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Morphological instabilities of stratified epithelia: a mechanical instability in tumour formation

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Morphological instabilities of stratified epithelia: a mechanical instability in tumour formation
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Interfaces between stratified epithelia and their supporting stromas commonly exhibit irregular shapes. Undulations are particularly pronounced in dysplastic tissues and typically evolve into long, finger-like protrusions in carcinomas. In previous work (Basan et al 2011 Phys. Rev. Lett. 106 158101), we demonstrated that an instability arising from viscous shear stresses caused by the constant flow due to cell turnover in the epithelium could drive this phenomenon. While interfacial tension between the two tissues as well as mechanical resistance of the stroma tend to maintain a flat interface, an instability occurs for sufficiently large viscosity, cell-division rate and thickness of the dividing region in the epithelium. Here, extensions of this work are presented, where cell division in the epithelium is coupled to the local concentration of nutrients or growth factors diffusing from the stroma. This enhances the instability by a mechanism similar to that of the Mullins–Sekerka instability in single-diffusion processes of crystal growth. We furthermore present the instability for the generalized case of a viscoelastic stroma.
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Transcript: English(auto-generated)
Epithelia constitute the most common tissue type in our body. They line the entire surface of the body as well as its cavities and tubes. Partly because they are under constant cell renewal, they are at the origin of most human tumors. Epithelia can either consist of a single layer of cells or be multilayered when they serve a protective function.
Here, we study multilayered epithelia, of which examples are the skin, the internal cavity of the mouth, or the lining of the cervix. Multilayered epithelia consist of tightly adhesive confluent cells.
They have a free surface on one side and are attached to a basement membrane on the other side, which separates them from a supporting connective tissue. Cells in healthy epithelia divide at the basement membrane, in part because they get the nutrients and growth factors they need from the connective tissue by diffusion processes.
This creates a flow of cells from the basement membrane to the free surface of the epithelia. Epithelia commonly exhibits undulations at the interface with the connective tissue. In cancerous and precancerous epithelia, the dividing layer becomes thicker, and these protrusions are typically more pronounced.
This is illustrated here, where we can see three different stages of cervical tumors, respectively Grade 1 on the top left illustration, Grade 2 on the bottom left, and Grade 3 on the right. In the paper, we address three questions. First, what are the forces responsible for the formation of these undulations?
Second, can we understand the apparent correlation between the thickness over which cells divide and the amplitude of these undulations? And third, what is the role played by nutrients or growth factors diffusion from the connective tissue?
Modeling the epithelium as a viscous fluid with cell division and cell death, we propose that the hydrodynamic instability plays a role in these undulations. In short, cell division above a nascent protrusion gives rise to a velocity gradient in the tissue. Associated stresses lead to a buildup of pressure in the protrusion, driving it further into the connective tissue.
We analyze the physics of this instability and find dependencies on tissue properties that are consistent with biological observations. For example, we find that increasing the thickness of the dividing region in the epithelium enhances the instability. We also investigate the role of the diffusion of nutrients coming from the connective tissue.
Comparing our models with or without this coupling, we find that the instability is globally enhanced when nutrient diffusion is properly taken into account. More precisely, the instability shows an extra maximum for small wave numbers that is at long wavelengths.
This additional peak is reminiscent of the instability known as the Merlin-Sikarka instability, which occurs in single diffusion processes of crystal growth. In the formation of snowflakes, for example, the diffusion of water vapor molecules in the air drives the shape instability.
In our case here, the additional long wavelength instability is due to the spatial inhomogeneities arising from nutrient diffusion limitations. In summary, we demonstrate the existence of a hydrodynamic instability in stratified epithelia that relies on shear forces due to the differential cell proliferation.
This instability may be at the origin of undulations between multilayered epithelia and their adjacent connective tissues, as frequently observed in biological samples, and which are characteristic of cancerous progression.