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Cachexia

Cachexia is a disorder characterized by the involuntary loss of body weight in addition to the loss of homeostatic control of both energy and protein balance; it has been acknowledged since the earliest written medical treatises. Cachexia occurs in association with malignant disease and with multiple chronic non-malignant diseases, including heart failure, kidney disease, chronic obstructive pulmonary disease, neurological disease, AIDS and rheumatoid arthritis. The main symptoms that are associated with cachexia in cancer patients are related to these factors and involve asthenia, anorexia, anemia and fatigue — altogether, contributing to a reduced quality of life. From all of the different definitions of cachexia, one concept becomes very clear: it is a multifactorial syndrome involving changes in several metabolic pathways, in many tissues and organs. It is well accepted that cachexia is indirectly responsible for the death of at least 20% of all cancer patients. The incidence of the syndrome among cancer patients is very high, although it varies by tumor type; in patients with gastric or pancreatic cancer, the incidence is more than 80%, whereas approximately 50% of patients with lung, prostate or colon cancer are affected, and around 40% of patients with breast tumors or some leukemia develop the syndrome.

Pro-inflammatory factors with catabolic actions have attracted the most attention as mediators of cachexia. Prostaglandins (in particular, prostaglandin E2) are known mediators of tumor-induced bone resorption and paraneoplastic hypercalcemia and have similarly been documented in animal models to be mediators of excess catabolism in skeletal muscle. Peptide inflammatory mediators of cachexia include IL-6, which is a key regulator of skeletal muscle, IL-1, tumor necrosis factor (TNF), IFNγ, leukemia inhibitory factor (LIF), growth/differentiation factor 15 (GDF15) and TNF-related weak inducer of apoptosis (TWEAK; also known as TNFSF12). Identified primarily through cell culture conditions and tumor xenograft models, these factors signal through their respective cell surface receptors and activate selective transcription factors, which in turn promote the transcription of ubiquitin-proteasome and autophagy components. These signaling molecules are synthesized by tumor or immune cells and their activities are sufficient to promote catabolism in target organs such as skeletal muscle, but confirmatory patient data have lagged.

In addition to inflammatory cytokines, other circulating factors have been described that exhibit pro-cachectic activity towards skeletal muscle. Activin A is a member of the TGFβ superfamily of growth factors that is produced by both tumor and immune cells. In cultured myotubes, activin A promotes atrophy; when it is overexpressed in mice, it promotes weight loss and skeletal muscle loss with higher potency than IL-6. Another pro-cachexia cytokine is TWEAK, which belongs to the TNF family. TWEAK acts through TNF receptor superfamily member 12A (TNFRSF12A), which, when overexpressed in tumors, correlates with cachexia. TWEAK's role was shown via neutralization with antibodies of TNFRSF12A, which inhibited weight loss and increased lifespan in a mouse model. Similar to TNF and IL-6, activin A and TWEAK can promote muscle atrophy in non-malignant conditions, making these factors and the respective receptors through which they signal potentially interesting therapeutic targets. Clinical trials for intervention studies targeting activin A and TWEAK have been initiated in both cancer and non-cancer indications.

Creative Biogene, as a leading biotechnology company, can offer various cachexia pathway-related products including stable cell lines, viral particles and clones for your pathogenesis study and drug discovery projects.

References:
  1. Argilés, Josep M, et al. Cancer cachexia: understanding the molecular basis. Nature Reviews Cancer, 2014, 14(11):754-762.
  2. Baracos V E, et al. Cancer-associated cachexia. Nature Reviews Disease Primers, 2018.
  3. Von H S , Anker S D . Treatment of cachexia: An overview of recent developments. Journal of the American Medical Directors Association, 2014, 15(12):866-872.

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