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Treating cancer cachexia to treat cancer

Treating cancer cachexia to treat cancer Skeletal muscle wasting is a major component of cachectic states found in a variety of disease settings, including cancer. As increasing caloric intake often provides little benefit in combating muscle loss in cachectic patients, a major research focus has been to develop strategies stimulating muscle anabolic pathways - in an attempt to fight the catabolic pathways induced during cachexia. Two recent papers have reported the beneficial effects of blocking the myostatin/activin signalling pathway in mouse models of cancer cachexia. We discuss the implications of their findings both with respect to the role that this signalling pathway may play in the aetiology of cachexia and with respect to the prospects for targeting this pathway as a therapeutic strategy in patients with cachexia. Background strategies that directly target muscle in order to preserve Loss of skeletal muscle mass can occur in a wide range muscle mass and function. Two recent papers by Benny- of disease states and has significant consequences, causing Klimek et al. [2] and Zhou et al. [3] have reported studies debilitating weakness and also metabolic dysfunction - as that investigated the potential beneficial effects of target- skeletal muscle is one of the major tissues in the body ing the myostatin/activin signalling pathway in order to responsible for regulating energy availability and energy provide such an anabolic stimulus to muscle in rodent expenditure. Loss of muscle mass can result either from models of cancer cachexia. primary muscle degenerative diseases, such as the mus- cular dystrophies, or as a secondary consequence of Discussion cachectic disease processes also affecting other tissues, Myostatin (MSTN) is a transforming growth factor-b such as cancer, burns, renal failure, sepsis and congestive (TGF-b) family member that normally acts to limit heart failure (for review, see [1]). In the latter class of muscle mass (for review, see [4]). Mutations in the conditions, muscle wasting is seen in many patients with Mstn gene have been shown to result in dramatic various distinct types of cancer. In fact, unexplained increases in muscle mass in multiple species [5-11], and weight loss and fatigue are often the presenting symp- inhibitors of MSTN signalling have been shown to toms that bring cancer patients to the doctor’s office. cause increases in muscle growth when administered Moreover, this wasting process, or cachexia, has been systemically to adult mice [12-15]. As a result, there cited as a major cause of actual mortality in patients with have been extensive efforts directed at developing cancer. The aetiology of cachexia has remained largely strategies and agents capable of modulating this signalling mysterious, although several cytokines, including tumour pathway for applications in a wide range of clinical necrosis factor-a, interleukin-6 and interleukin-1b,have settings. The finding that overexpression of MSTN in been implicated as playing a role in mediating the wast- mice could lead to the development of a cachexia-like ing process. One of the hallmarks of cachexia is that the syndrome characterized by an extensive loss of fat and loss of lean body mass cannot be prevented or reversed muscle [16] raised two important questions about poten- simply by increasing nutritional intake. Therefore, there tial therapeutic applications of targeting this pathway in has been considerable focus on developing anabolic patients with cachexia. First, does the inappropriate activation of this pathway play a causative role in the * Correspondence: sjlee@jhmi.edu; david.glass@novartis.com development of cachexia in humans? Second, whether or Johns Hopkins University School of Medicine, Department of Molecular not this signalling pathway is involved in the aetiology of Biology and Genetics, 725 N. Wolfe St., PCTB 803, Baltimore, Maryland 21205, cachexia, can blocking this pathway to preserve muscle USA Novartis Institutes for Biomedical Research, 100 Technology Square, mass thereby reduce morbidity and mortality in patients Cambridge, Massachusetts 02139, USA with cachexia? Full list of author information is available at the end of the article © 2011 Lee and Glass; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Lee and Glass Skeletal Muscle 2011, 1:2 Page 2 of 5 http://www.skeletalmusclejournal.com/content/1/1/2 Benny-Klimek et al.