Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

A new molecular mechanism for colorectal cancer: a new target for cancer therapies

04.06.2008
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 Gastroenteroloy1, 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 that still is 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 about:
»B-Raf »KRAS »Matos »Molecular »Mutation »RNA »RNAi »Rac1 »Rac1b »Seruca »V600 »colorectal »mutated »therapies »tumour

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.

Matos, Seruca, Jordan and colleagues’ RNAi experiment revealed that when the genes for B-Raf V600 or Rac1b were inactivated there was a reduction or in cell viability and/or division but, most striking, was the result of their combined inactivation. In fact, combined “inhibition” of the two genes resulted in 80% of the colorectal cancer cells dying in the period of 48 hours. This confirmed that the two molecules functionally cooperate in the development of some K-Ras negative colorectal tumours and explains why B-Raf mutations alone are not sufficient to achieve cancer, while also suggesting a promising specific molecular target for therapy against this type of cancer. Supporting the specific importance of Rac1b in BRAF-mutated colorectal cancer, its inactivation on KRAS-mutated colorectal cancers had no effect on cells’ survival or division.

Matos, Seruca, Jordan and colleagues’ results are extremely promising as they reveal that the relatively simple and very specific (so with less secondary effects for the patient) technique of RNAi can, when targeting both B-Raf V600 and Rac1b, kill almost all the colorectal tumour. This, if translated into a therapy for humans could be the difference between patients’ life or death and, as such, prompts the urgent need for further clinic-oriented investigation. But, as Peter Jordan one of the leaders of the project emphasizes “It is important to remember though, that despite these novel findings, it is still most crucial to move forwards with cancer prevention through changes in diet and life style”

The discovery of a new molecule involved in the pathogenesis of this cancer also raises the question of its suitability as a marker in order to identify and follow closely those individuals with propensity for the disease since the disease has such a high cure rate if detected early. In fact, although screening is already done, at the moment this is only done in individuals from families with the hereditary form of colorectal cancer.

Finally, high quantities of Rac1b have already been detected in some breast cancers what, with the new results, raise the possibility that the molecule can have a role in this (and others?) epithelial cancer and, as such, also needs to be further investigated.

Piece researched and written by Catarina Amorim
Catarina.Amorim@linacre.ox.ac.uk
1 Gastroenteroloy (2008) advanced only edition DOI: 10.1053/j.gastro.2008.05.052
“B-RafV600E cooperates with alternative spliced Rac1b to sustain colorectal cancer cell survival”
Authors of the original paper
Paulo Matos – paulo.matos@insa.min-saude.pt
Peter Jordan - peter.jordan@insa.min-saude.pt
Raquel Seruca - rseruca@ipatimup.pt

Catarina Amorim | alfa
Further information:
http://www.gastrojournal.org/home

Further reports about: B-Raf KRAS Matos Molecular Mutation RNA RNAi Rac1 Rac1b Seruca V600 colorectal mutated therapies tumour

More articles from Life Sciences:

nachricht At last, butterflies get a bigger, better evolutionary tree
16.02.2018 | Florida Museum of Natural History

nachricht New treatment strategies for chronic kidney disease from the animal kingdom
16.02.2018 | Veterinärmedizinische Universität Wien

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Demonstration of a single molecule piezoelectric effect

Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale

Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...

Im Focus: Hybrid optics bring color imaging using ultrathin metalenses into focus

For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.

But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...

Im Focus: Stem cell divisions in the adult brain seen for the first time

Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.

The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...

Im Focus: Interference as a new method for cooling quantum devices

Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters

Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...

Im Focus: Autonomous 3D scanner supports individual manufacturing processes

Let’s say the armrest is broken in your vintage car. As things stand, you would need a lot of luck and persistence to find the right spare part. But in the world of Industrie 4.0 and production with batch sizes of one, you can simply scan the armrest and print it out. This is made possible by the first ever 3D scanner capable of working autonomously and in real time. The autonomous scanning system will be on display at the Hannover Messe Preview on February 6 and at the Hannover Messe proper from April 23 to 27, 2018 (Hall 6, Booth A30).

Part of the charm of vintage cars is that they stopped making them long ago, so it is special when you do see one out on the roads. If something breaks or...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on High Temperature Shape Memory Alloys (HTSMAs)

15.02.2018 | Event News

Aachen DC Grid Summit 2018

13.02.2018 | Event News

How Global Climate Policy Can Learn from the Energy Transition

12.02.2018 | Event News

 
Latest News

Fingerprints of quantum entanglement

16.02.2018 | Information Technology

'Living bandages': NUST MISIS scientists develop biocompatible anti-burn nanofibers

16.02.2018 | Health and Medicine

Hubble sees Neptune's mysterious shrinking storm

16.02.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>