Abstract
Tumor budding is a histological phenomenon encountered in various cancers, whereby individual malignant cells and/or small clusters of malignant cells are seen in the tumor stroma. Postulated to be mirror epithelial-mesenchymal transition, tumor budding has been associated with poor cancer outcomes. However, the vast heterogeneity in its exact definition, methodology of assessment, and patient stratification need to be resolved before it can be routinely used as a standardized prognostic feature. Here, we discuss the heterogeneity in defining and assessing tumor budding, its clinical significance across multiple cancer types, and its prospective implementation in clinical practice. Next, we review the emerging evidence about partial, rather than complete, epithelial-mesenchymal phenotype at the tumor bud level, and its connection with tumor proliferation, quiescence, and stemness. Finally, based on recent literature, indicating a co-expression of epithelial and mesenchymal markers in many tumor buds, we posit tumor budding to be a manifestation of this hybrid epithelial/mesenchymal phenotype displaying collective cell migration.
Highlights
Tumor budding is a histological phenomenon encountered in various cancers, whereby individual malignant cells and/or small clusters of malignant cells are seen in the tumor stroma
It has been suggested that tumor budding assessment might help identify patients at risk for worse outcome in the following contexts: (i) patients with pT1 lesions or malignant polyps endoscopically resected with increased risk for nodal metastasis; (ii) patients with stage II disease who might benefit from adjuvant therapy; and (iii) patients with RC undergoing biopsy who might benefit from neoadjuvant therapy
The proliferative marker Ki-67 [131]. These findings suggest that tumor buds are quiescent, which further supports a putative involvement of Epithelial-Mesenchymal Transition (EMT) in tumor budding because (i) it corroborates with the ‘go-or-grow,’ or proliferation/migration dichotomy, hypothesis ([132], recently demonstrated in a developmental context by Matus and colleagues [133] who showed that the invasive phenotype requires cell cycle arrest); (ii) induction of EMT has been shown to be capable of both blocking the cell cycle and conferring resistance to apoptosis in multiple contexts [134,135,136,137]; and (iii) overexpression of miR-200 and consequent mesenchymal-epithelial transition (MET) can restore sensitivity to apoptosis and anoikis, a form of cell-death triggered by separation from the extracellular matrix [138]
Summary
“tumor budding” basically means the presence of clusters of undifferentiated malignant cells in the tumor stroma, which are located mainly (but not exclusively) in close proximity ahead of the invasive front of a tumor (reviewed in [1,2,3]). This critique was properly addressed by Carr and colleagues [8] through serial sections of colon cancer, and in more detail by Bronsert and colleagues [10] through 3D reconstructions from 2D serial sections of various tumor types These studies clearly showed that tumor budding is not a static snapshot, but rather a dynamic process by which the tumor extends numerous fingerlike projections, each containing numerous cells, which, at a later point, break apart from the main tumor mass as small cell clusters. CRC was the first cancer type in which budding was addressed systematically, providing the most abundant and consistent body of literature, which accounts for the standardization efforts in this emerging subfield
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