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 De nouvelles connaissances sur les métastases.

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Date d'inscription : 23/02/2005

MessageSujet: Re: De nouvelles connaissances sur les métastases.   Mer 13 Mar 2013 - 20:00

Mar. 13, 2013 — It's the spread of the original cancer tumor that kills most people. That's why cancer researchers vigorously search for drugs that can prevent metastases, the spread of cancer. The research team co-led by Angela Wandinger-Ness, PhD, and Larry Sklar, PhD, at the University of New Mexico Cancer Center has found a chemical compound that appears to control cell migration and adhesion, two important characteristics of metastatic cancer cells. The team recently published a paper describing how the first-in-class compound acts on various cells.

C'est les métastases qui tuent et non le cancer original. C'est pourquoi les chercheurs travaillent sur un médicament qui pourrait arrêter métastases. Des chercheurs ont trouvé une molécule chimique qui semble contrôler la migration de la cellule et son adhésion, 2 importantes caractéristiques de la cellule cancéreuse.

Dr. Wandinger-Ness, a UNM Professor of Pathology and Director of the Fluorescence Microscopy and Cell Imaging Shared Resource, studies proteins called GTPases. GTPases act like chemical switches to control how cells behave: how much a cell grows, what shape it assumes, when it enters the next growth stage, and how tightly it sticks to its surroundings, among several hundred other things. Dr. Wandinger-Ness was interested in a particular GTPase called Cdc42; it controls cell migration and cell adhesion. "It's an important target in many diseases," says Dr. Wandinger-Ness. "Cancer is just one. But there were no compounds that target this GTPase." So she collaborated with Dr. Sklar and Tudor Oprea, MD, PhD, to find a compound that did. And they were successful.

Le docteur Wandiger-Ness étudie les protéines appelées GTPases. Les GTPases agissent comme des interrupteurs pour controler le comportement des cellules : comment une cellules grossit, quelle forme elle prend, quand elle va entreprendre la prochaine étape de son évolution et aussi comment elle se tient ou elle colle dans son entourage parmi des centaines d'autres choses. Le docteur s'est intéressé en particulier à une GTPase appelé Cdc42, elle controle la migration de la cellule et son adhésion. C'est une cible importante de plusieurs maladies. Le cancer est l'une d'elle seulement. Mais il n'y avait pas de molécules qui cible GTPases. Aussi elle a collaboré avec le Skar et le docteur Tudor Oprea pour en trouver une et ils ont trouvé.

Dr. Sklar is a UNM Professor of Pathology and co-Leader of the Cancer Biology and Biotechnology Research Group at the UNM Cancer Center. He created and now oversees the UNM Center for Molecular Discovery. Dr. Oprea is a UNM Professor of Medicine and co-Director of the Flow Cytometry & High Throughput Screening Shared Resource at the UNM Cancer Center. He analyzed Cdc42 using three-dimensional molecular rendering software. The team used Dr. Oprea's analysis of Cdc42 to visualize how a compound might interact with the Cdc42 GTPase to stifle its activity. Then they searched for such a compound in the UNM Molecular Discovery library.

The search process was akin to finding a needle in a haystack, but the latest high throughput flow cytometry equipment and molecular rendering software available at the UNM Cancer Center speeded their analysis significantly. The team analyzed thousands of compound candidates by first narrowing their search to the few hundred likely candidates and then testing those against several kinds of GPTases at a time. "From a purely discovery perspective, that's a high impact, novel way to look for small molecules," says Dr. Sklar. The compound they found is called CID2950007.

Structurally similar to NSAIDs -- non-steroidal anti-inflammatory drugs -- CID2950007 restrains the Cdc42 GTPase from changing a cell's cytoskeleton. Much like a skeleton gives a human body shape, a cell's cytoskeleton keeps the cell from collapsing on itself. The cytoskeleton enables a cell to move by growing amoeba-like legs called filopodia. Cdc42 also helps to keep cells where they need to be by enabling them to adhere more tightly to their surroundings. So, while uncontrolled growth and movement are hallmarks of metastatic cancer cells, growth and adherence are important traits for healthy cells. Tightly controlling just how Cdc42 causes a cell to behave is crucial.

