• A protein that accelerates aging halts cancer

    August 07, 2013

    The discovery was based on the creation and study of "mossaics": mice that carry the prelamin A protein in half of their cells

    Microscope view of the heart tissue of a mossaic mouse. Cells with prelamin A and without it (in brown) can be observed. © IMOMA

    A scientific research, resulting from several years of collaboration between the Institute of Oncological and Molecular Medicine of Asturias (IMOMA) and the University of Oviedo, and in which English and German scientists have participated, has revelead that prelamin A, a protein that causes accelerated aging, is capable of halting the development of malignant tumors. This discovery translates into an advance in the understanding of the relation between the mechanisms that cause aging and those that cause cancer. The results have been published in "Nature Communications". The conclusions of this publications may inspire new therapies against cancer that, in turn, reinforce the hopes placed in some of the strategies that are currently being tested to combat accelerated aging.

    The research has been co-directed by Carlos López-Otín, Tenured Professor of the University of Oviedo, and Jaun Cadiñanos, director of the Laboratory of Molecular Medicine of the IMOMA, and the experimental aspect has been conducted mostly by Jorge de la Rosa de Saa, PhD intern of the María Cristina Masaveu Peterson Foundation. The Project has also been funded by the Botín Foundation, the Ministry of Economics and Competitiveness, the Wellcome Trust, the Cajastur Social Fund and the Medical Center of Asturias Foundation.

    Aging and cancer are intimately-related processes, but the connections between them are complex. Thus, the risk of tumors appearing grows with age and, nevertheless, some of the mechanisms that favor aging also halt the growth and development of tumors. A clear example of these mechanisms is the activation of the most studied tumoral suppressor, the P53 protein. The research revealed that another protein, known as prelamin A, responsible for the accelarated aging experienced by patients of progeria, is also capable of halting the development of malignant tumors. To achieve this, the Asturian researchers employed mossaics: mice that have been genetically modified to carry the prelamin A protein in half of their cells.

    "Los ratones que acumulan prelamina A en todas sus células desarrollan envejecimiento acelerado y no viven más de 4-5 meses, lo cual dificulta mucho el estudio del cáncer, ya que no da tiempo a que la enfermedad se desarrolle", indica Jorge de la Rosa. "Los ratones mosaico, sin embargo, viven lo mismo que los ratones normales, y mantienen un 50% de células con prelamina A en todos sus tejidos, lo cual nos ha permitido estudiar el efecto de esta proteína sobre el cáncer", comenta Juan Cadiñanos. Además, para facilitar el seguimiento de los dos tipos de células, los investigadores "pintaron" con fluorescencia roja las células sin prelamina A (ver foto). "The mice that accumulate prelamin A in all of their cells develop accelerated aging and do not live more than 4 or 5 months, something that makes it harder for us to study cancer, since it does not give the disease enough time to develop", explains Jorge de la Rosa. "Mossaic mice, nevertheless, live as long as normal mice, and have 50% of their cells with prelamin A in all of their tissues, which has allowed us to study the effect of this protein on cancer", comments Juan Cadiñanos. Moreover, in order to facilitate following the two types of cells, the researchers "painted" with red fluorecence the cells that lacked prelamin A (see photo).

    The results of the study shed numerous surprises for the researchers. First, it is surprising that mossaic mice are completely healthy and do not present any of the alterations that have the mice with progeria caused by prelamin A. Furthermore, the cells with prelamin A show several defficiences when found in mice with accelerated aging, though they behave in the exact same way as the cells without prelamin A in mossaic mice. "These results show the strength of living organisms when they act as coordinated units, since the presence of "healthy" cells allows them to "cure" the alterations found in "ill" cells. The results also encourage hope in the treatment of patients with accelerated aging, since they suggest that it would not be necessary to correct the defects of all of the cells, but probably only of some of them", points out José María Pérez Freije, Professor of the University of Oviedo.

    The second suprise was that mossaics developed the same number of tumors as normal mice, and that their tumors derived from the same amount of cells with and without prelamin A. This was unexpected, since the presence of prelamin A has been associated with the activation of mechanisms that halt the multiplication of cells and, thus, that may stop the creation of tumors, which are, essentially, the results of uncontrolled cellular development.

    Nevertheless, there was still one last surprising discovery: the mossaics, in comparison with normal mice, presented a very reduced number of malignant tumors, those capable of breaking the barriers that keep them confined and thus invade neighboring tissues. Since the researchers have observed this phenomenon in the oral cavity of the mossaic mice, they proceeded to check whether this also happened in human tumoral cells. "We observed that, once we introduced the production of prelamin A in the cells obtained from human malignant tumors, their invasive capacity was drastically reduced. This happened with human cells of oral, lung and breast cancer", indicates Rubén Cabanillas, from IMOMA.

    "The results obtained are very stimulating from a scientific point of view, and they may lead to the development and application of new medium-term therapies against accelerated aging or, even, in long term for cancer, but we have to be aware that mossaic mice that we have employed are a very useful experimental model, but one that has a very particular set of characteristics, and that reality may be different for patients of progeria or cancer", concludes Professor López-Otín.