Abstract
The adenoma-to-carcinoma progression in colon cancer is driven by a sequential accumulation of genetic alterations at specific tumor suppressors and oncogenes. In contrast, the multistage route from the primary site to metastasis formation is underlined by phenotypic plasticity, i.e., the capacity of disseminated tumor cells to undergo transiently and reversible transformations in order to adapt to the ever-changing environmental contexts. Notwithstanding the considerable body of evidence in support of the role played by epithelial-to-mesenchymal transition (EMT)/mesenchymal-to-epithelial transition (MET) in metastasis, its rate-limiting function, the detailed underlying cellular and molecular mechanisms, and the extension of the necessary morphologic and epigenetic changes are still a matter of debate. Rather than leading to a complete epithelial or mesenchymal state, the EMT/MET-program generates migrating cancer cells displaying intermediate phenotypes featuring both epithelial and mesenchymal characteristics. In this review, we will address the role of colon cancer heterogeneity and phenotypic plasticity in metastasis formation and the contribution of EMT to these processes. The alleged role of hybrid epithelial/mesenchymal (E/M) in collective and/or single-cell migration during local dissemination at the primary site and more systemic spreading will also be highlighted.
Highlights
Tumor Heterogeneity in Colon CancerColon cancer is the third most commonly diagnosed malignancy and the second leading cause of cancer-related death worldwide
It is generally accepted that primary colon carcinomas are heterotypic, i.e., they feature a heterogeneous composition of epithelial cancer cells intermingled with lymphocytes, stromal fibroblasts, endothelial, and other cell types from the micro- and macro-environment [3]
In order to successfully complete this challenging series of events, the most important feature of the metastasizing cancer cell is the capacity to adapt to the ever-changing environmental contexts by undergoing reversible changes in its cellular identity
Summary
Colon cancer is the third most commonly diagnosed malignancy and the second leading cause of cancer-related death worldwide. In order to successfully complete this challenging series of events, the most important feature of the metastasizing cancer cell is the capacity to adapt to the ever-changing environmental contexts by undergoing reversible changes in its cellular identity This ‘Dr Jekyll and Mr Hide’ feature of migrating cancer cells is often referred to as phenotypic plasticity [13] and is controlled by epigenetic mechanisms which regulate, among other processes, epithelial-to-mesenchymal transition (EMT) and the reverse mesenchymal-to-epithelial transition (MET) [14]. Rather than leading to a complete epithelial or mesenchymal state, the EMT/MET programs generate migrating cancer cells displaying intermediate phenotypes featuring both epithelial and mesenchymal characteristics These hybrid E/M cancer cells have been the focus of much attention in the most recent scientific literature as they are likely to be metastable and as such very efficient in causing metastasis [20]. E/M in collective and/or single-cell migration during local dissemination at the primary site and more systemic spreading will be highlighted
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