Galectin 1 regulation of skeletal muscle wasting in cancer cachexia

Galectin-1 in the Regulation of Skeletal Muscle Wasting in Human Cancer Cachexia

The modern oncology can control cancer progression leading to chronic treatments. In the absence of controls, patients reach a state slowly wasting. Orexigenic drugs (corticosteroids, megestrol acetate, medroxyprogesterone acetate, etc.) (Conlisk et al. p1051) Can increase appetite and alleviate anorexia and weight loss. We observe a parallel decrease in nausea and/or vomiting favourable anthropometric and biological parameters, and often an improved quality of life. The appetite stimulants alone are not sufficient to reverse the wasting process and must be associated with treatment of underlying diseases. (DeWys, p491-97)

T it cancer refers to more than one hundred types of diseases characterized by the appearance of malignant tumors. (Bruera, pp1383) This is the second leading cause of death after cardiovascular diseases. Oncogenesis is very similar from one cancer to another, but the clinical and biological characteristics are unique to each cancer. (Barber, p80-86)

The normal cell reproduces itself if it receives a signal from the cells that are close (controlled method of reproduction) and follows a reproductive cycle to apoptosis (programmed cell death). It recognizes its own place and anchored on the extracellular matrix (for an epithelial cell) and neighboring cells. (Feingold, p184-90)

trolled is due to mutations observed in at least two classes of genes, proto-oncogenes and tumor suppressor genes, play important roles in the regulation and cell reproduction. Oncogenes from proto-oncogenes by mutation, translocation or amplification, act as growth promoters. (Maguid, p843-57)

The tumor suppressor genes, in turn, have the primary function of acting as a brake on cell proliferation. When the proto-oncogens become carcinogenic, they cause uncontrolled growth of cells. The tumor suppressor genes involved in cancer development when inactivated, a cell cycle is then freed from all bondage inhibitory. (Wright, p120-24) The other feature of cancer cells is the ability to migrate. To avoid being recognized come abnormal cells floating, unable to anchor on other cells, cancer cells use intracellular messengers, suggesting wrongly proper anchoring and no failure. (Whinningham, p23-36)

They detach from the primary tumor and enter the tissues by releasing enzymes, metalloproteinases, which dissolve the basement membrane and other extracellular matrices. Then they cross the basement membrane and the layer of endothelial cells of a small blood vessel to be carried away by the bloodstream (or lymphatic) to another site in the body where they founded a new settlement (metastases). In the successive steps which lead them to their destination, they escape all the controls that subjugate normal cells. (Wigmore et al. p27-30)

Cancer cachexia and skeletal muscle wasting

Cachexia is a state of deep decay generally characterized by weakness, prostration, slow mental capacity, loss of appetite and reduction of fat and muscle mass. (Maguid, p843-57) It happens more often than having to locate internist pathologies underlying this symptom, that is, weight loss and weight loss, with fatigue generalized. Generally, these patients who have diabetes and do not know, eat, drink and urinate all the time and lose weight and lean muscle mass, or cancer patients, especially cancer of the lung or digestive tract. At best, do not eat for stress gastritis or benign ulcer. But let us see what must seek the good internist when encountering these patients. (Warmolts, p374-79)

typical of patients suffering from malignant tumors in pre-terminal (especially if located in the digestive tract, to ' esophagus or the stomach), has complex etiology in which different mechanisms come into play (anorexia, abnormal glucose metabolism and release of substances produced by the tumor from the host is capable of influencing the metabolism back toward catabolism) is often the most debilitating feature of this disease process. (Weindruch, p20-33)

The cancer cachexia is a severely debilitating paraneoplastic syndrome, which is characterized by an early weight loss, lack of appetite, but also and especially a loss of muscle mass, with depletion of fat deposits and deep metabolic changes. (Beller et al. p287) It adversely affects the quality of life of cancer patients. Today is no longer considered a terminal event but is seen as the final consequence of a series of metabolic and molecular alterations that occur very early when it is seen that is substantially non-reversible treatment with common nutritional, metabolic. (Bartlett, p260-67) pathogenesis of loss of muscle mass in the course of cancer has not yet been fully elucidated, as it depends on diverse factors, but it seems mainly by an imbalance between the rate of synthesis and protein degradation in muscles.