[2]andZhou et al. [3] examined Either by inoculating mice with Chinese hamster ovary the effect of blocking the MSTN pathway in mice bear- cells expressing this soluble receptor [2] or by injecting ing cachexia-inducing tumours. Previous studies had mice directly with the purified fusion protein [3], the shown that MSTN signals by binding initially to activin two groups showed that blocking this signalling pathway type II receptors [17] and that a soluble form of the was effective in preserving muscle mass in a wide range activin type IIB receptor (ActRIIB or ACVR2B), consist- of muscle groups, as well as in maintaining forelimb ing of its ligand binding domain fused to an immuno- grip strength in mice bearing various tumour cells globulin Fc domain, can inhibit signalling of MSTN and known to induce wasting. Interestingly, this protective effect was not observed when a different pharmacologi- other TGF-b family secreted proteins that signal via the ActRII receptors, such as the activins [15]. Moreover, cal agent was used to block this pathway, namely, the the soluble receptor had been shown to cause significant deacetylase inhibitor, trichostatin A (TSA). Although muscle growth (40%-60% in just 2 weeks) when admi- previous studies had shown that TSA could increase the nistered systemically to adult mice [15], presumably by expression of the MSTN antagonist, follistatin [18,19], acting as a ‘trap’ of the circulating ligands, binding them Benny-Klimek et al. found that treatment of tumour- in serum and, thereby, preventing binding and activation bearing mice with TSA could not prevent muscle loss of the cellular receptor complexes (Figure 1). even at doses capable of inducing muscle growth in Figure 1 Inhibition of myostatin (MSTN) and activin signalling by the soluble activin type IIB receptor (ActRIB). MSTN and activin signal to target cells by binding initially to the two activin type II receptors, ActRIIA and/or ActRIIB (also called Acvr2 and Acvr2b, respectively) and then to the type I receptors, ALK4 and/or ALK5. The activated type I receptors phosphorylate the intracellular mediators of signalling, Smad2 and/or Smad3. Signalling through this pathway results in the inhibition of muscle differentiation and growth. The activities of MSTN and activin are regulated normally by a number of different extracellular binding proteins, such as follistatin and FSTL-3. The soluble form of ActRIIB (ActRIIB/ Fc) can act as a ligand trap by binding MSTN and activin and preventing the ligands from binding to their true receptors. Lee and Glass Skeletal Muscle 2011, 1:2 Page 3 of 5 http://www.skeletalmusclejournal.com/content/1/1/2 normal mice. In addition to these effects on skeletal activin signalling had been disrupted by a targeted muscle, Zhou et al. reported that treatment with the mutation in the Inha gene, which encodes the inhibin-a soluble receptor could also prevent cardiac muscle atro- subunit. Inhibins and activins, which generally have phy in tumour-bearing mice. This finding is particularly counteracting biological activities, are dimers that differ significant, as there have been concerns that blocking with respect to their subunit composition, with inhibins MSTN signalling for clinical applications might have consisting of a and b subunits and activins consisting of just b subunits.Hence,micelacking inhibin-a have adverse effects on cardiac function. Perhaps the most excess levels of activin signalling, and previous studies spectacular result was the finding by Zhou et al.that have demonstrated that these mice develop both the soluble receptor was capable of increasing survival of mice inoculated with colon-26 (C26) carcinoma cells gonadal and adrenal tumours and exhibit a cachexia-like even though the intervention had no effect on actual syndrome characterized by severe weight loss, hepatocel- tumour growth. Hence, these studies have provided lular necrosis and gastric mucosal atrophy [23,24]. Zhou exciting and compelling data that blocking muscle wast- et al. show that these mice also develop skeletal muscle ing per se can have significant beneficial effects on both atrophy and that this muscle wasting can be blocked by morbidity and mortality in the setting of cancer and administering the soluble activin type IIB receptor. that agents capable of blocking this signalling pathway Although these studies demonstrate that excess activin may be effective means of achieving this end. activity can ultimately lead to muscle loss, additional What is less clear is whether these studies get us any studies are needed in order to help us to understand the closer to understanding the role that this signalling relevance of these findings to what may be happening in pathway may play in the aetiology of cachexia. The fact cancer cachexia. In particular, it will be important to that muscle mass is preserved by blocking this pathway determine the extent to which the effects on muscle does not necessarily mean that overactivity of the path- seen in this model reflect excess signalling of activin way is responsible for inducing wasting. Blocking MSTN directly to muscle versus activation of atrophy-inducing signalling with agents like the soluble receptor is known pathways as a result of tumour development. The inter- to induce significant muscle growth, and it could be pretation of these studies is somewhat complicated by that these anabolic effects may simply be compensating the fact that the development of tumours