Review

Regulation of Cancer Progression by b-Endorphin Neuron

Dipak K. Sarkar, Sengottuvelan Murugan, Changqing Zhang, and Nadka Boyadjieva

AbstractIt is becoming increasingly clear that stressful life events can affect cancer growth andmetastasis by modulating

nervous, endocrine, and immunesystems.Thepurposeof this review is tobrieflydescribe theprocess bywhich stressmay potentiate carcinogenesis and how reducing body stress may prevent cancer growth and progression. Theopioid peptide b-endorphin plays a critical role in bringing the stress axis to a state of homeostasis.We have recentlyshown that enhancement of endogenous levels of b-endorphin in the hypothalamus via b-endorphin neurontransplantation suppresses stress response, promotes immune function, and reduces the incidence of cancer in ratmodels of prostate and breast cancers. The cancer-preventive effect of b-endorphin is mediated through thesuppression of sympathetic neuronal function, which results in increased peripheral natural killer cell and macro-phage activities, elevated levels of anti-inflammatory cytokines, and reduced levels of inflammatory cytokines.b-endorphin inhibition of tumor progression also involves alteration in the tumor microenvironment, possiblybecause of suppression of catecholamine and inflammatory cytokine production, which are known to alter DNArepair, cell-matrix attachments, angiogenic process, and epithelial–mesenchymal transition. Thus, b-endorphin celltherapy may offer some therapeutic value in cancer prevention. Cancer Res; 72(4); 836–40. �2012 AACR.

Introduction

Emerging evidence suggests that chronic neurobehavioralstress can promote growth and progression of various cancers.Psychologic factors may alter immune and endocrine func-tions, and it has long been hypothesized that, through thispathway, stress may affect tumor growth and spread. On theother hand, it has long been known that relieving the stress ofcancer often leads to faster recovery and general well-being inpatients who are undergoing chemotherapy or radiotherapy(1). Recent work with animal models suggests that the body'sneuroendocrine response (release of hormones in circulation)following psychosocial or physical stress can significantlyaffect many aspects of the body's immune systems (2) andcan also, directly or via immune surveillance, alter importantprocesses of cells that help to protect against the formation ofcancer, such as DNA repair and the regulation of cell growth(3–5). Therefore, controlling the body's stress response may bebeneficial to immunity against cancer. Hence, in this review,wefirst briefly describe the process of how stress may affectimmunity and cancer growth and then summarize the dataobtained in animal studies showing how reduction of the stressresponse by b-endorphin cell transplantation may preventcancer growth and progression.

Neuroendocrine Response to Stress

Environmental and psychosocial stimuli initiate a cascade ofphysiologic changes in the central nervous system (CNS) andperiphery, which subsequently trigger the autonomic nervoussystem (ANS) and the hypothalamic–pituitary–adrenal axis(HPA; reviewed in ref. 6). Stressful experiences activate com-ponents of the limbic system, including the hypothalamus, thehippocampus, and the amygdala, which modulate the activityof hypothalamic and brain-stem structures that control theHPA and ANS activities. The hypothalamus secretes cortico-trophin-releasing hormone (CRH) and arginine vasopressinfrom the paraventricular nucleus of the hypothalamus, both ofwhich activate the pituitary to release hormones of the pro-opiomelanocortin peptides, such as adrenocorticotropic hor-mone (ACTH),which stimulate the secretion of glucocorticoidsfrom the adrenal cortex into the peripheral circulation. Stressresponse also involves secretion of adrenaline (epinephrine)from the chromaffin cells of the adrenalmedulla. In addition tothe activation of the HPA axis, stressful stimuli activate thesympathetic nervous system (SNS), what is often termed the"fight or flight" response. Like other parts of the nervoussystem, the SNS operates through a series of interconnectedneurons, many of which have direct connections with theneurons of the paraventricular nucleus, which run throughthe brain stem and the preganglionic neurons and terminate inthe ganglia near the spinal column. From these ganglia, post-ganglionic fibers run to the effector organs, including spleenand many other lymphoid tissues. The main neurotransmitterof the preganglionic sympathetic fibers is acetylcholine, achemical messenger that binds and activates nicotinic acetyl-choline receptors on postganglionic neurons. The principalneurotransmitter released by the postganglionic neurons is

Authors' Affiliation: Rutgers Endocrine Program, Rutgers, The StateUniversity of New Jersey, New Brunswick, New Jersey

Corresponding Author: Dipak K. Sarkar, Rutgers University, 67 PoultryFarm Lane, New Brunswick, NJ 08901. Phone: 732-932-1529; Fax: 732-932-4134; E-mail: Sarkar@aesop.rutgers.edu

doi: 10.1158/0008-5472.CAN-11-3292

�2012 American Association for Cancer Research.