Where there is a role played by the proteolytic system the ubiquitin / proteasome-dependent ATP in accelerated muscle protein degradation. (Maguid, p843-57) For these reasons, a substance has been studied, bortezomib proteasome injunction, to block the destruction of lean body mass. (Beal et al. p89-97)

For some 'time is in use megestrol acetate in the treatment of cancer cachexia: a progestin used to treat the source of advanced breast cancer, able to increase appetite and body weight in cancer patients. Such good results are obtained from AIDS-induced anorexia. According to the literature on the megestrol acetate seems well tolerated and does not cause water retention. (Straub, p1591-1611) Ghrelin is a novel growth hormone-releasing peptide (GH) can also induce a positive energy balance by reducing fat and stimulating the use of appetite through GH-independent mechanisms. (Fearon et al. p1345-50)

It appears that ghrelin improves cachexia and functional capacity in patients with COPD. proinflammatory cytokines, particularly TNF-alpha (Tumor Necrosis Factor) play an important role in pathogenesis of cancer cachexia. In addition, they demonstrated that they could lose in the prevention of cancer in mice causes their muscle cells to over produce dystrophin. (Bozzetti et al. p367)

Protein stops muscle brake

The focus of this approach is a messenger protein called activin. It looks like myostatin, hold another chemical messenger that is responsible for muscle growth in check. If omitted, the skeletal muscles begin to proliferate excessively. (Mantovani, p296) The Zhou and her colleagues are now used in cancer cachexia in mice: They blocked the activin in the body of animals with the help of a specially developed protein-antagonist. (Bruera, p113)

Cancer cachexia pathophysiology

In addition, cachexia is described in those patients with involuntary weight loss. Cancerous processes produce an imbalance in the energy balance by decreasing food intake and increased catabolism, resulting in a clearly negative balance. (Kung T. et al. p579-85) They look at different factors determining cachexia, from metabolic unbalances produced by tumoral products and endocrine disorders or inflammatory response produced by cytokines, all leading to increased lipolysis, muscle protein loss and anorexia. (Mantovani, p296)

In addition to the causes of anorexia are multiple, from chemotherapy agents, radiotherapy or immunotherapy, which can produce different degrees of nausea, vomiting, diarrhea, and also to impairments of perceptions in the taste and smell, to obstruction of the digestive system pain, depression, constipation. (Steiner et al. p144-49)

From the knowledge of the different mechanisms producing anorexia-cachexia syndrome have been studied in artificial nutrition-calorie diets with relative success, a variety of drugs that were positive for the appetite gain as progestogens, steroids, and with lesser clinical evidence cannabinoids, cyproheptadine, mirtazapine (antidepressant) and olanzapine (antipsychotic). (Fearon et al. p1345-50) Others have studied for its anti-inflammatory cytokines due to its action, such as melatonin, omega-3 polyunsaturated acids, pentoxifylline and thalidomide, but the latter are still scarce clinical data for everyday use. (Bhattacharyya et al. p56-78)

Same happens with anabolic drugs derived from testosterone or metabolic inhibitors such as hydrazine sulfate. (Warmolts, p374-79) Undoubtedly especially progestogens megestrol and corticosteroids are first-line choice in the anorexia-cachexia syndrome to increase appetite and weight and the first impact in improving the quality of life and comfort in patients with advanced cancer. (Beal et al. p89-97)

The regulation of appetite and eating patterns is mediated by different psychological, gastrointestinal, metabolic and nutritional, as well as various neural and endocrine mechanisms. The anorectic cancer patient experiences a sensation of fullness early and decreased appetite. (Mantovani, p296)

Sometimes the causes of anorexia may result from their own cancer treatment (chemotherapy, radiotherapy or immunotherapy), which may induce nausea and vomiting to varying degrees. (Leppanen et al. p5549-65) They can also contribute to reduced intake alterations in perception of food and psychological reasons (depression). Sometimes, anorexia can be attributed to a direct effect of the tumor, where it is located in the hypothalamus or at the digestive system. (Beal et al. p89-97)

However, in most cases the origin of the anorexia associated with cachexia appears to be the metabolic alterations experienced by the patient as a result of the presence of tumor. (Warmolts, p374-79) Different factors, both humoral and source segregated by the host in response to tumor growth, or secreted by the tumor cells themselves may play an important role in the response anorexic. (Fearon et al. p1345-50)

In short, anorexia appears to be more an effect than the cause of weight loss and, in fact, decreased intake may manifest after it has been weight loss. (Bhattacharyya et al. p56-78) In any case, malnutrition due to reduced food intake only exacerbates the cachectic state, promoting a kind of positive feedback mechanism that can eventually lead to death.

