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Research horizon: the bugs in cell communication

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Research horizon: the bugs in cell communication

Speaking, listening, understanding, interpreting, answering...certain rules govern communication between human beings. A discussion can become a cacophony in no time if the rules are not respected. It's the same for living cells. Just imagine the pandemonium if the several hundred thousand billion cells in our body suddenly stopped "understanding" each other.

The "bugs" in cell communication

Biologists have felt this to be true ever since 1858, when Rudolf Virchow produced his cell theory saying that all cells are derived from other cells. But the theory was not confirmed until the early 20th century when, in 1902, William Bayliss and Ernest Starling discovered the first hormone, secretin. Secretin is produced by cells in the upper part of the small intestine, and it carries a "message" that produces a "response" from pancreatic cells. This is to secrete digestive enzymes. Since then, there have been more and more surprises in cell communication studies. In the 1930s, Henry Dale and Otto Loewi discovered that neurones, the nerve cells that produce an electric current, communicate with each other using not electricity, but chemical mediators called neurotransmitters. Twenty years later, Earl Sutherland showed that the way hormones worked on their receptors was more complicated, because some of them activate a "second messenger" in the cell. This discovery has opened up the world of cell signalling, which has become the bread and butter of biology today. Today we know that there is a complicated cell "theatre" in which cells are in contact with similar cells inside tissues, and bathe in a background noise made up of hundreds of chemical signals from other cells, but they only "hear" some of the signals. Since the body depends on this communication, problems can obviously happen if the signals break down or are scrambled. In fact, biologists believe that in most medical conditions, a breakdown in cell communication will have occurred at some point. Here we will look at three of these communication "bugs". Osteoarthritis, a disease affecting the cartilage of joints; cancer, in which many different molecular signals are involved, such as little molecules called chemokines; and nervous system disorders that can be caused by cell death messengers, and which researchers are trying to prevent or cure by using neuron growth stimulation factors.

Osteoarthritis or cartilage "under the influence"

In osteoarthritis, some cells in the joints are modified "under the influence" of inflammatory mediators. The result is slow but irreversible destruction of the cartilage. Throughout our life, we give our joints a very hard time. With time, pains appear that tell us rheumatic conditions are setting in, and the most common of these is osteoarthritis. This condition affects over 15% of the population in industrialized countries (85% of over 70s). It is also called degenerative joint disease, an explicit way of saying that the elastic part of the joint, the cartilage, is progressively being destroyed.

Greedy enzymes

Intuitively, it would seem that the erosion is mechanical, and caused by forces on the joints. "Not at all", says Prof Francis Berenbaum, Head of Rheumatology in the St Antoine Hospital, and researcher in the UPMC Physiology and Physiopathology Unit (UMR CNRS 7079, IFR 83). Joints are not made of inert mechanical parts, but of living tissue. As well as cartilage, there are the tips of the bones which fit into it, and the synovial tissue which produces a lubricating liquid. In fact, cartilage degeneration is caused by the increased production of certain enzymes called metalloproteases (MMP), by cells of the cartilage itself, chondrocytes. It's a case of self-destruction! Whatever causes a joint to self-destroy? In fact cartilage is composed of a "matrix" secreted by the chondrocytes, which are distributed through it. It is made up of protein fibres called collagens and a sort of gel made of large protein and sugar molecules called proteoglycans. And the very chondrocytes that produce the matrix trigger its destruction by synthesising metalloproteases that can attack the collagens and the proteoglycans! In parallel, they transform and secrete a matrix, but of a poorer quality.

Dr Jekyll and Mr Hyde

Why do chondrocytes have this dual role? Answer: because of poorly understood initial events, which cause them to liberate chemical mediators, known to be involved in the inflammatory defence reaction, explains Francis Berenbaum. These mediators, mainly cytokines (especially interleukin 1) and lipid mediators such as prostaglandin E2 (PGE2), in turn activate the production of metalloproteases by these same cells. Furthermore, the chondrocytes carry receptors that are sensitive to mechanical pressure, and they interpret this in the same way as chemical signals.
In this tumult of cell communication, the two other components of the joints, bone and synovial tissue, also play their part. So when cartilage begins to break down, small fragments of matrix fall into the joint cavity and cause the synovial cells (synoviocytes) to produce inflammatory mediators which cause the destruction of the cartilage.

