Natural protection against cancer

Healthy skin cells can get rid of cancer neighbors

Vyacheslav Kalinin, "Elements"

A fundamentally new mechanism has been discovered by which healthy tissues can get rid of tumor-bearing mutant cells. It turned out that in response to the appearance of mutant cells originating from dividing stem cells, normal skin hair follicle cells can accelerate division, surround and remove mutant cells. It is not yet known to what extent the open phenomenon is applicable to other tissues and organs and what specific mechanisms are involved in this. This is likely to be the subject of active research in the near future.

Fig. 1. Dynamics of mutant cell growth in the hair follicle. a – the expression of a mutant gene is induced in stem cells, causing increased proliferation. b – the population of mutant cells (red) is growing rapidly. c – healthy cells multiply rapidly and surround mutant cells in the middle of the follicle. d – healthy cells remove mutant cells and ensure further normal tissue growth. A drawing from the popular synopsis to the article under discussion in Nature

When a cell divides, duplication of its genome may with some probability go wrong, and as a result, mutations will appear in the descendant cells. The more actively the cells divide and the faster the tissue is renewed, the more mutant cells appear in it. Mutations can change the normal behavior of a cell, disrupt its differentiation, take its division out of control and turn it into an uncontrollably dividing malignant cell, giving rise to a cancerous tumor. And it is still unclear how, in such a situation, even very actively renewing tissues and organs remain normal, maintaining their homeostasis – the constancy of structure and functions. Is this due to the suppression of oncogen activity or in some other way?

Thus, using the methods of high-efficiency sequencing of a new generation, it was shown that oncogenic mutations are observed in a certain number of human skin cells (skin cells are just rapidly updated) (I. Martincorena et al., 2015. High burden and pervasive positive selection of somatic mutations in normal human skin). And despite this, the structure of the skin remains normal – cancerous tumors do not form.

A group of researchers led by Valentina Greco (see Greco lab) from the Yale University School of Medicine tried to figure out what happens to mutant cells in the skin. Using genetic engineering methods, they obtained lines of laboratory mice in which the newly formed hair follicle stem cell (HFSC) stem cells (hair follicle stem cell, HFSC) could artificially induce the synthesis of mutant activated protein β-catenin, which is involved in interactions between cells and about which it is known that its activation stimulates the formation of tumors (mostly benign) in epithelial tissues. In the article under discussion, scientists from the Greco laboratory continued their work with follicle stem cells, within the framework of which, in particular, methods based on fluorescence microscopy were previously developed that allow for a long time to observe the "life" of these cells in the follicles of living mice (see P. Rompolas et al., 2012. Live imaging of stem cell and progeny behavior in physiological hair-follicle regeneration).

After starting the synthesis of β-catenin using the Cre system (see Cre-Lox recombination) in the cells monitored, the follicles swelled and new outgrowths formed in them within 1-2 weeks (Fig. 2). But suddenly it turned out that then the growth stopped and in about 80% of cases the outgrowths disappeared, and the follicles returned to their original normal state in a month (the remaining ones returned to normal for a little longer), later showing nothing unusual.

Fig. 2. The expression of mutant β-catenin causes abnormal growth of hair follicles first, and then their regression. The numbers 1 and 2 indicate two close follicles. The nuclei of follicle stem cells (HFSCs) are highlighted in green. Purple highlights the outgrowths that appeared about two weeks after the inclusion of β-catenin expression. It can be seen that by the end of the month of research, they completely disappeared and did not appear in the future. The length of the scale segment is 50 microns. A drawing from the discussed article in Nature

Thus, after a short-term disruption of the structure of the hair follicle caused by β-catenin, the skin returns to normal homeostasis. Scientists decided to figure out how this happens. They labeled beta-catenin-expressing mutant cells and normal cells with different fluorescent proteins. Observations showed that mutant cells were mainly concentrated in the center of outgrowths. And before the outgrowths began to decrease, the mutants were tightly surrounded by actively dividing normal cells, and then removed from the tissue (Fig. 3). The authors do not specify exactly how the mutant cells disappeared, but apparently they were displaced from the follicle into the dermis, where these cells died. This process can be viewed on the video from the additional materials to the article.

