It is certain that patients with ulcerative colitis (UC) are more liable to develop a colon carcinoma than those without UC . In our experience, UC-associated carcinoma tends to be more poorly differentiated when the carcinoma invades deeper than the submucosa, even if it is well differentiated in the lamina propria. Although the prognosis of UC-associated carcinoma had been regarded as grave in the past [2, 3], clinicopathological studies suggested similarity to sporadic colorectal carcinoma [2–4]. However, it is still controversial, and the difference of invasion between UC-associated carcinoma and sporadic colon carcinoma has not yet been elucidated.
Focusing on factors for invasion, we earlier compared expression of cell adhesion molecules in UC-associated carcinomas with those in sporadic colonic adenocarcinomas, revealed significantly decreased expressions of CD44 and alpha-catenin and altered expression of beta-catenin in UC-associated lesions . However, it was unclear whether or not UC-associated carcinoma has a more invasive behavior and whether or not carcinoma cell differentiation influences the biological behavior in UC-associated lesions. Therefore, in the present study, we tried to compare UC-associated carcinoma cases with sporadic colorectal adenocarcinoma counterparts, focusing on prognosis, tumor cell differentiation, tumor budding, and several protein expressions.
Recently, tumor budding has become considered a major malignant characteristic of colorectal carcinomas [6, 7]. Defined as the presence of isolated single cells or small cell clusters (≤4 cells) scattered in the stroma at invasive fronts , this features loss of both glandular differentiation and cell cohesion that is crucial for the development of high-invasive properties. Tumor budding has been reported to be a risk factor for lymphatic involvement and lymph node metastasis in sporadic colorectal carcinomas [8, 9]. However, the prognoses of patients with UC-associated carcinomas are not known.
Regarding cell adhesion molecules, the down-regulation of CD44 expression is reported to correlate with metastasis and poor prognosis in various types of carcinoma [10, 11]. Recently, it was reported that CD44 reduction is caused in part by the proteolysis-based cleavage of its extracellular domain, which occurs in many malignant tumors . Zo-1 and occludin are tight junction-associated proteins, which seal the cells together and prevent diffusion of solutes from the outside . It was reported that both occludin and Zo-1 showed reduced expression in poorly differentiated gastrointestinal carcinoma .
When beta-catenin translocates into the nucleus and binds to the T-cell factor, it acts as a transcription factor for various genes , including matrix metalloproteinase-7 (MMP-7, matrilysin) , which is known to play roles in extracellular matrix degradation [16, 17]. One of the main targets of MMP-7 in epithelial basement membranes is the laminin-5 isoform, formed by association of α3, β3, and γ2 chains. Specific cleavage of the laminin-5γ2 chain by members of the MMP family has been proposed to favor cell migration [17, 18].
A modified blood group ABO/Lewis antigen, sialyl Lewis X (LeX) is present on the surfaces of human leukocytes [19, 20]. It was also reported to be expressed in colonic carcinoma cells while sialyl 6-sulfo LeX is characteristic of normal colonic epithelium , and it was considered to play an important role in metastasis through the binding to E-selectin on endothelial cells . Increased expression of sialyl LeX correlates with a poor prognosis in patients with colorectal carcinoma, demonstrating relations to the depth of tumor invasion, lymph node metastasis, lymphatic invasion, and the disease stage [23, 24].
In the present study, expression of CD44 extracellular domain, Zo-1, occludin, MMP-7, and laminin-5γ2 in association with beta-catenin nuclear localization, and levels of sialyl LeX were immunohistochemically investigated along with tumor budding in UC-associated and sporadic colon carcinomas, with the aim of elucidating differences in mechanisms of invasion and biological behavior between the two types of colon carcinomas in relation to prognoses.