Evidence seems to suggest that the presence of tumor budding or an infiltrating growth pattern is inversely correlated with the presence of immune and inflammatory responses at the invasive tumor front[8,9]. In fact, several tumor-associated antigens such as CD3, CD4, CD8, CD20, Granzyme B, FOXP3 and other immunological or inflammatory Vandetanib cancer cell types have been identified as potentially prognostic in patients with this disease[10-16]. Together, evidence seems to suggest that the balance between pro-tumor (including budding and infiltrating growth pattern) and anti-tumor (immune response or certain inflammatory cell types) factors at the invasive front of colorectal cancer may be decisive in determining tumor progression and the clinical outcome of patients with colorectal cancer.
The aim of this review is to outline the evidence supporting a pro-/anti-tumor factor model of colorectal cancer progression, one which highlights the dynamic interface between tumor and host-related factors at the invasive front of colorectal cancer. THE INVASIVE FRONT OF COLORECTAL CANCER: PRO-TUMOR FACTORS Tumor budding-migrating cancer stem cells (CSCs)? In 1985, a study of colonic adenocarcinoma in rats reported a peculiar feature at the invasive border of differentiated tumors[17,18]. Using both light and electron microscopy, Gabbert et al[18] observed neoplastic glands irregularly arranged into small strands and cords. In addition, they noted discontinuous small aggregates or single tumor cells which ultrastructurally did not possess junctional complexes, often had incomplete desmosomes, missing or rudimentary basement membranes and absent or incomplete brush borders.
They determined that at the invasive tumor front of colorectal cancer, differentiated tumors could acquire an undifferentiated phenotype. Their observation is credited for pioneering the concept known as de-differentiation at the invasive margin, which today is commonly referred to as ��tumor budding��. Tumor budding is a histological feature diagnosed at high magnification and is defined as single cells or clusters of up to four or five cells at the invasive tumor front[19]. Budding cells can be spotted using standard HE-stained tissue slides and their visualization is further facilitated using pan-cytokeratin stains (Figure (Figure1A1A and andBB)[7].
The process of tumor budding is likened to EMT observed during gastrulation in embryonic development[7]. In the early phase Dacomitinib of EMT, epithelial cells reduce intercellular contacts and cell-matrix contacts and reorganize the cytoskeleton to form cell membrane ruffles (lamellipodia) or cytoplasmic protrusions. Migration ensues and new cell-matrix contacts are formed providing cells with an anchorage for the contraction of the cell body. In colorectal cancer, tumor budding is a highly dynamic process giving temporal heterogeneity to the tumor. Figure 1 The invasive front of colorectal cancer.