in these mice for the muscle wasting that is being induced by activa- is itself dependent on activin signalling; that is, blocking tion of other pathways. In this respect, Zhou et al. activin activity using a soluble form of a different activin type II receptor had previously been shown to block not found Mstn messenger RNA (mRNA) levels in muscle only the cachexia-like syndromeinthesemicebut also to be elevated by about two-fold in C26 tumour-bearing mice. However, Benny-Klimek et al.showed usingtwo tumour progression [25]. different tumour lines (Lewis lung carcinoma and In a second set of studies, Zhou et al.surveyeda B16F10 melanoma) that Mstn knockout mice are not number of human tumours and identified several that only susceptible to tumour-induced wasting but, for rea- express high levels of activin A. They went on to show sons that are unclear, actually appear to exhibit an exag- that two of these tumour lines could induce muscle loss gerated response. Zhou et al. further examined the role when inoculated into nude mice and that this wasting of this signalling pathway by focusing on the possibility process could, again, be blocked by administering the that the culprit in cancer cachexia may not be MSTN soluble receptor. Although these findings were consis- itself but activins, which are TGF-b family members tent with the model that increased activin signalling capable of signalling through the same receptors as played a causative role in inducing wasting, it will be MSTN (for review, see [20]). Previous studies had important to carry out additional studies to further shown that several TGF-b family members, including characterize these human tumours with respect to their activins, are as active as MSTN in inhibiting myoblast ability to induce cachexia. For example, is there is corre- differentiation, acting through the ActRIIB pathway [21], lation between expression levels of activin in the tumour and that electroporation of an activin A expression cas- lines and their ability to induce wasting? Similarly, does sette directly into muscle can induce myofiber atrophy blocking activin expression in a given tumour line abro- [22], suggesting that activin A and MSTN may be cap- gate its ability to induce wasting? Furthermore, as in the able of activating the same signalling cascade leading to case of the tumours that developed in the inhibin-a wasting. Zhou et al. present two sets of studies examin- knockout mice, Zhou et al. reported that the soluble receptor also suppressed the growth of the human ing the possible role that activins may play in inducing tumours in mice, making it difficult to attribute the cancer cachexia. wasting process to the direct effects of activin on In one set of studies, they utilized a genetic model of tumourigenesis in which the normal balance of inhibin/ muscle. Lee and Glass Skeletal Muscle 2011, 1:2 Page 4 of 5 http://www.skeletalmusclejournal.com/content/1/1/2 disease states. Similarly, it will be critical to determine Conclusions whether the muscle anabolic capacity of agents like the What we are left with is the fundamental observation soluble receptor varies depending on the physiological and that blocking the MSTN/activin signalling pathway in disease context in which muscle loss is occurring. Given the context of cancer cachexia can have significant ben- the extensive effort that is being directed by both the aca- eficial effects on both morbidity and mortality, leaving demic and biotechnology/pharmaceutical research com- somewhat open the question of whether activation of munities to develop and test agents capable of blocking this pathway may play a causative role in this process. the MSTN/activin signalling pathway, it seems likely that This issue of causality could have important implica- we will have answers to at least some of these questions in tions not only for the understanding of the basic biology the near future. of cachexia but also for pursuing this therapeutic strat- egy to treat cachectic patients. It seems reasonable to expect that the aetiology of cachexia may be complex Abbreviations and/or heterogeneous and may result from aberrant ActRIIB: ACVR2B (activin receptor type IIB); C26: colon-26; MSTN: myostatin; TGF-β: transforming growth factor-β; TSA: trichostatin A. activity of multiple signalling pathways, particularly if one also considers cachexia that results not only from Acknowledgements cancer but also from a variety of other disease processes. We thank Alan Abrams for generating the schematic diagram in Figure 1. Work in SJL’s laboratory is supported by grants from the National Institutes Hence, it is certainly possible that the MSTN/activin of Health (AR059685, AR060636, and NS065973) and the Muscular Dystrophy pathway may be activated in only a subset of patients Association. Work in DJG’s laboratory is supported by Novartis. and that the extent to which a given patient’s cachexia Author details is responsive or refractory to this therapeutic approach Johns Hopkins University School of Medicine, Department of Molecular may be dependent on the extent to which the pathway Biology and Genetics, 725 N. Wolfe St., PCTB 803, Baltimore, Maryland 21205, is activated in any individual case. USA. Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, Massachusetts 02139, USA. A causal link between skeletal muscle wasting and activation of MSTN signalling has, perhaps, been more Competing interests convincingly established in the cachexia seen in the set- Under a licensing agreement among MetaMorphix, Inc (MMI), Pfizer Inc and the Johns Hopkins University, SJL is entitled to a share of royalty received by ting of heart failure. In particular, Mstn expression has the University on sales of products related to MSTN. SJL and the University been shown to be upregulated in the heart in animal own MMI stock, which is subject to certain restrictions under University models of ischemic and pressure overload injury [26-28] policy. SJL, who is the scientific founder of MMI, is a consultant to MMI on research areas discussed in this paper. The terms of these arrangements are as well as in humans with heart failure [29]. Impor- being managed by the University in accordance with its conflict of interest tantly, mice carrying a heart-specific knockout of the policies. DJG is an employee of Novartis. Mstn gene appear to be resistant to skeletal muscle loss Received: 6 October 2010 Accepted: 24 January 2011 following transverse aortic constriction [30]. Hence, if Published: 24 January 2011 this same mechanism is responsible for the development of cardiac cachexia in humans, blocking MSTN signal- References ling in this disease context has the potential to target 1. Glass DJ: Signaling pathways perturbing muscle mass. Curr Opin Clin Nutr Metab Care 2010, 13:225-229. the actual root cause of skeletal muscle wasting, which 2. Benny Klimek ME, Aydogdu T, Link MJ, Pons M, Koniaris LG, Zimmers TA: has been shown to be a significant risk factor for mor- Acute inhibition of myostatin-family proteins preserves skeletal muscle tality in patients with heart failure [31]. in mouse models of cancer cachexia. Biochem Biophys Res Commun 2010, 391:1548-1554. On the other hand, this question of underlying mechan- 3. Zhou X, Wang JL, Lu J, Song Y, Kwak KS, Jiao Q, Rosenfeld R, Chen Q, ism may be of purely academic interest if this therapeutic Boone T, Simonet WS, et al: Reversal of cancer cachexia and muscle approach turns out to be effective in preserving muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell 2010, 142:531-543. mass and reducing morbidity and mortality, regardless of 4. Lee S-J: Regulation of muscle mass by myostatin. Annu Rev Cell Dev Biol the underlying cause of the cachexia. Indeed, the studies 2004, 20:61-86. by Zhou et al. showing that the soluble receptor can 5. McPherron AC, Lawler AM, Lee S-J: Regulation of skeletal muscle mass in mice by a new TGF-β superfamily member. Nature 1997, 387:83-90. improve survival of mice bearing certain tumours without 6. Grobet L, Martin LJR, Poncelet D, Pirottin D, Brouwers B, Riquet J, directly perturbing the pathways that induce cancer or the Schoeberlein A, Dunner S, Ménissier F, Massabanda J, et al: A deletion in consequent downstream activation of atrophy-signalling the bovine myostatin gene causes the double-muscled phenotype in cattle. Nature Genet 1997, 17:71-74. molecules secreted by the tumour provides compelling 7. Kambadur R, Sharma M, Smith TPL, Bass JJ: Mutations in myostatin (GDF8) support for the notion that maintaining muscle mass is in double-muscled Belgian Blue and Piedmontese cattle. Genome Res per se helpful in improving survival in otherwise cachectic 1997, 7:910-916. conditions. An important question is how generalizable 8. McPherron AC, Lee S-J: Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci USA 1997, 94:12457-12461. this beneficial effect on survival will turn out to be, not 9. Schuelke M, Wagner KR, Stolz LE, Hübner C, Riebel T, Kömen W, Braun T, only with respect to cachexia induced by other types of Tobin JF, Lee S-J: Myostatin mutation associated with gross muscle cancers but also with respect to cachexia induced by other hypertrophy in a child. N Engl J Med 2004, 350:2682-2688. Lee and Glass Skeletal Muscle 2011, 1:2 Page 5 of 5 http://www.skeletalmusclejournal.com/content/1/1/2 10. Clop A, Marcq F, Takeda H, Pirottin D, Tordoir X, Bibe B, Bouix J, Caiment F, heart failure and after mechanical unloading. Eur J Heart Fail 2010, Elsen JM, Eychenne F, et al: A mutation creating a potential illegitimate 12:444-453. microRNA target site in the myostatin gene affects muscularity in sheep. 