Oct. 22, 2008 Genes are not the be all and end all of carcinogenesis. At the Institut Curie, the team of Emmanuel Farge, Inserm Director of Research (UMR 168 CNRS/Institut Curie), has just shown, in collaboration with the Sylvie Robine and her group (UMR144 CNRS/Institut Curie), that mechanical pressure can alter gene expression, and in particular activate the oncogenes(1) Myc and Twist, which are implicated in the early stages of colon cancer.
Although inactivation of the APC gene remains the genetic precondition for the development of this type of cancer, mechanical pressure on the colon speeds up carcinogenesis in animal models. And what if the increase if tumor mass were itself the cause of this pressure? This discovery reported in Human Science Frontier Journal opens up new horizons in research into the mechanical sensitivity of tumors.
Cancer stems from alteration in a cell’s genetic material. Yet a single event is not enough to transform a health cell into a cancer cell. Rather, cancer results from a succession of accidents. The APC (adenomatous polyposis coli) gene is mutated in 80% cases of colon cancer. This alteration is often described as the initiator of carcinogenesis. Although the loss of APC is necessary for development of a colon tumor, it is not sufficient. Other perturbations are needed.
At the Institut Curie, the Mechanics and Genetics of Embryo and Tumor Development team headed by Emmanuel Farge(2) is studying the effect of mechanical stress on gene expression during tumor and embryo development. Farge and colleagues recently demonstrated that morphogenetic movements, which occur in early development of Drosophila embryo, trigger expression of the Twist gene, which controls the differentiation of gastric tissues. They have studied the changes induced by mechanical pressure on the expression of the protein ß-catenin and of two oncogenes controlled by it: Myc, which is involved in tumor growth, and Twist, which contributes to the invasiveness of tumors. The deregulation of ß-catenin is often described as being correlated with loss of the APC gene, in development of colon cancer.
What happens when pressure is applied to the colon of a mouse that has already “lost” a copy of the APC gene? Farge and colleagues observed a relocalization of ß-catenin from the cytoplasm towards the nucleus of the cells, followed by activation of the expression of the oncogenes Myc and Twist, which can then play their full part in carcinogenesis. In the absence of one copy of the APC gene, mechanical pressure of the order of magnitude equivalent to that exerted by intestinal transit would therefore stimulate tumor development.
Mechanical stress is therefore likely to affect the gene expression profile in colon cells already carrying an APC mutation. The events leading to formation of a cancer are not only, therefore, the prerogative of genetics: perturbations in the tumor environment can also participate. Mechanical sensitivity thus becomes a player in carcinogenesis.
So, while the mutation of the APC gene initiates tumor development, growth in tumor mass could accelerate development by compressing neighboring tissues.
Not all then is purely “genetic” or “cellular” in the development of the colon cancer and certain stages could result from mechanical effects. This discovery should prompt reassessment of preventive and therapeutic approaches, at least in colon cancer, and even in oncology in general.
(1) Genes associated with cancers
(2) Emmanuel Farge is Inserm Director of Research in UMR 168 CNRS/Institut Curie.
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- DESPRAT Desprat et al. Tissue Deformation Modulates Twist Expression to Determine Anterior Midgut Differentiation in Drosophila Embryos. Developmental Cell, September 2008; 15 (3): 470 DOI: 10.1016/j.devcel.2008.07.009
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