CancerResearch

Cancer Res; 72(4) February 15, 2012836

on March 7, 2021. © 2012 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

Published OnlineFirst January 27, 2012; DOI: 10.1158/0008-5472.CAN-11-3292

noradrenaline (norepinephrine). The other division of the ANSis the parasympathetic nervous system, which is responsiblefor stimulation of "rest and digest" activities that occur whenthe body is at rest and normally functioning, in opposition tothe sympathetic neurons. The main neurotransmitter of theparasympatheticfibers is acetylcholine. Acetylcholine acts on 2types of receptors, the nicotinic cholinergic (at postganglionicneurons) and muscarinic (at the target organ).The so-called "fight or flight" response can also be seen as an

energy redirection program, and the "rest and digest" activitiescan be seen as an energy storage program (7). During thesebody responses, hormones and neurotransmitters that provideenergy-rich fuels to stores and those that provide energy-richsubstrates are being released. Additionally, altered productionand secretion of various proinflammatory cytokines, such asTNF-a, interleukins-1b (IL-1b) and -6 (IL-6), and circulatingactivated immune cells, are being imposed. Many of theseconditions contribute to the metabolic syndromes that oftenco-occur with cancer.

Neuroendocrine–Neuroimmune Pathways ofCancer

Recently, the results of various studies on animals andhumans point to the fact that the body's psychophysiologicreactions during stress are associated with a greater likelihoodof incidence or relapse of cancer (5, 8). At cellular and molec-ular levels, psychologic stress-associated increase in produc-tion of epinephrine, norepinephrine, and cortisol cause anupregulation of DNA damage sensors Chk1 and Chk2 and theprotooncogene CDC25A, which is involved in cell-cycle delayfollowing DNA damage, resulting in increased cell transfor-mation and/or tumorigenicity (9). The findings of transgenic,knockout, and in vitro models suggest that a dysregulatedstress response downregulates tumor suppressor genes, suchas PTEN, or DNA repair genes, such as BRCA1 (10). Animalstudies have shown that activation of the SNS (which happensduring various stresses) increased lung tumor metastases,whereas pretreatment of animals with b-adrenergic antago-nists (to block the activity of SNS activation) and indomethacin(to block inflammation) synergistically blocked the effects ofbehavioral stress on lung tumor metastasis. Consistent withthese findings are recent data showing that b-adrenergicantagonists promote ovarian cancer cell spreading and adhe-sion to laminin-5 and enhance the adhesion to a fibronectinmatrix (11). Thus, catecholamines may promote cancer cell–matrix attachments. Norepinephrine and epinephrine can alsopromotemigration and the invasive potential of ovarian cancercells by increasingmatrixmetalloproteinase 2 (MMP-2), MMP-9, and some other MMPs that are important for tumor cellpenetration (12). In addition, it has been found that stresshormones may promote angiogenic mechanisms in humantumors by increasing production of VEGF. IL-6, another keycytokine that plays an important role in tumor progression andangiogenesis, is also elevated by norepinephrine in variouscancer animal models (13). Thus, chronic stress activates notonly the HPA axis but also production of catecholamine andseveral inflammatory cytokines, which may promote cancer

growth and progression at biochemical and molecular levels(14).

Studies from human and animal models have also shownthat acute and chronic stressful events have adverse effects on avariety of immunologic mechanisms, such as trafficking ofneutrophils, macrophages, antigen-presenting cells, natural kill-er (NK) cells, andT andB lymphocytes (5, 15). Exposure to stressmodulates cell-mediated immunity by suppressing lymphocyteproliferation and NK activation, lowering the number of CD4þ

cells in the peripheral blood and altering CD4 to CD8 T-cellratios (5, 16). Studies have also shown that depression and stressmight have effects on carcinogenesis indirectly through thepoorer destruction or elimination of abnormal cells by reducedNK cell activity. Decreased NK cell activity is also associatedwith growth and progression of a variety of cancers in animalsand humans, because NK cells seem to represent a first line ofdefense against the metastatic spread of tumor cells (17).

