Modeling TGF-β signaling in human skin

By using artificial human skin, a research group has managed to block invasive growth in a skin cancer model.

The study has been published in Science Signaling and looks at what actually happens when a cell turns into a cancer cell.

“We have been studying one of the cells’ signalling pathways, the so-called TGF beta pathway. This pathway plays a critical role in the cell’s communication with its surroundings, and it controls e.g. cell growth and cell division. If these mechanisms are damaged, the cell may turn into a cancer cell and invade the surrounding tissue,” explains the senior author.

Under normal circumstances, your skin cells will not just start to invade the hypodermis and wreak havoc. Instead, they will produce a new layer of skin. But when cancer cells emerge, the cells no longer respect the boundaries between skin layers, and they start to invade each other. This is called invasive growth.

“We already have various drugs that can block these signalling pathways and which may be used in tests. We have used some of them in this study,” explains a co-author of the study.  

The artificial skin used by the researchers in the new study consists of artificial, genetically manipulated human skin cells. Skin cells are produced on subcutaneous tissue made of collagen. This makes the cells grow in layers, just like real human skin.

Unlike mice models, the skin model, which is another word for artificial skin, allows researchers to introduce artificial genetic changes relatively quickly, which provide insight into the systems that support skin development and renewal.

This way they are also able to reproduce and follow the development of other skin disorders, not just skin cancer.

“By using artificial human skin we are past the potentially problematic obstacle of whether results from tests on mice models can be transferred to human tissue. Previously, we used mice models in most studies of this kind. Instead, we can now conclude that these substances probably are not harmful and could work in practice, because the artificial skin means that we are closer to human reality,” says the senior author.

The loss of TGF-β1 or SMAD4 promoted cell cycling and delayed epidermal differentiation. The loss of TGF-βRII, which abrogates both SMAD4-dependent and SMAD4-independent downstream signaling, more strongly affected cell proliferation and differentiation than did loss of SMAD4, and it induced invasive growth.

TGF-βRII knockout reduced cell-matrix interactions, and the production of matrix proteins increased the production of cancer-associated cell-cell adhesion proteins and proinflammatory mediators and increased mitogen-activated protein kinase (MAPK) signaling. Inhibiting the activation of the ERK and p38 MAPK pathways blocked the development of the invasive phenotype upon the loss of TGF-βRII.

The artificial skin used by the researchers resembles the skin used to test cosmetics in the EU, which banned animal testing in 2004. However, artificial skin does not allow the researchers to test the effect of a drug on the entire organism, the author points out. Skin models like the one used here have been used by cosmetics companies since the mid-1980s.

“We can study the effect focussing on the individual organ – the skin – and then we reap experiences with regard to how molecules work, while we seek to determine whether they damage the structure of the skin and the healthy skin cells,” the author says.