30. Heineke J, Auger-Messier M, Xu J, Sargent M, York A, Welle S, Molkentin JD: Nature Genet 2006, 38:813-818. Genetic deletion of myostatin from the heart prevents skeletal muscle 11. Mosher DS, Quignon P, Bustamante CD, Sutter NB, Mellersh CS, Parker HG, atrophy in heart failure. Circulation 2010, 121:419-425. Ostrander EA: A mutation in the myostatin gene increases muscle mass 31. Anker SD, Ponikowski P, Varney S, Chua TP, Clark AL, Webb-Peploe KM, and enhances racing performance in heterozygote dogs. PLoS Genetics Harrington D, Kox WJ, Poole-Wilson PA, Coats AJ: Wasting as independent 2007, 3:779-786. risk factor for mortality in chronic heart failure. Lancet 1997, 12. Bogdanovich S, Krag TOB, Barton ER, Morris LD, Whittemore LA, Ahima RS, 349:1050-1053. Khurana TS: Functional improvement of dystrophic muscle by myostatin doi:10.1186/2044-5040-1-2 blockade. Nature 2002, 420:418-421. Cite this article as: Lee and Glass: Treating cancer cachexia to treat 13. Whittemore LA, Song K, Li X, Aghajanian J, Davies MV, Girgenrath S, Hill JJ, cancer. Skeletal Muscle 2011 1:2. Jalenak M, Kelley P, Knight A, et al: Inhibition of myostatin in adult mice increases skeletal muscle mass and strength. Biochem Biophys Res Commun 2003, 300:965-971. 14. Wolfman NM, McPherron AC, Pappano WN, Davies MV, Song K, Tomkinson KN, Wright JF, Zhao L, Sebald SM, Greenspan DS, Lee S-J: Activation of latent myostatin by the BMP-1/tolloid family of metalloproteinases. Proc Natl Acad Sci USA 2003, 100:15842-15846. 15. Lee S-J, Reed A, Davies M, Girgenrath S, Goad M, Tomkinson K, Wright J, Barker C, Ehrmantraut G, Holmstrom J, et al: Regulation of muscle growth by multiple ligands signaling through activin type II receptors. Proc Natl Acad Sci USA 2005, 102:18117-18122. 16. Zimmers TA, Davies MV, Koniaris LG, Haynes P, Esquela AF, Tomkinson KN, McPherron AC, Wolfman NM, Lee S-J: Induction of cachexia in mice by systemically administered myostatin. Science 2002, 296:1486-1488. 17. Lee S-J, McPherron AC: Regulation of myostatin activity and muscle growth. Proc Natl Acad Sci USA 2001, 98:9306-9311. 18. Iezzi S, Di Padova M, Serra C, Caretti G, Simone C, Maklan E, Minetti G, Zhao P, Hoffman EP, Puri PL, Sartorelli V: Deacetylase inhibitors increase muscle cell size by promoting myoblast recruitment and fusion through induction of follistatin. Dev Cell 2004, 6:673-684. 19. Minetti GC, Colussi C, Adami R, Serra C, Mozetta C, Parente V, Fortuni S, Straino S, Sampaolesi M, Di Padova M, et al: Functional and morphological recovery of dystrophic muscles in mice treated with deacetylase inhibitors. Nat Med 2006, 12:1147-1150. 20. Moustakas A, Heldin CH: The regulation of TGFβ signal transduction. Development 2009, 136:3699-3714. 21. Trendelenburg AU, Meyer A, Rohner D, Boyle J, Hatakeyama S, Glass DJ: Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size. Am J Physiol Cell Physiol 2009, 296: C1258-C1270. 22. Gilson H, Schakman O, Kalista S, Lause P, Tsuchida K, Thissen JP: Follistatin induces muscle hypertrophy through satellite cell proliferation and inhibition of both myostatin and activin. Am J Physiol Endocrinol Metab 2009, 297:E157-E164. 23. Matzuk MM, Finegold MJ, Su J-GJ, Hsueh AJW, Bradley A: α-Inhibin is a tumor-suppressor gene with gonadal specificity in mice. Nature 1992, 360:313-319. 24. Matzuk MM, Finegold MJ, Mather JP, Krummen L, Lu H, Bradley A: Development of cancer cachexia-like syndrome and adrenal tumors in inhibin-deficient mice. Proc Natl Acad Sci USA 1994, 91:8817-8821. 25. Li Q, Kumar R, Underwood K, O’Connor AE, Loveland KL, Seehra JS, Matzuk MM: Prevention of cachexia-like syndrome development and reduction of tumor progression in inhibin-deficient mice following administration of a chimeric activin receptor type II-murine Fc protein. Mol Hum Reprod 2007, 13:675-683. 26. Sharma M, Kambadur R, Matthews KG, Somers WG, Devlin GP, Conaglen JV, Fowke PJ, Bass JJ: Myostatin, a transforming growth factor-beta Submit your next manuscript to BioMed Central superfamily member, is expressed in heart muscle and is upregulated in and take full advantage of: cardiomyocytes after infarct. J Cell Physiol 1999, 180:1-9. 27. Shyu KG, Lu MJ, Wang BW, Sun HY, Chang H: Myostatin expression in • Convenient online submission ventricular myocardium in a rat model of volume-overload heart failure. Eur J Clin Invest 2006, 36:713-719. • Thorough peer review 28. Lenk K, Schur R, Linke A, Erbs S, Matsumoto Y, Adams V, Schuler G: Impact • No space constraints or color figure charges of exercise training on myostatin expression in the myocardium and • Immediate publication on acceptance skeletal muscle in a chronic heart failure model. Eur J Heart Fail 2009, 11:342-348. • Inclusion in PubMed, CAS, Scopus and Google Scholar 29. George I, Bish LT, Kamalakkannan G, Petrilli CM, Oz MC, Naka Y, • Research which is freely available for redistribution Sweeney HL, Maybaum S: Myostatin activation in patients with advanced Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Skeletal Muscle Springer Journals

Treating cancer cachexia to treat cancer

Lee, Se-Jin; Glass, David
Skeletal Muscle , Volume 1 (1) – Jan 24, 2011
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Springer Journals
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Copyright © 2011 by Lee and Glass; licensee BioMed Central Ltd.