Stress is also associated with altered inflammatory and anti-inflammatory cytokine ratios in systemic circulation. It increasesexpression of IL-1b and TNF-a and reduces expression of IL-2and IFN-g (18). Sustained elevation of TNF-a is known to inhibitthe activity of protein tyrosine phosphatase, causing reducedproduction of the MHC class I antigen of the cell surface andleading to malignant cells escaping immune surveillance (8).Although many specific details remain to be delineated, it isbecoming increasingly clear that stressful life events can affectcancer growth, progression, and metastasis by modulatingnervous, endocrine, and immune systems of the body.

The Endogenous Opioid Peptide b-EndorphinReduces the Body's Stress Response, IncreasesInnate Immune Functions, and Prevents CancerGrowth and Progression

b-Endorphin, an endogenous opioid polypeptide primarilyproducedby the hypothalamus and the pituitary gland, is knownto have the ability to inhibit stress hormone production andproduce analgesia and a feeling of well-being (19). b-endorphinis a cleavage product of pro-opiomelanocortin, which is also theprecursor hormone for ACTH and a-melanocyte–stimulatinghormone (a-MSH). In the hypothalamus, the primary productsof pro-opiomelanocortin are b-endorphin and a-MSH, whereasin the pituitary, pro-opiomelanocortin produces all 3 products(b-endorphin, a-MSH, and ACTH). b-endorphin neuronal cellbodies are primarily localized in the arcuate nuclei of thehypothalamus, and its terminals are distributed throughout theCNS, including the paraventricular nucleus of the hypothalamus(20). In the paraventricular nucleus, these neurons innervateCRH neurons and inhibit CRH release (21), whereas a m-opioidreceptor antagonist increases it (22). During stress, secretion ofCRH and catecholamine stimulates secretion of hypothalamicb-endorphin and other pro-opiomelanocortin-derived peptides,which in turn inhibit the activity of the HPA axis (23). b-Endor-phin is known to bind to d- and m-opioid receptors to modulatethe neurotransmission in neurons of the ANS via neuronalcircuitry within the paraventricular nucleus. b-Endorphin pep-tides, produced from the pituitary pro-opiomelanocortin thatcirculates in the periphery, are primarily regulated by CRH and

b-Endorphin Neuron and Cancer Prevention

www.aacrjournals.org Cancer Res; 72(4) February 15, 2012 837

on March 7, 2021. © 2012 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

Published OnlineFirst January 27, 2012; DOI: 10.1158/0008-5472.CAN-11-3292

arginine vasopressin and may have less control over the ANSfunction.

In the CNS, the opioid peptide b-endorphin is reported tohave rewarding and reinforcing properties and to be involvedin stress response. Additionally, a low level of central b-endor-

phin is connected with the process of stress-related psychiatricdisorders, depression, and posttraumatic stress disorder (24,25). Abnormalities in b-endorphin neuronal function are cor-related with a higher incidence of cancers and infections inpatients with schizophrenia, depression, fetal alcohol

Figure 1. b-Endorphin neuronal cells in the hypothalamus control the neoplastic growth and progression of tumor cells, likely bymodulating one ormore of thefactors indicated. Effects include the activation of parasympathetic nervous system control of lymphoid organs, causing activation of innate immune cells(macrophages and NK cells) and an increase in anti-inflammatory cytokine levels in the circulation. The HPA axis and subsequent stress hormones releasedfrom the adrenal gland and sympathetic nerve terminals (glucocorticoids and catecholamines) may also be suppressed. In a tumor microenvironment,these hormonal and cytokine changes downregulate inflammation-mediated epithelial–mesenchymal transition (EMT) and, thereby, suppress cancerprogression. Collectively, these effects create an unfavorable environment for tumor initiation, growth, and progression.

Sarkar et al.