In the paper published February 4, 2013, the team of scientists report that CID2950007 was the only compound they found that affected the Cdc42 GTPase without affecting any other GTPases. This selectivity is important to control the compound's effects on a cell. They also found that the compound works by changing the physical structure of Cdc42, so it doesn't destroy Cdc42 but it does control how Cdc42 interacts with other proteins in the cell. Their studies showed that CID2950007 decreased filopodia growth and cell adhesion in ovarian cancer cells and prevented cell adhesion in white blood cells. And their studies demonstrated that CID2950007 blocked Hantavirus infection in monkey kidney cells. By affecting the Cdc42 GTPase, and thus the cytoskeleton, CID2950007 has the potential to fight not only cancer but also infectious diseases.

Human use of CID2950007 as a cancer drug is a long way off. Before the Food and Drug Administration approves any drug for human use, it first requires the successful results of several toxicity and dose escalation studies on several types of animals. Then, the clinical trials process, which can take over 10 years, may begin.

"There are going to be a lot of side effects because these adhesion proteins have many other functions," says Dr. Sklar. So refining CID2950007 into a drug will take further collaboration and studies before toxicity studies and dose escalation studies can begin. To refine the compound, the UNM Cancer Center researchers will continue to collaborate with Jeffrey Aubé, PhD, Kansas University Distinguished Professor of Medicinal Chemistry, and Jennifer Golden, PhD, Assistant Director of the Specialized Chemistry Center at Kansas University. Still, control of GTPase Cdc42 offers promise as a way to control cancer metastasis. Says Dr. Wandinger-Ness, "there's a lot of enthusiasm for a compound like this -- because there weren't any. This is a first-in-class."

"Il va y avoir beaucoup d'effets secondaires parce que ces protéines d'adhésion ont plusieurs autres fonctions." aussi raffiner CID2950007 en médicament demandera de plus amples collaboration et études avant que des études sur sa toxicité et sur la gradation des doses puissent commencer.

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MessageSujet: Re: De nouvelles connaissances sur les métastases.   Lun 25 Mai 2009 - 14:59

(May 25, 2009) — Research led by David Worthylake, PhD, Assistant Professor of Biochemistry and Molecular Biology at LSU Health Sciences Center New Orleans, may help lay the groundwork for the development of a compound to prevent the spread of cancer. The research will be published in the May 29, 2009 issue of the Journal of Biological Chemistry.

Certaines recherches pourraient sider à préparer le terrain pour des médicaments pour prévenir les métastases.

During the transition from a localized tumor to metastatic disease, cancer cells acquire the ability to detach from their neighboring cells and move to and invade tissue at distant points in the body.

Durant la tranformation de la tumeur locale vers une métastase, les cellules canécreuses acquirent la capacité de se détacher de leur cellules voisines et de se dépalcer pour envahir les tissus à un point distant.

He and his colleagues studied a protein in cells that is involved in regulating cell structure, cell-to-cell contact, and cell movement. When too much of this protein, called IQGAP1, is produced, it can weaken cell-to-cell contacts and promote cell migration and invasion – processes that occur during tumor metastasis.

On étudie une protéine qui régule la structure de la cellule, quand trop de cette protéine appelé IQGAP1 est produite cela peut affaiblir le contact de cellule à cellule et promouvoir la migration des cellules.

