LAT1 aberrant overexpression in PDAC predicts poor prognosis, independent of Ki-67 LI, and offers a potential target for future anticancer therapy with its inhibitors.

Vitamin A is essential to mucosal immunity and cell differentiation. The fact that lack of it might involve chronic inflammation and increased risk of cancer has been reported. Little is known about the mechanism of vitamin A deficiency in the development of colitis and its influence on development of colorectal cancer. To determine the influence of vitamin A deficiency on colitis and colorectal cancer development, an experimental study using a colitis mouse model was performed. Dextran sulfate sodium (DSS) colitis was induced in vitamin A-deficient and vitamin A-supplemented mice. Further, colorectal carcinoma was induced by a combination of azoxymethane preinjection and DSS colitis. Results were compared between the two groups mainly by immunohistochemical analysis. Colitis was more severe and recovery from colitis was slower in vitamin A-deficient mice than in vitamin A-supplemented mice. Compared with vitamin A-supplemented mice, vitamin A-deficient mice had decreases in colonic subepithelial myofibroblasts and the ratio of mucosal IgA+/IgG+ cells, increases in CD11c+ dendritic cells, and a higher rate of development of colorectal carcinoma with colitis following azoxymethane. Vitamin A lipid droplets in subepithelial myofibroblasts were decreased in vitamin A-deficient mice, suggesting alterations in colonic crypt niche function. Thus, vitamin A inhibited colitis and the development of colorectal cancer.

The aim of the present study was to determine whether expression of molecules associated with cell cycle regulation and apoptosis might reflect tumor grade and patients' prognosis of gastrointestinal stromal tumor (GIST). Forty-nine cases of gastric GIST were divided into three grades; low, intermediate, and high risk. Ki-67, cyclin A, cyclin D1, cyclin E, p16(Ink4), p21(Waf1), p27(Kip1), cyclin-dependent kinase (cdk)2, cdk4 and single-strand DNA (ssDNA) were immunohistochemically stained and assessed. Ki-67, ssDNA, cyclin A and cdk2 had higher labeling indices (LI) in high-risk than in low-risk cases. Cyclin E expression was greater in the intermediate- than in the low-risk grade. On Kaplan-Meier analysis, tumor size, necrosis, cellularity, Ki-67, ssDNA, and cyclin A LI were significantly correlated with disease-free survival. Necrosis, cellularity, and Ki-67 LI were significant as prognostic factors on univariate, and Ki-67 LI on multivariate Cox hazard tests. Within the high-risk grade, high cellularity and low p27(Kip1) subgroups had the worst prognosis. The histological grade is related to cell turnover, assessed in terms of Ki-67, ssDNA, cyclin A, cyclin E, and cdk2 levels. Ki-67, ssDNA, and cyclin A are useful for prediction of prognosis, with cellularity and p27(Kip1) expression as further prognostic factors in high-risk cases.

Evidence has been provided in ulcerative colitis (UC) that early genomic instability of both epithelial and stromal cells is important for colorectal tumorigenesis, as well as remodeling and morphological alterations of mucosal crypts. To clarify roles of stromal cells in tumor development in UC, the present study focused on heterogeneous phenotypes of subepithelial myofibroblasts and interstitial cells, in association with mucosal remodeling. To clarify the relationship of alterations to tumorigenesis, mucosa of resected rectae from patients with UC (n= 49) and sporadic cancer (n= 10) were analyzed on immunohistochemistry and also on immunoelectron microscopy. Heterogeneous phenotypes of neural cell adhesion molecule (NCAM)+ and/or alpha-smooth muscle actin (alpha-SMA)+ subepithelial myofibroblasts and interstitial cells were demonstrated, corresponding to colonic stellate cells. Decrease of NCAM+ subepithelial myofibroblasts and interstitial cells, and increase of alpha-SMA+ interstitial cells were significant in UC with neoplasia as compared to without neoplasia. alpha-SMA+ muscularis mucosae was significantly more thickened in tumor cases. Deposits of Masson's trichrome+ and type III and I collagen in the muscularis mucosae and lamina propria appeared to increase in relation to the numbers of alpha-SMA+ interstitial cells. Mucosal remodeling with alterations of NCAM+ or alpha-SMA+ subepithelial and interstitial cells may play a critical role in UC-associated tumorigenesis.

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