Cancer Res; 72(4) February 15, 2012 Cancer Research838

on March 7, 2021. © 2012 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

Published OnlineFirst January 27, 2012; DOI: 10.1158/0008-5472.CAN-11-3292

syndrome, and obesity (reviewed in ref. 26). Despite thisevidence, the role of the neuronal b-endorphin in thesediseases is not well studied, because long-term peripheraladministrations of this opioid-like peptide, or its agonistanalogue, induce tolerance and dependence in animals andmake it difficult to study its action on chronic disease, likecancer, in animals. Furthermore, peripheral b-endorphinmay not act like central b-endorphin, and therefore, datafrom b-endorphin knockout or transgenic mice on theneuroendocrine–immune axis are often difficult to interpret.We have recently circumvented this problem by usingb-endorphin cell transplantation, in which pure b-endorphinneurons are differentiated from neuronal stem cells in vitroand then transplanted in the paraventricular nucleus at asite where endogenous b-endorphin neurons make synapticcontact with both CRH and neuronal populations connectedwith the ANS (27). With this approach, it was feasible toincrease the influence of this opioid on 3 important com-ponents of body stress regulation: the HPA axis, sympatheticneurons, and parasympathetic neurons. As they do in vivo, invitro–differentiated b-endorphin cells, when transplantedinto the paraventricular nucleus of the hypothalamus ofstress hyperresponsive and immune-deficient fetal alco-hol–exposed rats, reduced plasma levels of corticosteroneand improved NK-cell cytolytic function in these rats (23).b-endorphin transplantation also suppressed plasma corti-costerone and increased NK cell activity in control rats.We have previously shown that the neural stem cell–derived

b-endorphin neurons, when injected into the paraventricularnucleus, remained viable at the site of transplantation for along period and suppressed carcinogen-induced prostate can-cer development in rats (27). Additionally, we showed thatsupplementation of b-endorphin neurons through transplantsprevented carcinogen-induced mammary tumorigenesis andtumor metastasis (26). Importantly, when the b-endorphintransplants were given at the early stage of tumor develop-ment, many tumors were destroyed, possibly because ofincreased innate immune activity, and the surviving tumorslost their ability to progress to high-grade cancer owing tob-endorphin cells' suppressive effects on epithelial–mesenchy-mal transition regulators. Another remarkable effect of theb-endorphin transplantation was that it promoted the activa-tion of the innate immune (NK cells andmacrophages) activity,following tumor cell invasion, to such an extent that tumor cellmigration to another site was completely halted. NK cells andmacrophages are critical components of the innate immunesystem and play a vital role in host defense against tumor cells

(28, 29). Hence, the increased level of innate immunity mayhave caused unfavorable conditions for cancer cell survival. Inthe b-endorphin cell–treated animals, the lower inflammatorymilieu that was achieved by the higher level of anti-inflam-matory cytokines and the lower level of inflammatory cyto-kines may have also been involved in inhibiting cancer growthand transformation. Several studies have identified the involve-ment and roles of inflammatory cytokines in breast malignan-cy (30). The cancer-preventive and inflammatory cytokinesuppression effects of the b-endorphin neuronal transplantcould be reversed by treatment with a b-receptor agonist or bya nicotine acetylcholine receptor antagonist. This findingsuggests that the suppression of sympathetic neuronal func-tion and the stimulation of parasympathetic neuronal activityare the processes that b-endorphin neurons engage to activateperipheral immunity and anti-inflammatory cytokines to con-trol tumor growth and progression (Fig. 1).

Concluding Remarks

Neurobehavioral stress has been shown to promote tumorgrowth and progression, possibly by altering the production ofhormones, catecholamine, and inflammatory cytokines.Although the cellular mechanisms of stress-activated chemi-cals on tumor growth and progression are not apparent, it hasbeen found that these chemicals decrease immune surveillanceand alter the tumor microenvironment, including cell-matrixattachments, cell migration, invasive potential, and angiogenicmechanisms. Reduction of body stress via b-endorphin neuraltransplants in the brain decreases cancer growth and progres-sion in animal models of breast and prostate cancers, possiblyby altering ANS functioning, leading to activation of innateimmunity and reduction in systemic levels of inflammatoryand anti-inflammatory cytokine ratios. Thus, it is apparent thatstress prevention by b-endorphin cell therapy might be ben-eficial in controlling breast, prostate, and possibly othercancers.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Grant Support

This work was partly supported by NIH grant R37AA08757.

Received September 30, 2011; revised October 25, 2011; accepted October 30,2011; published OnlineFirst January 27, 2012.

References1. Montgomery M, McCrone SH. Psychological distress associated with

the diagnostic phase for suspected breast cancer: systematic review.J Adv Nurs 2010;66:2372–90.

2. Reiche EM, Nunes SO, Morimoto HK. Stress, depression, the immunesystem, and cancer. Lancet Oncol 2004;5:617–25.

3. Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, et al.Chronic stress promotes tumor growth and angiogenesis in a mousemodel of ovarian carcinoma. Nat Med 2006;12:939–44.

4. Antoni MH, Lutgendorf SK, Cole SW, Dhabhar FS, Sephton SE, McDo-nald PG, et al. The influence of bio-behavioural factors on tumourbiology: pathways and mechanisms. Nat Rev Cancer 2006;6:240–8.