The research team focused on the area of IQGAP1 that interacts with two smaller proteins Cdc42 and Rac which, when activated, contribute to cell destabilization, cell movement, and invasion. This region on IQGAP1 is related to proteins that accelerate deactivation of another small protein similar to Cdc42 and Rac. However, IQGAP1 does not deactivate Cdc42 and Rac – in fact, IQGAP1 prolongs their activated states. The researchers determined the atomic structure of this region of IQGAP1 and furthermore, built a model of their IQGAP1 structure bound to the previously determined structure of Cdc42 in order to understand why IQGAP1 does not deactivate Cdc42. The model provides detailed information about the (likely) specific contacts made between IQGAP1 and Cdc42. The model also shows that IQGAP1 is missing a key component required to rapidly deactivate Cdc42, and that binding to IQGAP1 likely disturbs the positions of components of Cdc42 that are required for even normal rates of deactivation, explaining how IQGAP1 prolongs the activated state of Cdc42.

IQGAP1 interagit avec des protéines plus petites Cdc42 et Rac qui lorsqu'elles sont activées contribuent à la déstabilisation de la cellule.

"This knowledge could serve as a guide for further studies to define IQGAP1 function and perhaps the design of a small molecule to regulate Cdc42/IQGAP1 interaction to prevent cancer cells from moving to and invading other parts of the body," concludes Dr. Worthylake.

Cette connaissance peut servir à dessiner une molécule pour contrer les effets de Cdc42/IQGAP1 et prévenir les métastases.
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MessageSujet: Re: De nouvelles connaissances sur les métastases.   Ven 31 Oct 2008 - 0:34

(Oct. 31, 2008) — Scientists have discovered the two key processes that allow cancer cells to change the way they move in order to spread through the body, reports a study in the journal Cell.

Les scientifiques ont découvert les deux processus clés qui permettent aux cellules cancéreuses de changer de forme et ainsi de se déplacer dans le corps.

The progression of cancer cells from one part of the body to another (“metastasis”) is one of the biggest problems in curing cancer, therefore this research brings new hope of future therapies to fight cancer. The discovery has been made by Dr Victoria Sanz-Moreno in the research team led by Professor Chris Marshall at The Institute of Cancer Research, in work funded by Cancer Research UK.

La progression des cellules cancéreuses d'un endroit à l'autre dans le corps est un des plus grands problèmes du cancer, cette étude amène donc de l'espoir pour de nouvelles thérapies.

Professor Marshall says:
“The spreading of cancer cells from one part of the body to another, called metastasis, is one of the biggest causes of death from cancer. By explaining a key part of that process, our research brings new hope for future therapies to fight cancer.
“The research has found the constant competition between two proteins called ‘Rac’ and ‘Rho’ is responsible for allowing the cancer cells to change shape and spread through the body.

"Le fait que les cellules cancéreuses se déplacent dans le corps est une des plus grandes causes de décès par le cancer. En expliquant une partie essentielle du processus notre étude amène de nouveaux espoirs pour des thérapies pour combattre le cancer. Les chercheurs ont trouvé une compétition constnte entre 2 protéines appelé "Rac" et "Rho" qui permettent au cancer de changer de forme à travers le corps."

“We have shown that cells from melanoma (an aggressive type of skin cancer) are able to rapidly alternate between two different forms of movement where cells have either a round shape or a more stretchy “elongated” shape.
“Together with Dr Erik Sahai and Dr Sophie Pinner at the Cancer Research UK London Research Institute we have been able to see cells in live tumours carrying out these different forms of movement. These alternate shapes and ways of moving may enable tumour cells to deal with different situations during cancer spread. For example, tests indicated that a round shaped tumour cell may have more durability to survive in our bloodstream than elongated shaped tumour cells.”

Nous avons démontré que les cellules de mélanome sont capables d'alterner rapidement entre 2 différentes formes de mouvements qui font qu'elles sont rondes ou allongées. Ces deux forment font que les cellules peuvent "dealer" avec différentes situation durant leurs migrations. Par exemple, les tests indiquent qu'une forme ronde peut avoir plus de résistancepour survivre dans notre système sanguin qu'une forme allongé.

The Rac process involves a protein called NEDD9, (which has previously been shown to be involved in melanoma metastasis) activating Rac through another protein called DOCK3. This Rac activity serves a dual purpose, both encouraging the cell to become elongated and simultaneously suppressing the competing Rho activity. Conversely, when cells adopt the round form a protein activated by Rho, called ARHGAP22, switches off Rac activation.