Fig. 3. A detailed illustration of the growth and regression of the hair follicle (circled with a dotted line). Cells expressing mutant β-catenin are stained with red dye, healthy HFSCS are stained with green. A drawing from the discussed article in Nature

In similar experiments, in which a stronger oncogene, the Hras protein, was used instead of β-catenin, similar results were obtained: the follicles first grew strongly, but then their regression was observed, after which they either died off or again became a normal component of the skin.

Since mutants were always surrounded by normal cells before disappearing, the authors faced the question of how exactly healthy cells recognize mutants. Earlier, scientists from the Greco group showed that hair growth controlled by normal cells is stimulated by ligands interacting with proteins of the Wnt family. The mammalian Wnt signaling pathway is involved in the control of cell division, embryogenesis, cell differentiation, and tumor development. The authors showed that inactivation of the Wntless gene, which regulates the production of Wnt protein activator ligands, deprived normal cells of the ability to encapsulate mutant cells (Fig. 4).

Fig. 4. An active Wnt signaling pathway is required to correct hair follicle tissue. When the Wntless gene is inactivated, there is no enhanced growth of normal cells, and they do not surround the cells that secrete β-catenin. As in Fig. 3, mutant cells are shown in red, healthy HFSCS are shown in green. The length of the scale segments is 50 microns. A drawing from the discussed article in Nature

Direct suppression of normal cell division by artificial induction of the proliferation-blocking Cdkn1b protein in them was accompanied by the multiplication of β–catenin-producing mutants and the formation of cyst-like structures without signs of regression (Fig. 5) - just as in the absence of Wnt ligands.

5. Expression of CDKN1b protein in normal cells, suppressing their proliferation, leads to continued growth of mutant β-catenin producers, and regression of hair follicles does not occur. A drawing from the discussed article in Nature

Thus, the article under discussion describes a fundamentally new mechanism by which normal tissue can resist the formation of tumors. It turned out that the cells of the hair follicles of the skin have extraordinary plasticity, expressed in the ability to eliminate defects and maintain skin homeostasis. At the same time, the results raise many questions that have yet to be answered.

How exactly do healthy cells "feel" their mutant neighbors? The authors have shown that this can occur through communication between mutant and normal cells via the Wnt signaling pathway. But it is unclear whether other signaling pathways are involved in the elimination of these defects, whether a similar protective mechanism works in other tissues and which signaling pathways are used in its implementation.

Further, how do mutant cells overcome the action of this mechanism and initiate the formation of tumors (which, alas, sometimes still form)? It is known that stem cells that have undergone the process of differentiation and stopped dividing do not necessarily remain in this state. If necessary, they can "dedifferentiate" and turn into progenitor cells. So, there are no stem cells in the pancreas. And the only way to repair the damage to her tissue is to turn part of her cells into a state that allows them to divide again and repair the defect. Such plasticity can be useful in some situations, and in others it is fraught with the possibility of a cancerous tumor. Mutations of the Kras oncogene, related to Hras, are present in almost all cancerous tumors of the pancreatic ducts. It has been shown that the presence of these mutations in differentiated non-dividing cells very rarely causes cancer. But if the gland is damaged, for example, in pancreatitis and some of its cells begin to divide to eliminate the defect, mutant Kras prevents reverse differentiation, promotes their further growth, and a malignant tumor may form (J. C. Mills, O. J. Sansom, 2015. Reserve stem cells: Differentiated cells reprogram to fuel repair, metaplasia, and neoplasia in the adult gastrointestinal tract).

In general, this work is absolutely innovative. Many researchers have focused on studying the reaction of healthy cells to an already formed tumor – on how they prevent or contribute to the further development of the tumor. In contrast, the mechanisms of this interaction at the stage of tumor origin are investigated here. In particular, it was possible for the first time to demonstrate the process of competition of various cells in mammals in vivo (in this case, the elimination of mutant cells by normal ones). It can be assumed that the phenomenon discovered by the authors, which is of great importance both for medicine and for the general biology of the cell, will be actively studied in the near future.

Sources:
1) Brown et al., Correction of aberrant growth preserves tissue homeostasis // Nature. 2017. V. 548. P. 334–337.
2) J. Burclaff, J. C. Mills. Cell biology: Healthy skin rejects cancer // Nature. 2017. V. 548. P. 289-290. (Popular synopsis to the article under discussion.)

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