The success was remarkable, according to the researchers: Even muscles that had already lost half of its mass, recovered visible. (Leppanen et al. p5549-65) At the same time, the mice survived for several weeks longer than their untreated counterparts and also developed a healthy appetite again. (Mantovani, p296) The new study is therefore interesting in two respects: First, it demonstrates that the muscle loss at least in animal models in fact, affects the chances of survival, and secondly, it shows a way, may be how to prevent this degradation, and even reversed. (Bruera et al. p857)

Muscle atrophy

Muscle atrophy is a medical term that refers to the decrease in the size of skeletal muscle, losing muscle strength because of the strength of muscle is related to its mass. (Burnfoot, p323-34)

All changes in cell morphological character may affect isolated cells or groups of them, therefore the modification of a whole tissue. (Bhattacharyya et al. p56-78) All stimuli that may act on a cell are actually functional stimuli: when they exceed the physiological limits may injure the cell to reverse the processes of life, or cause significant modifications regressive. (Warmolts, p374-79)

The atrophy is therefore the morphological expression of a functional and structural involution of a cell or tissue. It is an acquired deficiency, which normally involves a preexisting cellular and tissue, and for that reason must be distinguished from hypoplasia of the aplasia and agenesis. (Warmolts, p374-79) Moreover, the atrophy must be distinguished from a disease that entails structural reduction of an organ, or part thereof due to a necrotic destructive process, in which case there is a massive cell death. (Ryan et al. p355-63)

There are several diseases and disorders that cause a decrease in muscle mass, including inactivity, cachexia present in patients with cancer or heart failure, chronic obstructive pulmonary disease, extensive burns, liver failure, electrolyte disturbances, anemia. Others can cause muscle wasting syndromes such as malnutrition, denervation of motor neurons and in spinal muscular atrophy of childhood and the inflammatory myopathies and dystrophies, among others. (Warmolts, p374-79)

In the microscopic appearance are three main types of atrophy, simple atrophy, degenerative atrophy and atrophy number. Simple atrophy is a decrease in the volume of muscle components leads to shrinkage or reduction in size of the tissue and organ. (Bhattacharyya et al. p56-78) Atrophy is more common, affecting more differentiated cells. It can be seen during the prolonged fast in almost all body tissues, mainly in muscle tissue. (Fearon et al. p1345-50)

Numerical atrophy exists when the disappearance of cellular elements causes the decrease in the volume of an organ, the volume reduction is progressive and proportional to the number of cells and tissues normally affects labile elements.

In degenerative atrophy can see big changes to the cytoplasm and nucleus of cells and organ tissue. This process can lead to the occurrence of necrosis. (Bhattacharyya et al. p56-78) In all cases of atrophy, the cytoplasm is the most affected is almost always a reduction in quantity of it, so much so that, observing the atrophic tissue under a microscope can distinguish a discrete cell densification caused by the reduction uniform cell volume. (Leppanen et al. p5549-65) These changes are accompanied by profound alterations in cytoplasmic, turbidity, presence of pigment granules and decreased number of mitochondria. (Ryan et al. p355-63)

There are several diseases and disorders that cause a decrease in muscle mass, including inactivity, as in the sedentary (do nothing) or a cast- cachexia or body wasting syndrome present in patients with cancer or heart failure, chronic obstructive pulmonary disease, extensive burns, hepatic disorders, electrolyte, anemia, etc. Other syndromes can cause muscle atrophy such as malnutrition, denervation of neurons in the motor and spinal muscular atrophy of childhood and myopathies and inflammatory dystrophies, among others. (Conlisk et al. p1051)

Mechanisms of action

To understand what happens in a muscle of a patient with muscular dystrophy is useful to recall, albeit brief summary, it is done and how a normal muscle. (Leppanen et al. p5549-65) It consists of a central part of the contractile (muscle belly) and from one end device (tendon) that ensures contact with the bony surface of the muscle. The tendon ends can be of various shape: when the muscle is inserted by two tendons to bone is called the biceps, triceps tendon with three, four quadriceps. (Dunlop, p76-82)

The muscle is the engine that ensures each form of motion of our body and this happens through the contractile activity that allows the movement of bone segments with which the muscle makes contact. (DeWys, p491-97)

When a muscle contraction produces a motor effect for an individual defines this muscle is agonist. When the contracts 'agonist, is released at the same time that the muscle action contrary (the' antagonist) (Bhattacharyya et al. p56-78) for example, when you want to flex the forearm is active as an agonist, the biceps and, simultaneously releasing the triceps brachii and if you want to do the opposite movement, ie to extend the forearm, then the pattern is reversed: the biceps relaxes and the triceps contracts. (Eigler, p487)

If this is not balanced equilibrium and the agonist and antagonist muscles contract simultaneously has the so-called phenomenon of "co-contraction," which occurs in certain pathological conditions where there is spasticity (but which can be determined even under normal conditions, such as Alert sharp reactions in the face of a sudden perception of danger). (Gagnon, p675-88)

Galectins and galectin

Galectin 1 is a protein overexpressed by many cancers; it is involved in multiple processes of tumor development including tumorigenesis, proliferation and migration of tumor cells and their metastasis, resistance to radiation and chemotherapy, their escape the immune system or angiogenesis. (Leppanen et al. p5549-65)

