Genetic evolution of tumours according to their growth dynamics.

Jan 11 2008

A study co-directed by the Universidad Complutense de Madrid and La Paz hospital in Madrid identifies a protein of high expression in cells located at the tumour boundary that could play an essential role in the evolution of tumours and their invasive potential.

It is well accepted that tumour growth is a very complex process with many intervening factors, and in spite of being the subject of most investigations on a global scale; there are still many aspects that remain unknown, one of the most interesting of which is the relation between the dynamics of solid tumour growth and their gene expression.

The universal dynamics of tumour growth (Brú A, Albertos S, Luis Subiza J, García-Asenjo JL, Brú I. Biophys J. 2003) established that the growth dynamics of all tumours is similar. Such growth dynamics implied that the growth rate of the tumour follows a lineal function and that most of its activity takes place at the outer tumour boundary. This establishes a huge difference in the number of cell divisions that a cell located at the tumour boundary undergoes from the original tumour cell, when compared to the traditional model based on the Gompertzian growth pattern. Considering a tumour 2 cm3 in volume, following the previous model, a cell at the boundary of the tumour will divide 32 times from the original tumour seed, and using the new growth dynamics for solid tumour, the number of boundary cell divisions is estimated at 800 times from the original tumour seed.

Bearing in mind that there is a correlation between the genetic evolution (accumulation of anomalies and aberrations) and the number of cell divisions of a cell, and that the cells at the tumour boundary are always the ones with the largest number of divisions, there must exist a difference in the genetic expression inside the solid tumour depending on the distance from the tumour seed. Based on this hypothesis, the research groups managed by Dr. Antonio Brú from the department of applied mathematics at the Universidad Complutense de Madrid and Dr. López-Collazo from the research and investigation department at the La Paz hospital in Madrid, started working on the study of the genetic expression profiles of sample cells from the C6 cell line of brain tumours inoculated in rats. Several researchers from different Spanish research institutions participated in the study; the genetic expression of samples at the centre, the outer tumour boundary and the healthy adjacent tissue were analysed.

The results of the investigation are now published in the December edition of the specialised magazine Medical Oncology (Position-dependent expression of GADD45alpha in rat brain tumours. Brú A, Del Fresno C, Soares-Schanoski A, Albertos S, Brú I, Porres A, Rollán-Landeras E, Dopazo A, Casero D, Gómez-Piña V, García L, Arnalich F, Alvarez R, Rodríguez-Rojas A, Fuentes-Prior P, López-Collazo E. Med Oncol. 2007;24 (4):436-44). Among the conclusions reached, the most relevant comes from the difference in the nuclear protein GADD45a, which regulates the cellular response to DNA damage and stress signals. This protein is expressed in many normal tissues, particularly in cells in a quiescent state (G0 phase of the cell cycle). The concentration of GADD45a increases during G1 phase of the cell cycle and greatly decreases when the cell is at S phase, demonstrating its crucial role in the response function to many stress or genotoxic signals. This protein has also been related to the programmed cell-death, the survival of cells and their innate immunity. In particular, it has been demonstrated that it inhibits cyclin B/CDC2, which constitutes a protein complex that controls the transition G2/M in the cellular cycle.

According to the conclusions, this protein is expressed in much higher levels at the boundary than at the inside of solid tumours. This gives GADD45a a more important role in the evolution of the tumour and its invasive capability. The control of this cellular apoptosis regulator at the tumour expansion boundary is predicted by the universal dynamics of tumour growth elaborated by Dr. Brú and his team over the last few years. These results allow for a better understanding of the genetic and phenotypic evolution that are currently explained in different theories of evolution as well as relating it to the growth dynamics of the tumour.