Le processus Rac implique une protéine appelé NEDD9 qui active Rac à travers une autre protéine appelé DOCK3. Cette activité de Rac sert un double usage enourager la cellule à devenir allongé et supprimer simultanément la compétition de Rho. inversement, quand les cellules adoptent la forme ronde c'est qu'elle sont activé par Rho appelé ARHGAP22 qui annule l'activité de Rac.

Dr Victoria Sanz-Moreno says: “Until now the conversion between different types of movement of individual cancer cells had been observed but the key players had not been identified. We are excited to discover that the amount and the activity of these proteins in the tumour cell regulates its shape and the mechanism for it to move and invade surrounding tissue. We hope these insights can be used to help develop future therapies”.

"Jusqu'à maintenant le changement entre les différents types de mouvement des celllules canécreuses avait été observé mais les joueurs clés n'étaient pas connus. Nous sommes excités de découvrir que ces protéines régulent ces activités et son mécanisme qui fait que les cellules se déplacent et envahisssent les tissus avoisinants. Nous espérons que ces nouvelles observations vont déboucher sur de nouvelles thérapies."

Melanoma cells were being studied in this research and their behaviour is also expected to occur in many other types of cancer. Melanomas are a major target for cancer therapies because although they are the least common, they are the most serious type of skin cancer. There are about 160,000 new cases of melanoma worldwide each year, including the rarer types that affect the bowel or eye rather than the skin.

On croit que ce qui a été observé pour le mélanome se produit dans plusieurs cancers
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MessageSujet: Re: De nouvelles connaissances sur les métastases.   Ven 22 Aoû 2008 - 15:07

(Aug. 21, 2008) — Scientists in the Department of Biology & Biochemistry at the University of Bath have started a three year study into the junctions that hold cells together, giving insight into how cancer cells can break off and spread to other parts of the body.

Des scientifiques ont fait une étude sur 3 ans pour comprendre comment les cellules cancéreuses se détachent de la tumer pour aller répandre le cancer ailleurs.

Cancer affects one in three people at some point in their lives, with most cancer deaths being caused by the development of secondary tumours in other parts of the body. This research, funded by leading medical charity Cancer Research UK, could help scientists better understand what causes cancer to spread and may suggest new ways it could be treated in the future.

Normal cells are held together by junctions on the cell surface, but in some cancers these junctions are lost. This makes the cancerous cells more likely to break off and spread tumours to other parts of the body. Dr Andrew Chalmers and Dr Paul Whitley, both lecturers from the Department of Biology & Biochemistry, are studying how a group of proteins called ESCRTs are involved in the loss of these junctions in kidney and intestine cells.

Des chercheurs étudient un groupe de protéines, les ESCRTs qui sont impliquées dans la perte des jonctions qui tiennent normalement les cellules ensembles.

“ESCRTs are like the recycling units of the cell; they oversee the constant intake, break down and replenishing of junctions on the cell surface,” explained Dr Chalmers.

“In a cancer cell where ESCRTs are damaged, the junctions may not be restored properly; this can cause cells to separate and migrate to form secondary tumours in other parts of the body.

Quand ces ESCRTs sont endommagées par le cancer cela peut faire que les cellules ne tiennent plus enemble.

“Previous studies have shown a link between ESCRTs and the loss of junctions in cells of fruit flies, so we want to see whether this is also true in humans.”

Une étude précédente avait démontrer le procédé chez la mouche à fruit et les chercheurs veulent savoir si c'est vrai pour l'humain aussi.
During this three year project, the researchers plan to block ESCRTs in cells grown in the lab to see the effects on the junctions. They will also be looking at whether mutations of ESCRTs are more common in certain types of cancer.

Dr Paul Whitley added: “This work should tell us more about the role of ESCRTs in cancer and provide possible new targets for therapy in the future.”

