Scientists in Portugal just found a new molecular mechanism behind colorectal cancer in which a mutated and a normal, but over-expressed, gene cooperate and are both needed to create the disease.
The research, published in the journal Gastroenteroloy, also reveals how a technique called RNA interference can - by inactivating both genes - kill, in just 48 hours, as much as 80% of cancer cells. These are extremely promising results if transferred into new therapies for humans against a disease, which is still one of the most common cancers in the western world.
Colorectal cancer affects the colon, rectum and appendix and is not only the third most common form of cancer, but also the second cancer-related cause of death in the Western world, according to the World Health Organization. The disease kills about 655,000 people per year worldwide, with 16,000 only in the UK, even if it has a high cure rate if early detected and treated.
It is known that about 30 to 40 percent of colorectal cancer cases result from a mutated KRAS gene, which affects cell division. When this gene is mutated it becomes hyper-activated, leading to uncontrolled cell multiplication, which, together with resistance to death, are the hallmarks of all cancerous cells. And in fact, the capabilities of KRAS mutations to induce cancer depend on another molecule - Rac1 - that complements its effect on cell division by inhibiting cell death and further stimulating cell division. Together they create immortal and abnormally growing cells, the exact definition of cancer cells.
More recently, among colorectal cancers negative for the KRAS mutation, a related abnormality has been identified, this time on a gene called BRAF, which, like KRAS, is also involved in cell growth and division. When studied in laboratory, however, BRAF mutations were not enough by themselves to produce cancer, suggesting that a second event was necessary for malignant transformation. The fact that therapies targeting BRAF have a low success rate in these tumours , further supported the existence of a second event and highlighted the urgency to further investigate the mechanism behind BRAF-mutated cancers, which, after all, comprise as much as 10% of all colorectal cancers cases.
Paulo Matos, Raquel Seruca, Peter Jordan and colleagues at the Centre of Human Genetics in the National Health Institute Dr. Ricardo Jorge in Lisbon and the Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal have previously found abnormally high quantities of a variant of Rac1 - called Rac1b - among some colorectal cancers. This - together with the fact that Rac1 is crucial for K-Ras-induced tumours - led the researchers to hypothesise that maybe Rac1b was the (mysterious) partner of B-Raf V600 in colorectal tumours.
To test this possibility Matos, Seruca , Jordan and colleagues analysed cells from 61 different colorectal cancer patients, together with normal mucosa cells from 13 patients. Confirming their hypothesis a strong association between the most common Raf mutation - B-Raf V600 - and Rac1b was found, with 82% of B-Raf V600 positive tumours showing Rac1b over-expression. In contrast, K-Ras mutated tumours and normal mucosal tissue had almost no Rac1b.
The next question to Matos, Seruca , Jordan and colleagues was to see if the two molecules did in fact cooperate in the formation of the tumour, since B-Raf V600 was known to be incapable, by itself, of producing cancer. For this, the researchers inhibited the gene for B-Raf V600 or the one for Rac1b, or both at the same time, and analysed the resulting tumour cells.
Gene inhibition was done using a method called RNA interference (or RNAi). The first step during gene expression is to pass the information, contained in the gene (the piece of DNA) to be expressed, into a molecule of RNA called messenger RNA. The RNAi method consists in introducing into the cells a small double molecule of RNA with the same sequence of the messenger RNA corresponding to the gene we want to inactivate. Because double RNA molecules do not occur naturally the cell will destroy it, triggering too the destruction of the messenger RNA with the same sequence and effectively silencing the gene, as its expression is interrupted. The big advantage of this method is its specificity, since, contrary to other cancer treatments like radio- or even chemo-therapy, it will only result in the death of the target cells.