Our main findings suggest that positive expression of EpCAM and ABCG5 within tumor buds is a frequent event selleck chemicals llc and may confer a significant and adverse prognosis in patients with colorectal cancer, particularly in lymph node-negative patients expressing ABCG5. Several of these putative CSC markers have previously been evaluated in tumor buds. Horst et al[31] assessed CD133 in colorectal cancers using 3 different antibodies. They reported pronounced expression of CD133 in tumor glands close to the invasive margin but restricted to glandular differentiated cells and a general lack of CD133 in the tumor buds themselves. They further found that nuclear ��-catenin expression and CD133 were not correlated and that the 2 protein markers may stain different, yet overlapping populations of tumor cells[32].

Our results of only a few CD133-positive tumor budding cases and no prognostic differences between patients with CD133-positive and -negative tumor budding are in line with these findings. Investigating rectal cancers, Gosens et al[33] found strong membranous EpCAM staining in the tumor center and a progressive loss at the tumor front associated with high tumor grade, tumor budding, and a poor local and distant recurrence-free survival. This was also accompanied by a concomitant increase in cytoplasmic EpCAM staining as well as overexpression of ��-catenin. We also observed a pronounced loss of EpCAM toward the invasive tumor front, particularly in tumors with infiltrating margins, as well as a shift in localization of EpCAM expression from membrane to cytoplasm.

The findings of this study indicate that despite this loss towards the border, patients with EpCAM-positive tumor buds have a most unfavorable survival time, a result which was maintained in multivariable analysis. Although EpCAM, like CD44, is known for its cell-adhesion function, it seems to have versatile roles in signaling, cell migration, proliferation, and differentiation depending on the microenvironment[34]. In the normal epithelium, EpCAM supports adhesion, whereas in carcinoma it seems to prevent strong cell-cell adhesion, enabling cell migration and metastasis similar to E-cadherin. The intracellular localization of EpCAM and its identification by immunohistochemistry may represent differential roles of this protein in colorectal cancer progression and partially explain why, despite loss of expression from normal at tumor center to tumor border, the positive expression in buds is linked to a poorer patient outcome.

Masaki et al[35] have also described associations between membranous CD44 and CD44v6 expression and a higher degree of tumor budding. However, Batimastat it is unclear from these studies whether expression was evaluated in the tumor center, then correlated with tumor budding or whether expression was evaluated in buds themselves.