Cette étude pourrait fournir des cibles nouvelles dans le futur.
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MessageSujet: De nouvelles connaissances sur les métastases.   Jeu 9 Aoû 2007 - 1:49

Metastasis -- when cancer cells dissociate from the original tumor and migrate via the blood stream to colonize distant organs -- is the main cause of cancer death. A team of scientists at the Weizmann Institute of Science has now revealed new details about the mechanisms controlling metastasis of breast cancer cells.

Les métastases

Quand les cellules cancéreuses se dissocient de la tumeur originale et migrent à travers le système sanguin pour coloniser d'autres endroits du corps, cela constitue la cause principale de la mort. Une équipe de scientifiques à l'institut Weizmann a révélé de nouveaux détails à propos des mécanismes controlant les métastases du cancer du sein.

Their findings, published recently online in Nature Cell Biology, add significantly to the understanding of metastasis and may aid, in the future, in the development of anti-cancer drugs.

Leurs découvertes publiées récemment dans la revue "Nature Cell Bilogy" apporte beaucoup à la compréhension des métastases et pourrait aider, dans le futur aux développements de nouveaux médicaments anti-cancer.

For a cell such as a cancer cell to migrate, it first must detach itself from neighboring cells and the intercellular material to which it is anchored. Before it can do this, it receives an order from outside the cell saying: 'prepare to move.' This signal takes the form of a substance called a growth factor, which, in addition to controlling movement, can activate a number of processes in the cell including division and differentiation. The growth factor attaches to a receptor on the cell wall, initiating a sequence of changes in the cellular structure. The cell's internal skeleton -- an assembly of densely-packed protein fibers -- comes apart and the protein fibers then form thin threads on the outside of the cell membrane that push the cell away from its neighbors. In addition, a number of protein levels change: some get produced in higher quantities and some in less.
Pour qu'une cellule cancéreuse puisse migrer, elle doit d'abord se détacher des cellules avoisinantes et du matériel intercellulaire à laquelle elle est anchrée. avant de le faire, elle reçcoit un ordre de l'extérieur qui lui dit de se préparer à déménager. Cet ordre prend la forme d'un signal chimique appelé "facteur de croissance" lequel, en plus de controler le mouvement de la cellule, peut activer beaucoup de processus dans la cellule incluant la division et la différentiation. Le facteur de croissance se lie à un récepteur sur la paroi de la cellule et initie une séquence de changement dans la structure de la cellule, le squelette intérieur de la cellule si on veut, celui-ci est fait de fibres de protéines de différente densité. Les fibres de protéines en viennent à former de petit fils sur l'extérieur de la cellule qui poussent la cellule loin de son voisinage. En plus, beaucoup de changement dans le niveau des protéines se font. quelques protéine deviennent plus nombreuses et d'autres moins nombreuses.

To understand which proteins are modulated by the growth factor and the nature of the genetic mechanisms involved in cancer cell migration, a team of researchers pooled their knowledge and resources.

Pour ocmprendre quels protéines sont changé par le facteur de croissance et la nature des mécanismes génétics impliqués dans la migration des cellules, les chercheurs de différents horizon ont mis leurs connaissances en commun.

This team, headed by Prof. Yosef Yarden of the Weizmann Institute's Biological Regulation Department and his research group, including Drs. Menachem Katz, Ido Amit and Ami Citri; Tal Shay, a student in the group of Prof. Eytan Domany of the Physics of Complex Systems Department; and Prof. Gideon Rechavi of the Chaim Sheba Medial Center at Tel Hashomer.

To begin with, the team mapped all of the genetic changes that take place in the cell after the growth factor signal is received. As they sifted through the enormous amount of data they received, including details on every protein level that went up or down, one family of proteins stood out. Tensins, as they're are called, are proteins that stabilize the cell structure. But to the scientists' surprise, the amounts of one family member rose dramatically while, at the same time, the levels of another dropped.

