Competition for access to a survival factor has been found to explain why incoming cells from the bone marrow replace resident cells in the thymus. Reducing this competition can cause tumours to form. See Article p.465
The idea that cells in the body compete in a Darwinian manner — that is, according to the laws of natural selection — has been postulated several times. First, in 1881, zoologist Wilhelm Roux anticipated that cells and 'parts' of an organism must fight with each other to form the body during embryonic development. A few years later, neuroscientist Santiago Ramón y Cajal predicted that neurons undergo a competitive struggle for space and nutrition. This suggestion gained support with neurologist Rita Levi-Montalcini's discovery of growth factors, and their integration into the 'neurotrophic theory', which proposed that neurons compete for limiting amounts of survival-promoting factors, a process that potentially eliminates unfit cells. On page 465 of this issue, Martins et al.1 describe another example in which Darwinian competition between cells occurs naturally — in this case, serving as a potent tumour-suppressor mechanism in the thymus.
The thymus is a specialized organ of the immune system. Located in the thoracic cavity, its function is to host a type of immature white blood cell, the T cell, and to develop such cells into mature T cells that are capable of recognizing harmful foreign substances. The normal function of the thymus depends on a continuous supply of cells from the bone marrow2. When these bone-marrow-derived progenitors reach the thymus, they replace thymus-resident progenitors (Fig. 1a).
Martins and colleagues were inspired by previous research in Drosophila fruit flies showing that slowly proliferating cells are recognized and eliminated by cells proliferating at a normal rate, through a mechanism proposed to involve competition for extracellular factors3. In a distinctive case of the 'random walks' by which science moves forward, those researchers were themselves motivated by the trophic theories4 discussed above: that Darwinian-like competition among cells for factors required for survival leads to elimination of a fraction of the cell population.
Martins et al. resolved to analyse whether, in mice, the normal replacement of thymus-resident progenitors by bone-marrow-derived colonizing cells shows the hallmarks of this type of competition. They found that competition for the blood-cell survival factor interleukin-7 (IL-7) could explain this replacement. IL-7 can activate the expression of an intracellular pro-survival protein, Bcl2 (ref. 5). The authors propose that IL-7 availability is limited for thymus-resident progenitors and that, in the presence of bone-marrow-derived progenitors, this leads to lower levels of Bcl2 in thymus-resident cells and, therefore, their death.
The next (and perhaps the most intriguing) question the researchers asked was: what would be the consequences of a lack of competition in this organ? In other words, what would happen in the absence of incoming bone-marrow progenitors? It was known that in the absence of incoming cells, the thymus-resident progenitors can self-renew and produce T cells6, compensating for this loss. But the surprise came when Martins and colleagues observed that the lack of competition from colonizing bone-marrow cells resulted in the formation of tumours (Fig. 1b), owing to the genetic transformation of the thymus-resident progenitors. Interestingly, the transformation of the thymus-resident progenitors produced a tumour type that resembled human T-cell acute lymphoblastic leukaemia in many aspects, including the type of genomic changes, the cells' gene-transcription profiles and the presence of activating mutations in the gene Notch1. The results suggest that cell competition is required to periodically replace thymus-resident progenitors with fresh bone-marrow-derived progenitors, and that if this process is interrupted the thymic cells become cancerous.
Thus, this study describes an exciting Darwinian mechanism that functions to prevent cancer in the thymus. But there are several aspects to this process that warrant further investigation. For example, it seems from the authors' findings that cells in the thymus have a higher propensity to develop tumours than cells in other organs, but why might this be the case? Is the environment of the thymus cancer-promoting — do progenitors suffer cellular or genetic insults while performing their tasks in the thymus? Or do cells moving from the bone marrow to the thymus come with a pre-programmed 'expiry date' and become malignant after this?
It is also apparent from work in Drosophila that trophic theories are inadequate to explain cell competition. In flies, the amount of survival factor for which cells compete does not need to be limiting, because there is a fascinating mechanism — based on 'fitness fingerprints' displayed on cell membranes — that allows cells to compare their fitness directly7,8. If similar systems enable mammalian cells to exchange fitness information, thymic progenitors might be able to detect and eliminate less-efficient cells even if there is no scarcity of the molecules they compete for. One testable prediction of this model is that progenitors with impaired IL-7 signalling will modify their fitness fingerprints accordingly, and actively reveal their fitness to neighbouring cells.
What are the consequences of Martins and colleagues' discovery for cancer treatment? T-cell acute lymphoblastic leukaemia is an aggressive cancer that frequently shows more-pronounced resistance to chemotherapy than does the more common form of blood cancer, B-cell lymphoma. Targeting the genes involved in cell competition might provide an avenue for treating and diagnosing T-cell leukaemia.
This work may also have immediate consequences for gene-therapy treatments in humans, because the scenario described by Martins et al. in mice also occurs in patients receiving gene therapy for severe combined immunodeficiency — in a subset of patients, the genetically modified precursor cells that are administered generate T cells in the absence of bone-marrow-derived precursors. It now seems that this lack of competition may predispose those patients to tumour formation. Despite these open questions and the various directions in which this research may develop, it is clear that exciting days lie ahead for the study of cell competition in relation to cancer9,10.
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Cell Cycle (2015)