Obesity: a heavily weighted risk factor

The vicious circle is maintained by the fatty tissue, its cells bursting with fat and which liberate special cytokines called adipokines. Francis Berenbaum's team has shown that one of these, visfatine, causes the chondrocytes to produce prostaglandins and metalloproteases. This process, as well as the mechanical pressure from the extra weight, partly explains why more obese people than average have osteoarthritis, particularly in the knees. So we have the main pieces of the osteoarthritis puzzle. Can we hope for effective therapies? The miracle cure would be a drug that can slow the self-destruction process of cartilage – regenerating and repairing the cartilage are too far off for the moment.Unfortunately, the first anti-metalloproteases to be tested caused unbearable pain in the muscles and tendons. While waiting for them to be made more specific, various inhibitors are being tested, or are under clinical trial: anti-cytokines (anti-interleukin 1, anti-TNF), anti-adipokines, anti-PGE2, bone cell activity modulators, such as strontium ranelate used in treating osteoporosis, biochemical inhibitors that "command" metalloprotease synthesis, etc. Research will be long and complicated, but well worth the effort, given the growing scale of the osteoarthritis epidemic.

Cellular attraction, a key to cancer?

Some chemokines, small proteins responsible for attracting immune cells from blood to tissues, are involved in the growth and survival of cancer tumours and for the spread of secondary tumours. These results can open opportunities to counteract these attractions or use them in therapy. When the body is faced with an emerging cancer cell, it is far from passive. The smallest proliferating mass is very quickly targeted by the defence Armada of the immune system. "Killer" cells, NK cells and T lymphocytes, infiltrate the mass and try to eliminate the abnormal cells. However, some tumours manage to escape or resist. And for several years now, it has been known that small proteins, chemokines or chemo-attracting cytokines play an important role in this mechanism.

Blood cell recruiters

Chemokines are produced by immune cells but also by infected or cancerous tissues. Their prime function is to attract or "recruit" white blood cells where they are needed, for example to fight an infectious microbe. This process happens through interaction between chemokines and their receptors, which are "hooks" on the cell surface. In the case of cancer, this interaction has beneficial effects, particularly because it attracts killer white blood cells into the tumour. But on the other side of the coin, it also has negative effects, emphasizes Christophe Combadière, chemokine specialist in the UMPC Cell and Tissue Immunology lab (Inserm U543). Firstly, some chemokines produced by the killers attract another type of white blood cell, monocytes, which are the precursors of macrophages. The infiltration level of these cells, call TAM (tumour-associated macrophages), is related to tumour development. The more macrophages there are in a tumour, the more the tumours seem to be undetectable by the immune system, and the more readily they grow, continues Christophe Combadière. One of the main reasons for this facilitation is that some of the recruited monocytes tend to stimulate the growth of blood vessels (angiogenesis) from which tumours get the nutritive substances and oxygen they need. This is because they emit chemokines which attract the endothelial cells that make up blood vessels. So the tumours are well-fed, and they grow.
Mouse pancreas tumour showing infiltration by white cells, monocytes (in green), which congregate near blood vessels (their endothelial cells show them in pink).

http://www.chuv.ch/cpo_researchNouvelle fenêtre

Development of secondaries

Another key role of chemokines is that they regulate how metastases (secondary tumours) are distributed through the body. This is because the formation of cancerous cells at a distance from the initial tumour depends on factors that make the "environment" favourable for them. The UMPC team, working with Jean-Charles Soria's group at the Gustave Roussy Institute (Villejuif, Paris), has shown that the presence of a chemokine receptor, fractalkine (or CX3CL1), on the surface of cancer cells determines the formation of secondaries in the brain, because some brain cells produce this chemokine.
When the receptor CXCR4 is expressed (lung and pancreas cancer, leukemia, lymphomas), this predicts that metastases will appear in the liver.