Subject
Life Sciences; Cell Biology; Developmental Biology; Biochemistry, general; Systems Biology; Biotechnology
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2044-5040
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10.1186/2044-5040-1-2
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Abstract

Skeletal muscle wasting is a major component of cachectic states found in a variety of disease settings, including cancer. As increasing caloric intake often provides little benefit in combating muscle loss in cachectic patients, a major research focus has been to develop strategies stimulating muscle anabolic pathways - in an attempt to fight the catabolic pathways induced during cachexia. Two recent papers have reported the beneficial effects of blocking the myostatin/activin signalling pathway in mouse models of cancer cachexia. We discuss the implications of their findings both with respect to the role that this signalling pathway may play in the aetiology of cachexia and with respect to the prospects for targeting this pathway as a therapeutic strategy in patients with cachexia. Background strategies that directly target muscle in order to preserve Loss of skeletal muscle mass can occur in a wide range muscle mass and function. Two recent papers by Benny- of disease states and has significant consequences, causing Klimek et al. [2] and Zhou et al. [3] have reported studies debilitating weakness and also metabolic dysfunction - as that investigated the potential beneficial effects of target- skeletal muscle is one of the major tissues in the body ing the myostatin/activin signalling pathway in order to responsible for regulating energy availability and energy provide such an anabolic stimulus to muscle in rodent expenditure. Loss of muscle mass can result either from models of cancer cachexia. primary muscle degenerative diseases, such as the mus- cular dystrophies, or as a secondary consequence of Discussion cachectic disease processes also affecting other tissues, Myostatin (MSTN) is a transforming growth factor-b such as cancer, burns, renal failure, sepsis and congestive (TGF-b) family member that normally acts to limit heart failure (for review, see [1]). In the latter class of muscle mass (for review, see [4]). Mutations in the conditions, muscle wasting is seen in many patients with Mstn gene have been shown to result in dramatic various distinct types of cancer. In fact, unexplained increases in muscle mass in multiple species [5-11], and weight loss and fatigue are often the presenting symp- inhibitors of MSTN signalling have been shown to toms that bring cancer patients to the doctor’s office. cause increases in muscle growth when administered Moreover, this wasting process, or cachexia, has been systemically to adult mice [12-15]. As a result, there cited as a major cause of actual mortality in patients with have been extensive efforts directed at developing cancer. The aetiology of cachexia has remained largely strategies and agents capable of modulating this signalling mysterious, although several cytokines, including tumour pathway for applications in a wide range of clinical necrosis factor-a, interleukin-6 and interleukin-1b,have settings. The finding that overexpression of MSTN in been implicated as playing a role in mediating the wast- mice could lead to the development of a cachexia-like ing process. One of the hallmarks of cachexia is that the syndrome characterized by an extensive loss of fat and loss of lean body mass cannot be prevented or reversed muscle [16] raised two important questions about poten- simply by increasing nutritional intake. Therefore, there tial therapeutic applications of targeting this pathway in has been considerable focus on developing anabolic patients with cachexia. First, does the inappropriate activation of this pathway play a causative role in the * Correspondence: sjlee@jhmi.edu; david.glass@novartis.com development of cachexia in humans? Second, whether or Johns Hopkins University School of Medicine, Department of Molecular not this signalling pathway is involved in the aetiology of Biology and Genetics, 725 N. Wolfe St., PCTB 803, Baltimore, Maryland 21205, cachexia, can blocking this pathway to preserve muscle USA Novartis Institutes for Biomedical Research, 100 Technology Square, mass thereby reduce morbidity and mortality in patients Cambridge, Massachusetts 02139, USA with cachexia? Full list of author information is available at the end of the article © 2011 Lee and Glass; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Lee and Glass Skeletal Muscle 2011, 1:2 Page 2 of 5 http://www.skeletalmusclejournal.com/content/1/1/2 Benny-Klimek et al.[2]andZhou et al. [3] examined Either by inoculating mice with Chinese hamster ovary the effect of blocking the MSTN pathway in mice bear- cells expressing this soluble receptor [2] or by injecting ing cachexia-inducing tumours. Previous studies had mice directly with the purified fusion protein [3], the shown that MSTN signals by binding initially to activin two groups showed that blocking this signalling pathway type II receptors [17] and that a soluble form of the was effective in preserving muscle mass in a wide range activin type IIB receptor (ActRIIB or ACVR2B), consist- of muscle groups, as well as in maintaining forelimb ing of its ligand binding domain fused to an immuno- grip strength in mice bearing various tumour cells globulin Fc domain, can inhibit signalling of MSTN and known to induce wasting. Interestingly, this protective effect was not observed when a different pharmacologi- other TGF-b family secreted proteins that signal via the ActRII receptors, such as the activins [15]. Moreover, cal agent was used to block this pathway, namely, the the soluble receptor had been shown to cause significant deacetylase inhibitor, trichostatin A (TSA). Although