Cachexie | EPFL Graph Search

La cachexie est un affaiblissement profond de l’organisme (perte de poids, fatigue, atrophie musculaire) lié à une dénutrition très importante. La cachexie n'est pas une maladie en elle-même, mais le symptôme d'une autre. La définition formelle de la cachexie est la perte de masse corporelle telle qu'elle ne peut plus être inversée ni trouvée à l'aide d'une nutrition adaptée. Elle est observée au cours de plusieurs maladies : anorexie mentale, cancer (cachexie cancéreuse, produite par des substances sécrétées par la tumeur, les cachexines), BPCO, insuffisance cardiaque, insuffisance hépatique, insuffisance rénale, tuberculose, SIDA, alzheimer, certaines protozooses intestinales chez les patients immunodéprimés (comme la cryptosporidiose ou les microsporidioses) ou certaines maladies auto-immunes. La cachexie réduit les patients à un état d'immobilité dû à l'anorexie, à l'asthénie et à l'anémie, mais aussi par atteinte musculaire par hypercatabolisme protéique et donc perte de masse maigre (sarcopénie). Le mécanisme exact par lequel la cachexie cause ces symptômes est encore mal compris ; il est probable que les cytokines inflammatoires, telles que le TNF-α (également nommé cachexine pour cette raison), l'interféron gamma (IFNγ), et l'interleukine 6 (IL-6) aient un rôle à y jouer, ainsi que le facteur inducteur de protéolyse sécrété par la tumeur elle-même. Les patients atteints d'anorexie mentale présentent de hauts niveaux plasmatiques de ghréline, phénomène que l'on remarque également chez les sujets atteints de cachexie cancéreuse. Il n'existe pas de traitement établi pour la cachexie, mais plutôt une série de composés dont un effet secondaire serait de ralentir la cachexie cancéreuse, souvent en stimulant l'appétit ou augmentant la masse musculaire : on peut notamment citer les corticoïdes, les stéroïdes anabolisants ou l'acétate de megestrol. Tous ces produits ou familles de composés (une vingtaine) font l'objet d'études à divers niveaux mais, à cette date (2003), aucun ne semble avoir passé avec succès le stade des essais de phase (essais cliniques randomisés en double aveugle sur de larges groupes).

Paracrine Activin-A Signaling Promotes Melanoma Growth and Metastasis through Immune Evasion

Daniel Constam, Susanna Eveliina Kallioinen, Olivier Andreas Dubey, Patrick Mueller

The secreted growth factor Activin-A of the transforming growth factor beta family and its receptors can promote or inhibit several cancer hallmarks including tumor cell proliferation and differentiation, vascularization, lymphangiogenesis and inflammation. However, a role in immune evasion and its relationship with tumor-induced muscle wasting and tumor vascularization, and the relative contributions of autocrine versus paracrine Activin signaling remain to be evaluated. To address this, we compared the effects of truncated soluble Activin receptor IIB as a ligand trap, or constitutively active mutant type IB receptor versus secreted Activin-A or the related ligand Nodal in mouse and human melanoma cell lines and tumor grafts. We found that although cell-autonomous receptor activation arrested tumor cell proliferation, Activin-A secretion stimulated melanoma cell dedifferentiation and tumor vascularization by functional blood vessels, and it increased primary and metastatic tumor burden and muscle wasting. Importantly, in mice with impaired adaptive immunity, the tumor-promoting effect of Activin-A was lost despite sustained vascularization and cachexia, suggesting that Activin-A promotes melanoma progression by inhibiting antitumor immunity. Paracrine Activin-A signaling emerges as a potential target for personalized therapies, both to reduce cachexia and to enhance the efficacy of immunotherapies.

2017

Molecular and cell-based therapies for muscle degenerations: a road under construction

Marco Cassano, Stefania Crippa

Despite the advances achieved in understanding the molecular biology of muscle cells in the past decades, there is still need for effective treatments of muscular degeneration caused by muscular dystrophies and for counteracting the muscle wasting caused by cachexia or sarcopenia. The corticosteroid medications currently in use for dystrophic patients merely help to control the inflammatory state and only slightly delay the progression of the disease. Unfortunately, walkers and wheel chairs are the only options for such patients to maintain independence and walking capabilities until the respiratory muscles become weak and the mechanical ventilation is needed. On the other hand, myostatin inhibition, IL6 antagonism and synthetic ghrelin administration are examples of promising treatments in cachexia animal models. In both dystrophies and cachectic syndrome the muscular degeneration is extremely relevant and the translational therapeutic attempts to find a possible cure are well defined. In particular, molecular-based therapies are common options to be explored in order to exploit beneficial treatments for cachexia, while gene/cell therapies are mostly used in the attempt to induce a substantial improvement of the dystrophic muscular phenotype. This review focuses on the description of the use of molecular administrations and gene/stem cell therapy to treat muscular degenerations. It reviews previous trials using cell delivery protocols in mice and patients starting with the use of donor myoblasts, outlining the likely causes for their poor results and briefly focusing on satellite cell studies that raise new hope. Then it proceeds to describe recently identified stem/progenitor cells, including pluripotent stem cells and in relationship to their ability to home within a dystrophic muscle and to differentiate into skeletal muscle cells. Different known features of various stem cells are compared in this perspective, and the few available examples of their use in animal models of muscular degeneration are reported. Since non coding RNAs, including microRNAs (miRNAs), are emerging as prominent players in the regulation of stem cell fates we also provides an outline of the role of microRNAs in the control of myogenic commitment. Finally, based on our current knowledge and the rapid advance in stem cell biology, a prediction of clinical translation for cell therapy protocols combined with molecular treatments is discussed.

Frontiers Research Foundation2014

Molecular and cell-based therapies for muscle degenerations: a road under construction

Marco Cassano, Stefania Crippa

Frontiers Research Foundation2014