Pour commencer, l'équipe a colligé tous les changements génétics qui prennent place dans la cellule après que le signal du facteur de croissance est reçu. Ils ont fait le tri parmi l'énorme quantité de renseignements, incluant des détails sur le niveau bas ou haut des protéines et ils ont sorti une famille de protéine appelée "tensin". Ces protéines servent à stabiliser la structure la protéine. Mais à la surprise des scientifiques, le niveau d'une protéine de cette famille monte alors que le niveau d'une autre protéine de la même famille descend.

Despite the familial similarity, the team found a significant difference between them. The protein that drops off has two arms: One arm attaches to the protein fibers forming the skeleton, and the other anchors itself to the cell membrane. This action is what stabilizes the cell's structure. The protein that increases, on the other hand, is made up of one short arm that only attaches to the anchor point on the cell membrane. Rather than structural support, this protein acts as a kind of plug, blocking the anchor point, and allowing the skeletal protein fibers to unravel into the threads that push the cells apart. The cell is then free to move, and, if it's a cancer cell, to metastasize to a new site in the body.

En dépit de la similarité de ces protéines, l'équipe de chercheurs a trouvé une différence fondamentale entre elles. La protéine qui décroit est celle qui stabilise et elle a deux bras un qui s'attache à la structure de fibres de protéine de la cellule et l'autre à la membrane de la cellule elle-même. L'autre qui décroit a seulement un bras court qui s'attache à la membrane de la cellule. Cete protéine agit comme un bouchon qui bloque le point d'anchrage de la cellule et permet au squelette intérieur de la cellule de se former en poils qui vont pousser la cellule à partir et si c'est une cellule cancéreuse à aller métastaser ailleurs dans le corps.

In experiments with genetically engineered cells, the scientists showed that the growth factor directly influences levels of both proteins, and that these, in turn, control the cells' ability to migrate. Blocking production of the short tensin protein kept cells in their place, while overproduction of this protein plug increased their migration.

Dans des expériences avec des cellules génétiquement modifiées, les scientifiques ont démontré que le facteur de croissance influence le niveau des 2 protéines et que celles-ci contrôlent à leur tour la mogration de la cellule. En bloquant la production de la protéine tensin courte (avec 1 bras...) la cellule reste en place et en la surproduisant la cellule migre.

Next, the scientists carried out tests on tumor samples taken from around 300 patients with inflammatory breast cancer, a rare but swift and deadly form of the disease, which is associated with elevated growth factor levels. The scientists found a strong correlation between high growth factor activity and levels of the 'plug' protein. High levels of this protein, in turn, were associated with cancer metastasis to the lymph nodes -- the first station of migrating cancer cells as they spread to other parts of the body.

Ensuite en étudiant des échantillons de patientes atteintes du cancer du sein inflammatoire, les scientifiques ont vérifié qu'il y a une corrélation très forte entre le niveau de facteur de croissance et le niveau de la protéine-bouchon (ou celle responsable de la métastase)

In another experiment, the scientists examined the effects of drugs that block the growth factor receptors on the cell walls. In patients who received these drugs, the harmful 'plug' proteins had disappeared from the cancer cells. Prof. Yarden: 'The mechanism we identified is clinically important. It can predict the development of metastasis and possibly how the cancer will respond to treatment.' This discovery may, in the future, aid in the development of drugs to prevent or reduce the production of the unwanted protein, and thus prevent metastasis in breast or other cancers.

Dans un autre expérience, les scientifiques ont examiné les effets de médicaments qui bloquent le facteur de croissance sur les parois des cellules. Chez les patients qui ont reçu ces médicaments, la protéine nuisble avait disparu. Selon le professeur Yarden ;"Le mécanisme que nous avons identifié est cliniquement important. Cela peut prédire le développement des métastases et comment le cancer va répondre aux traitements." Cette découverte peut dans le futur aider au développement de médicaments pour prévenir ou réduire la production de la protéine indésirable et dès lors prévenir les métasrases du cancer du sein ou de d'autres cancers.
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MessageSujet: Re: De nouvelles connaissances sur les métastases.   Aujourd'hui à 18:11

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