muscle growth (40%-60% in just 2 weeks) when admi- previous studies had shown that TSA could increase the nistered systemically to adult mice [15], presumably by expression of the MSTN antagonist, follistatin [18,19], acting as a ‘trap’ of the circulating ligands, binding them Benny-Klimek et al. found that treatment of tumour- in serum and, thereby, preventing binding and activation bearing mice with TSA could not prevent muscle loss of the cellular receptor complexes (Figure 1). even at doses capable of inducing muscle growth in Figure 1 Inhibition of myostatin (MSTN) and activin signalling by the soluble activin type IIB receptor (ActRIB). MSTN and activin signal to target cells by binding initially to the two activin type II receptors, ActRIIA and/or ActRIIB (also called Acvr2 and Acvr2b, respectively) and then to the type I receptors, ALK4 and/or ALK5. The activated type I receptors phosphorylate the intracellular mediators of signalling, Smad2 and/or Smad3. Signalling through this pathway results in the inhibition of muscle differentiation and growth. The activities of MSTN and activin are regulated normally by a number of different extracellular binding proteins, such as follistatin and FSTL-3. The soluble form of ActRIIB (ActRIIB/ Fc) can act as a ligand trap by binding MSTN and activin and preventing the ligands from binding to their true receptors. Lee and Glass Skeletal Muscle 2011, 1:2 Page 3 of 5 http://www.skeletalmusclejournal.com/content/1/1/2 normal mice. In addition to these effects on skeletal activin signalling had been disrupted by a targeted muscle, Zhou et al. reported that treatment with the mutation in the Inha gene, which encodes the inhibin-a soluble receptor could also prevent cardiac muscle atro- subunit. Inhibins and activins, which generally have phy in tumour-bearing mice. This finding is particularly counteracting biological activities, are dimers that differ significant, as there have been concerns that blocking with respect to their subunit composition, with inhibins MSTN signalling for clinical applications might have consisting of a and b subunits and activins consisting of just b subunits.Hence,micelacking inhibin-a have adverse effects on cardiac function. Perhaps the most excess levels of activin signalling, and previous studies spectacular result was the finding by Zhou et al.that have demonstrated that these mice develop both the soluble receptor was capable of increasing survival of mice inoculated with colon-26 (C26) carcinoma cells gonadal and adrenal tumours and exhibit a cachexia-like even though the intervention had no effect on actual syndrome characterized by severe weight loss, hepatocel- tumour growth. Hence, these studies have provided lular necrosis and gastric mucosal atrophy [23,24]. Zhou exciting and compelling data that blocking muscle wast- et al. show that these mice also develop skeletal muscle ing per se can have significant beneficial effects on both atrophy and that this muscle wasting can be blocked by morbidity and mortality in the setting of cancer and administering the soluble activin type IIB receptor. that agents capable of blocking this signalling pathway Although these studies demonstrate that excess activin may be effective means of achieving this end. activity can ultimately lead to muscle loss, additional What is less clear is whether these studies get us any studies are needed in order to help us to understand the closer to understanding the role that this signalling relevance of these findings to what may be happening in pathway may play in the aetiology of cachexia. The fact cancer cachexia. In particular, it will be important to that muscle mass is preserved by blocking this pathway determine the extent to which the effects on muscle does not necessarily mean that overactivity of the path- seen in this model reflect excess signalling of activin way is responsible for inducing wasting. Blocking MSTN directly to muscle versus activation of atrophy-inducing signalling with agents like the soluble receptor is known pathways as a result of tumour development. The inter- to induce significant muscle growth, and it could be pretation of these studies is somewhat complicated by that these anabolic effects may simply be compensating the fact that the development of tumours in these mice for the muscle wasting that is being induced by activa- is itself dependent on activin signalling; that is, blocking tion of other pathways. In this respect, Zhou et al. activin activity using a soluble form of a different activin type II receptor had previously been shown to block not found Mstn messenger RNA (mRNA) levels in muscle only the cachexia-like syndromeinthesemicebut also to be elevated by about two-fold in C26 tumour-bearing mice. However, Benny-Klimek et al.showed usingtwo tumour progression [25]. different tumour lines (Lewis lung carcinoma and In a second set of studies, Zhou et al.surveyeda B16F10 melanoma) that Mstn knockout mice are not number of human tumours and identified several that only susceptible to tumour-induced wasting but, for rea- express high levels of activin A. They went on to show sons that are unclear, actually appear to exhibit an exag- that two of these tumour lines could induce muscle loss gerated response. Zhou et al. further examined the role when inoculated into nude mice and that this wasting of this signalling pathway by focusing on the possibility process could, again, be blocked by administering the that the culprit in cancer cachexia may not be MSTN soluble receptor. Although these findings were consis- itself but activins, which are TGF-b family members tent with the model that increased activin signalling capable of signalling through the same receptors as played a causative role in inducing wasting, it will be MSTN (for review, see [20]). Previous studies had important to carry