Sci. Signal., 24 August 2010
Cancer Cachexia Reversing Your Losses
Elizabeth M. Adler
Science Signaling, AAAS, Washington, DC 20005, USA
Advanced cancers are commonly accompanied by cachexia, a condition associated with severe weight loss and muscle wasting that accounts for a substantial fraction of cancer deaths (see Tisdale). Noting that signaling through the activin type 2 receptor ActRIIB is associated with various cancers and that a dominant-negative form of ActRIIB elicits muscle hypertrophy, Zhou et al. explored the effects of blocking ActRIIB signaling in mouse models of cancer cachexia. After confirming that a recombinant soluble ActRIIB decoy receptor (sActRIIB) inhibited myostatin- and activin-mediated Smad2/3 signaling in C2C12 myoblasts, Zhou et al. administered sActRIIB to colon 26 carcinoma–bearing mice (C26 mice), which undergo a lethal wasting syndrome. sActRIIB, administered at either the onset of cachexia or in advanced cachexia, reversed weight loss and prolonged survival; it prevented loss of muscle mass and enhanced grip strength without affecting fat loss, tumor growth, or serum abundance of the proinflammatory cytokines interleukin-6 (IL-6), IL-1β, or tumor necrosis factor–. Moreover, it blocked cardiac atrophy. sActRIIB also reversed muscle wasting and anorexia; blocked cardiac atrophy; and prolonged life in mice lacking inhibin (inhibin- KO mice), which spontaneously develop gonadal tumors. Nude mice implanted with CHO cells transfected with activin A or with activin-secreting human tumor lines developed symptoms of cachexia; these were blocked by antibodies directed against activin (in the former group) or sActRIIB (in the latter). Indeed, sActRIIB suppressed tumor growth in the last-named groups, as it did in inhibin- KO mice. sActRIIB also blocked various abnormalities in muscles from C26 or inhibin- KO mice. These included increases in the mRNAs encoding ubiquitin and the E3 ligases Atrogin-1 and MuRF1, increased ubiquitin conjugation, increased Smad2 and Akt signaling, and increased FOXO3a abundance and activity. Morphometric analysis revealed that sActRIIB promoted hypertrophy of inhibin- KO mouse muscles, and in vivo analyses of both these and wild-type mice revealed increases in the numbers of myofiber nuclei labeled with bromodeoxyuridine and markers for muscle stem cells. Thus, the authors conclude that antagonizing ActRIIB signaling may provide a therapeutic approach to treating cancer cachexia and thereby prolonging survival.
X. Zhou, J. L. Wang, J. Lu, Y. Song, K. S. Kwak, Q. Jiao, R. Rosenfeld, Q. Chen, T. Boone, W. S. Simonet, D. L. Lacey, A. L. Goldberg, H. Q. Han, Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell 142, 531–543 (2010). [PubMed]
M. J. Tisdale, Reversing cachexia. Cell 142, 511–512 (2010). [PubMed]
Citation: E. M. Adler, Reversing Your Losses. Sci. Signal. 3, ec255 (2010).
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