Inhibitors and immunotherapy

This knowledge obviously leads researchers to envisage preventing the chemokine-receptor interaction mechanism, to block tumour angiogenesis or the spread of metastases. However, Christophe Combadière says: "Beware!": if we use drugs to inhibit chemokine receptors directly, the immune response will break down. The current idea is to "target" tumours using what are called "bispecific" antibodies, that carry a specific marker for the tumour to be eradicated on one side and an antagonist for the targeted molecule on the other. The European network Innochem (Innovative Chemokine-based Therapeutic Strategies, 2005-1010) is particularly involved in this research.
Researchers are also thinking of using chemokines that can activate the natural anti-tumour response by recruiting T lymphocytes or, in the case of antitumour vaccines, as adjuvants that can boost the immune response, or as recruiters for cells that present the antigens to the killer lymphocytes and thus prime the anticancer reaction.

Controlling the development and death of neurons

Within the IFR integrative biology unit of the UPMC (IFR 83, CNRS), several teams are trying to decipher the signals and mechanisms at work in neuron growth, and test, in animal models, molecules that protect or repair neurons.
Lesions of the central nervous system (brain or spinal cord) due to trauma, stokes or neurodegenerative diseases are one of the main causes of death and disability in the world. In order to restrict these lesions, we need to prevent the "active" death of neurons, known as apoptosis, which occurs when the blood supply to the cells is no longer sufficient (cerebral ischemia). When this happens, various signals in the neuron environment indirectly activate "death enzymes" known as caspases.

Inhibition of neuron death

Axon regeneration of a neuron on a suitable substrate - © F. Nothias
In the UMPC Neurobiology of Adaptive Processes lab, direct by Jean Mariani, Christiane Charriaut-Marlangue's team is working on an animal model she has developed which mimics consequences to the brain of neonatal cerebral ischemia arising from a difficult birth. In 2004, this model was used to test a neuroprotecter molecule developed by Theraptosis, a French biotech company (Romainville, Paris), a caspase inhibitor that blocks neuron death in case of cerebral ischemia. The company is about to test the molecule, known as TRP601, on adult volunteers. The alternative is to try to repair the damaged areas by stimulating neuron growth or regeneration or by grafting stem cells that can change into functional neurons. This is based on an observation made in the 1970s: neurons of newborn animals can recreate the extensions, called axons, and functional connections with other cells after a lesion by replacing the destroyed cells. So the aim is to recreate the conditions for this "plasticity" of the developing brain in more mature brains. In the UPMC, Rachel Sherrard's team in the Neurobiology of Adaptive Processes laboratory, has tested a trophic factor, BDNF (Brain Derived Neurotrophic Factor) at a dose precisely defined by previous research. In young adult rats, BDNF leads to the formation of new axons on a neuron path involved in controlling movement (see photo). More recently, this team has shown that these axons interact with the intact neuron cell network and that the new connections restore movement coordination associated with this neuron path.

The role of the cytoskeleton

But how do neuron extensions grow to create new connections after a lesion? To understand the process, Fatiha Nothias's team in the UPMC Neurobiology of Intercellular Signals laboratory analyzed the molecular mechanisms that control movements of the cell "framework", the cytoskeleton. It is made up of protein microtubes called tubulin and MAPs (microtubule associated proteins), and actin filaments. In a growing axon, the cytoskeleton is permanently being reorganized, explains Fatiha Nothias, and this reorganization is modulated by external signals (transmitted by receptors) and internal signals that converge on the cytoskeleton proteins and change the way they are organized.
So the aim is to sort out which molecule does what in this mechanism, in order to stimulate axon regeneration and develop therapeutic strategies. The objective is still far off, but the surest way to get there is to "decipher" how the cytoskeleton building process is regulated.