Abstract
Cell and tissue polarity are tightly coupled and are vital for normal tissue homeostasis. Changes in cellular and tissue organization are common to even early stages of disease, particularly cancer. The digestive tract is the site of the second most common cause of cancer deaths in the developed world. Tumours in this tissue arise in an epithelium that has a number of axes of cell and tissue polarity. Changes in cell and tissue polarity in response to genetic changes that are known to underpin disease progression provide clues about the link between molecular-, cellular- and tissue-based mechanisms that accompany cancer. Mutations in adenomatous polyposis coli (APC) are common to most colorectal cancers in humans and are sufficient to cause tumours in mouse intestine. Tissue organoids mimic many features of whole tissue and permit identifying changes at different times after inactivation of APC. Using gut organoids, we show that tissue polarity is lost very early during cancer progression, whereas cell polarity, at least apical–basal polarity, is maintained and changes only at later stages. These observations reflect the situation in tumours and validate tissue organoids as a useful system to investigate the relationship between cell polarity and tissue organization.
Highlights
Tissue polarity is a key feature of epithelia, which line all cavities in the body [1]
Epithelia are the site for most human cancers, and the loss of tissue organization found in malignancies is usually accompanied by loss of polarity, the degree of change and the stage at which this loss occurs varies with tumour and tissue type
Paneth cells reside at the bottom of intestinal crypts where they help to create the niche for stem cells, whereas goblet and enteroendocrine cells are distributed throughout the epithelium at different densities in different parts of the intestinal tract [2,3]
Summary
Tissue polarity is a key feature of epithelia, which line all cavities in the body [1]. The axis from crypt to villus (small intestine) or crypt to lumen (colon) distinguishes cells closer to the gut wall from those closer to the lumen Whether this axis along which cells differentiate and migrate has molecular features of planar cell polarity (PCP) such as the planar-polarized distribution of specific proteins is not known, but the directional migration and differentiation along this axis suggests that elements of PCP may operate. Absorptive cells have an average lifespan of 3–5 days in the intestine and are constantly replenished from stem cell pools This translates into 20–50 million cells being lost per minute in humans creating the most highly turning over tissue in the body [10]. Understanding how loss of normal APC contributes to tissue organizational and polarity changes can inform about the contribution of different cellular processes to cell and tissue polarity and the relationship between them
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