out additional studies to further shown that several TGF-b family members, including characterize these human tumours with respect to their activins, are as active as MSTN in inhibiting myoblast ability to induce cachexia. For example, is there is corre- differentiation, acting through the ActRIIB pathway [21], lation between expression levels of activin in the tumour and that electroporation of an activin A expression cas- lines and their ability to induce wasting? Similarly, does sette directly into muscle can induce myofiber atrophy blocking activin expression in a given tumour line abro- [22], suggesting that activin A and MSTN may be cap- gate its ability to induce wasting? Furthermore, as in the able of activating the same signalling cascade leading to case of the tumours that developed in the inhibin-a wasting. Zhou et al. present two sets of studies examin- knockout mice, Zhou et al. reported that the soluble receptor also suppressed the growth of the human ing the possible role that activins may play in inducing tumours in mice, making it difficult to attribute the cancer cachexia. wasting process to the direct effects of activin on In one set of studies, they utilized a genetic model of tumourigenesis in which the normal balance of inhibin/ muscle. Lee and Glass Skeletal Muscle 2011, 1:2 Page 4 of 5 http://www.skeletalmusclejournal.com/content/1/1/2 disease states. Similarly, it will be critical to determine Conclusions whether the muscle anabolic capacity of agents like the What we are left with is the fundamental observation soluble receptor varies depending on the physiological and that blocking the MSTN/activin signalling pathway in disease context in which muscle loss is occurring. Given the context of cancer cachexia can have significant ben- the extensive effort that is being directed by both the aca- eficial effects on both morbidity and mortality, leaving demic and biotechnology/pharmaceutical research com- somewhat open the question of whether activation of munities to develop and test agents capable of blocking this pathway may play a causative role in this process. the MSTN/activin signalling pathway, it seems likely that This issue of causality could have important implica- we will have answers to at least some of these questions in tions not only for the understanding of the basic biology the near future. of cachexia but also for pursuing this therapeutic strat- egy to treat cachectic patients. It seems reasonable to expect that the aetiology of cachexia may be complex Abbreviations and/or heterogeneous and may result from aberrant ActRIIB: ACVR2B (activin receptor type IIB); C26: colon-26; MSTN: myostatin; TGF-β: transforming growth factor-β; TSA: trichostatin A. activity of multiple signalling pathways, particularly if one also considers cachexia that results not only from Acknowledgements cancer but also from a variety of other disease processes. We thank Alan Abrams for generating the schematic diagram in Figure 1. Work in SJL’s laboratory is supported by grants from the National Institutes Hence, it is certainly possible that the MSTN/activin of Health (AR059685, AR060636, and NS065973) and the Muscular Dystrophy pathway may be activated in only a subset of patients Association. Work in DJG’s laboratory is supported by Novartis. and that the extent to which a given patient’s cachexia Author details is responsive or refractory to this therapeutic approach Johns Hopkins University School of Medicine, Department of Molecular may be dependent on the extent to which the pathway Biology and Genetics, 725 N. Wolfe St., PCTB 803, Baltimore, Maryland 21205, is activated in any individual case. USA. Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, Massachusetts 02139, USA. A causal link between skeletal muscle wasting and activation of MSTN signalling has, perhaps, been more Competing interests convincingly established in the cachexia seen in the set- Under a licensing agreement among MetaMorphix, Inc (MMI), Pfizer Inc and the Johns Hopkins University, SJL is entitled to a share of royalty received by ting of heart failure. In particular, Mstn expression has the University on sales of products related to MSTN. SJL and the University been shown to be upregulated in the heart in animal own MMI stock, which is subject to certain restrictions under University models of ischemic and pressure overload injury [26-28] policy. SJL, who is the scientific founder of MMI, is a consultant to MMI on research areas discussed in this paper. The terms of these arrangements are as well as in humans with heart failure [29]. Impor- being managed by the University in accordance with its conflict of interest tantly, mice carrying a heart-specific knockout of the policies. DJG is an employee of Novartis. Mstn gene appear to be resistant to skeletal muscle loss Received: 6 October 2010 Accepted: 24 January 2011 following transverse aortic constriction [30]. Hence, if Published: 24 January 2011 this same mechanism is responsible for the development of cardiac cachexia in humans, blocking MSTN signal- References ling in this disease context has the potential to target 1. 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Lenk K, Schur R, Linke A, Erbs S, Matsumoto Y, Adams V, Schuler G: Impact • No space constraints or color figure charges of exercise training on myostatin expression in the myocardium and • Immediate publication on acceptance skeletal muscle in a chronic heart failure model. Eur J Heart Fail 2009, 11:342-348. • Inclusion in PubMed, CAS, Scopus and Google Scholar 29. George I, Bish LT, Kamalakkannan G, Petrilli CM, Oz MC, Naka Y, • Research which is freely available for redistribution Sweeney HL, Maybaum S: Myostatin activation in patients with advanced Submit your manuscript at www.biomedcentral.com/submit

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