Colon cancer genes and mechanical pressure

21 Oct 2008

Mechanical pressure accelerates the early stages of colon cancer

A team at the Institut Curie, Paris, lead by Emmanuel Farge, Inserm Director of Research, has shown that mechanical pressure can alter gene expression, and in particular activate the cancer-ecausing genes ‘Myc’ and ‘Twist’; implicated in the early stages of colon cancer.

Although inactivation of the APC (adenomatous polyposis coli) 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 the increase in tumour mass itself may cause this pressure. The discovery, reported in Human Science Frontier, opens up new horizons in research into the mechanical sensitivity of tumours.

Cancer stems from alteration in a cell’s genetic material. Yet a single event is not enough to transform a healthy cell into a cancer cell. Rather, cancer results from a succession of incidents. The APC 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 tumour, it is not sufficient. Other perturbations are needed.

At the Institut Curie, the Mechanics and Genetics of Embryo and Tumour Development team, headed by Emmanuel Farge, is studying the effect of mechanical stress on gene expression during tumour 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 genes controlled by it: Myc, which is involved in tumour growth, and Twist, which contributes to the invasiveness of tumours. The deregulation of ß-catenin is often described as being correlated with loss of the APC gene, in development of colon cancer.

Investigation was carried out into the effects of pressure applied to the colon of a mouse that has already ‘lost’ a copy of the APC gene. Farge and colleagues observed a relocalisation of ß-catenin from the cytoplasm towards the nucleus of the cells, followed by activation of the expression of the genes 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 tumour 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 tumour environment can also participate. Mechanical sensitivity thus becomes a player in carcinogenesis.

So, while the mutation of the APC gene initiates tumour development, growth in tumour mass could accelerate development by compressing neighbouring tissues.

It seems possible that the development of the colon cancer is not purely ‘genetic’ or ‘cellular’ and certain stages could result from mechanical effects. This discovery should prompt reassessment of preventive and therapeutic approaches, at least in colon cancer, and maybe oncology in general.