The nature of the receptor-against galectin-1 that is involved in the establishment of the synapse between the pre-B cells and stromal cells remains to be determined. (Feingold, p184-90) However, the cons-receptor galectin-1 has been identified in other biological systems: these extracellular matrix proteins (laminin and fibronectin) or surface receptors such as CD45, CD43, CD7, CD2, CD3 or GM1. GAL1 is involved in many biological functions such as adhesion, growth and cell death. (Song et al. p36-47)

GAL1 and cons-receptors act as potent regulators of homeostasis of the immune system, and these are the signals delivered by the various cons-receptors that determine the nature of biological responses. (Leppanen et al. p5549-65) The galectins induce contrasting effects on cell growth and the biological effect observed proliferation or apoptosis depends on the cell type and cell activation status. (Hengge, p129-38) For example, it was reported that GAL1 could both play a role in inhibition of proliferation of T cells and promote proliferation of vascular endothelial cells. Galectins also play a crucial role in the process of cell transformation and metastasis formation. (Dias-Baruffi et al., p114-49)

Under the microscope, the muscle is composed of a set of muscle fibers that are surrounded by a connective membrane is called the sarcolemma. (Hengge, p129-38) Each muscle fiber, in turn, is composed of a thousand myofibrils, which represent the fundamental contractile unit. (Leppanen et al. p5549-65) These myofibrils have an average length of 40-50 microns and a diameter of just one micron. (Feingold, p184-90)

To be able to contract, the muscle needs a command: This command comes through nerve endings that make contact with the muscle belly through the endplate, which is the terminal part of the neuron that is linked to the muscle fiber. (Grinspoon, p634-36)

In the case of a voluntary movement (for example, take a bucket and lift it off the ground), the order from the cerebral cortex, travels along nerve fibers to the core, and then continues towards the periphery from the bone until it reaches the muscles against are able to ensure the desired motor action (in our example, grasp the handle of the bucket and lift it). (Hengge, p129-38)

The muscles, however, are able to provide even involuntary movements, ie those that are carried out automatically or reflected (and, anyway, beyond our specific desire). And 'the case of the muscles that provide respiration, urination, etc. (Maguid, p843-57)

What happens in the case of muscular dystrophy? In this disease, the muscle undergoes a slow process of degeneration, characterized by necrosis (from the greek = dead) of muscle fibers and the concomitant appearance of fibrosis, or by replacement of normal contractile tissue of the muscle connective tissue. (Maguid, p843-57) The latter consists of fibers that have no ability to contract, for which the muscle slowly loses its function and the patient begins to experience progressive weakness. (Rowe, p623-24)

Note that the muscles of patients with muscular dystrophy does not appear to decrease in volume but on the contrary, some muscles - such as those of calves - you can have even more voluminous than normal (pseudohypertrophy) precisely because of fibrosis and the accumulation of adipocytes (fat cells) going to replace degenerated muscle cells. (Holroyde, p78) In addition to the muscles in DMD are also affected other systems and devices. In the osteoarticular load should be noted that the vertebral column shows a progressive deformity or alteration of curves that normally characterize (lordosis and scoliosis) (Leppanen et al. p5549-65)

Proteomics

Proteomics is a large scale study of proteins, particularly their structure and function. Proteins are vital parts of living organisms because they are the main components of the metabolic pathways of cells. (Aebersold and Mann, p198-207)

Proteomics is considered the next step in the study of biological systems, after genomics. (Sarto et al. p1627-29) This is because the different cell types express different genes, implying that it must be determined until the core set of proteins produced in an additional factor of complexity are changes that can occur in the structure or base sequence protein, that is, one that encoded in the genome. (Banks et al. p689-700)

These changes come primarily from two sources: the trimming or alternative splicing of the mRNA encoding the protein and posttranslational modifications (phosphorylation, methylation, acetylation, etc.) that normally serve to modify or modulate the activity, function or location of a protein in different physiological or metabolic contexts. (Brunet et al. p629-38)

Proteomics is a relatively recent science. For its final takeoff has been necessary the definitive consolidation of the mass spectrometry as a technique applied to the analysis of biological molecules and exponential growth in the number of entries for genes and/or protein in the databases. (Sarto et al. p1627-29) This, combined with the use of powerful methods of fractionation and separation of peptides and proteins such as 2D-PAGE (electrophoresis two-dimensional polyacrylamide) and high resolution liquid chromatography (HPLC), has consolidated proteomics since the mid-90's of last century, as science for massive protein analysis. (Celis et al. p3003-3009)

The term proteomics was coined in 1997 as an analogy with genomics, the study of genes. The word "proteome" is the fusion of "protected Ina" and "oma gene" and was coined by Marc Wilkins in 1994, while working on this concept as a PhD student.