of the profound maturation-stimulating effects of progesterone is also applied for tumors in young patients to avoid the necessity of hysterectomy. 1) Such therapy alone, however, is not considered to be sufficient to eradicate carcinomas from the endometrium, since alterations in tumor morphology through cell maturation or differentiation are induced, but not cell death. 2, 3)β-Catenin was originally identified as a major component of the cadherin adhesion system, binding to both E-cadherin cytoplasmic and α-catenin amino-terminal domains.4) The cytoplasmic level of β-catenin is tightly regulated through degradation via the ubiquitin-proteasome pathway, whereby serine and threonine residues in exon 3 are phosphorylated by glycogen synthetase kinase (GSK)-3β and ubiquitinylated by binding to proteins such as adenomatous polyposis coli (APC), and axin. 5)Stabilization of cytoplasmic β-catenin due to up-regulation of wingless/wnt signalling or abnormalities of either APC or β-catenin proteins can lead to its interaction with nuclear transcription factors of the T cell factor-lymphoid enhancer factor (TCF/LEF) family, resulting in activation of target genes. [6][7][8] Recently, ovarian hormones have been reported to be capable of regulating several cell adhesion-related molecules, including E-cadherin, α-and β-catenins and cad-11.9-11) Moreover, changes in expression level and subcellular distribution of the β-catenin occur during morphological alterations through cell differentiation in several colorectal carcinoma cell lines. 12,13) Our previous findings indicated that β-catenin abnormalities may play an important role in relatively early events during the endometrial hyperplasia-carcinoma sequence.14) In the present study, to clarify possible associations between β-catenin and alteration of morphology in respon...

In order to investigate cell kinetics and cell cycle regulator protein expression with reference to the growth pattern of early gastric carcinomas (EGCs), we evaluated a total of 240 EGCs with submucosal invasion clinicopathologically and 106 submucosal invasive lesions immunohistochemically. The incidence of lymph node metastasis was relatively high (36.4%) in the superficially spreading growth (SUP) type tumors whereas the penetrating growth (PEN) type had a low incidence (5.7%, P < 0.001) and correlated with submucosal tumor size. Ki67 labeling was lower in submucosal areas of the SUP-type tumors (median, 37.3%) than the PEN-type tumors (51.0%, P < 0.001). ssDNA labeling in the lamina propria, indicative of apoptotic activity, was higher in the SUP-type tumors (0.55%) than in PEN-type (0.30%, P < 0.01) lesions. The expression of cell cycle regulator p21WAF1/CIP1 was lower in the SUP-type tumors (lamina propria 15.6%, submucosa 2.6%) than in PEN-type tumors (lamina propria 26.5%, submucosa 4.4%, P < 0.05-0.001). In conclusion, differences in cell kinetics and p21WAF1/CIP1 expression might influence the growth pattern of EGCs. The SUP-type EGC, characterized by high apoptotic in the lamina propria and low proliferative activities in the submucosa, is associated with frequent lymph node metastasis, suggesting a strong correlation between tumor size in the submucosa and metastatic potential.

To clarify kinetics in ulcerative colitis (UC)-associated lesions, cell proliferation, apoptosis, and expression of apoptosis-inhibitory proteins were studied. Ki-67 labeling and survivin and bcl-2 expression were examined immunohistochemically in 22 low-grade dysplasias (LGDs), 25 high-grade dysplasias (HGDs), and 13 adenocarcinomas associated with UC, and for comparison in 21 sporadic adenomas with LGD, 22 sporadic adenomas with HGD, and 21 invasive adenocarcinomas. Apoptosis was studied with nick-end labeling and immunohistochemical analysis of single-stranded DNA. In UC-associated LGDs, Ki-67--positive cells were more frequent in the lower than the upper half of the crypt, related to bcl-2 expression, while in sporadic adenomas such cells were more common in the upper half. No difference in apoptosis was found between UC-associated LGDs and sporadic adenomas with LGD or between UC-associated HGDs and sporadic adenomas with HGD. However, UC-associated carcinomas exhibited a lower apoptotic count than their sporadic invasive counterparts. This seemed related to higher survivin expression without a significant difference between the 2 types of invasive lesions regarding bcl-2 levels. Apoptosis is less frequent in UC-associated than in sporadic invasive colon carcinomas, this being linked to elevated survivin expression. The control of apoptosis may be different in the 2 types of tumorigenesis.