Microenvironmental control of epithelial cell fate
Wakefield, Seth Emerson
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Cancer is a devastating condition, yet its prevalence is not surprising when one considers the possibility that growth and motility define the default state of epithelial cells. What is more surprising is that epithelial cells can be induced to a “fragile quiescent state” in multicellular organisms through constant inhibitory influences from extracellular sources. In other words, the immotile and growth-constrained behavior we associate with epithelia (quiescence) is not the default state cells in a multicellular organism, but rather must be exogenously induced by tissue-specific (and systemic) factors. Quiescence therefore, is a fragile existence for any cell, as the removal of differentiating signals should cause the cell to revert to a migratory, stem-like default state. It will be argued that cancer is better understood as a disease of tissues rather than individual cells, and the complexities of tissues cannot be inferred from the study of cells in isolation. In-vitro studies which have been used to explain carcinogenesis will be critically reviewed and their relevance to in-vivo conditions will be questioned. Complex signaling mechanisms define the relationship between the epithelium and other cells in a metazoan tissue. These signals originate both from the stromal/mesenchymal compartments and between epithelial cells. Studies have shown that carcinogenic insults which affect the stroma alone can turn an otherwise normal epithelium cancerous, while transplanting “cancerous” epithelial cells into an otherwise normal stroma does not result in neoplasm formation. Experimental evidence has confirmed that the differentiation fate of any epithelial cell is malleable depending on its environmental context. Further, it was previously thought that epithelium had to dramatically change identity in order to be capable of migration. It will be shown that collective motility is an endogenous capability of epithelial cells, and multiple non-mammalian and mammalian in-vivo studies of collective epithelial motility will be reviewed to better understand epithelial motility in cancer. In fact, it will be shown that the creation of adhered epithelial sheets requires the same morphological changes necessary for motility. Lastly, evidence that heterogeneous cell populations contribute to epithelial cell migration in development and metastasis will be presented.