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 Newly discovered bacteria-binding protein in the intestine
08.12.2016 | University of Gothenburg

nachricht The balancing act: An enzyme that links endocytosis to membrane recycling
07.12.2016 | National Centre for Biological Sciences

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

Will Earth still exist 5 billion years from now?

08.12.2016 | Physics and Astronomy

Oxygen can wake up dormant bacteria for antibiotic attacks

08.12.2016 | Health and Medicine

Newly discovered bacteria-binding protein in the intestine

08.12.2016 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>