5. Ben-Eliyahu S. The promotion of tumor metastasis by surgery andstress: immunological basis and implications for psychoneuroimmu-nology. Brain Behav Immun 2003;17[Suppl 1]:S27–36.

6. Tsigos C, Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuro-endocrine factors and stress. J Psychosom Res 2002;53:865–71.

b-Endorphin Neuron and Cancer Prevention

www.aacrjournals.org Cancer Res; 72(4) February 15, 2012 839

on March 7, 2021. © 2012 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

Published OnlineFirst January 27, 2012; DOI: 10.1158/0008-5472.CAN-11-3292

7. Straub RH, Cutolo M, Buttgereit F, Pongratz G. Energy regulation andneuroendocrine-immune control in chronic inflammatory diseases. JIntern Med 2010;267:543–60.

8. Moreno-SmithM, Lutgendorf SK, SoodAK. Impact of stress on cancermetastasis. Future Oncol 2010;6:1863–81.

9. Flint MS, Baum A, Chambers WH, Jenkins FJ. Induction of DNAdamage, alteration of DNA repair and transcriptional activation bystress hormones. Psychoneuroendocrinology 2007;32:470–9.

10. Hermes GL, Delgado B, Tretiakova M, Cavigelli SA, Krausz T, ConzenSD, et al. Social isolation dysregulates endocrine andbehavioral stresswhile increasing malignant burden of spontaneous mammary tumors.Proc Natl Acad Sci U S A 2009;106:22393–8.

11. Bos JL. Epac proteins: multi-purpose cAMP targets. Trends BiochemSci 2006;31:680–6.

12. Yang EV, Sood AK, Chen M, Li Y, Eubank TD, Marsh CB, et al.Norepinephrine up-regulates the expression of vascular endothelialgrowth factor, matrix metalloproteinase (MMP)-2, and MMP-9 in naso-pharyngeal carcinoma tumor cells. Cancer Res 2006;66:10357–64.

13. NilssonMB, Armaiz-Pena G, Takahashi R, Lin YG, Trevino J, Li Y, et al.Stress hormones regulate interleukin-6 expression by human ovariancarcinoma cells through a Src-dependent mechanism. J Biol Chem2007;282:29919–26.

14. Henry JP. Biological basis of the stress response. Integr Physiol BehavSci 1992;27:66–83.

15. Capuron L, Miller AH. Immune system to brain signaling: neuropsy-chopharmacological implications. Pharmacol Ther 2011;130:226–38.

16. Witek-Janusek L, Gabram S, Mathews HL. Psychologic stress,reduced NK cell activity, and cytokine dysregulation in womenexperiencing diagnostic breast biopsy. Psychoneuroendocrinology2007;32:22–35.

17. Padgett DA, Glaser R. How stress influences the immune response.Trends Immunol 2003;24:444–8.

18. Adler UC, Marques AH, Calil HM. Inflammatory aspects of depression.Inflamm Allergy Drug Targets 2008;7:19–23.

19. Akil H, Watson SJ, Young E, Lewis ME, Khachaturian H, Walker JM.Endogenous opioids: biology and function. Annu Rev Neurosci 1984;7:223–55.

20. Kawano H, Masuko S. Beta-endorphin-, adrenocorticotrophic hor-mone- and neuropeptide y-containing projection fibers from the arcu-

ate hypothalamic nucleus make synaptic contacts on to nucleuspreopticus medianus neurons projecting to the paraventricular hypo-thalamic nucleus in the rat. Neuroscience 2000;98:555–65.

21. Plotsky PM, Thrivikraman KV, Meaney MJ. Central and feedbackregulation of hypothalamic corticotropin-releasing factor secretion.Ciba Found Symp 1993;172:59–75, discussion 75–84.

22. Boyadjieva N, Advis JP, Sarkar DK. Role of beta-endorphin, cortico-tropin-releasing hormone, and autonomic nervous system in media-tion of the effect of chronic ethanol on natural killer cell cytolyticactivity. Alcohol Clin Exp Res 2006;30:1761–7.

23. BoyadjievaNI,Ortig€uelaM,ArjonaA,ChengX,SarkarDK. b-endorphinneuronal cell transplant reduces corticotropin releasing hormonehyperresponse to lipopolysaccharide and eliminates natural killer cellfunctional deficiencies in fetal alcohol exposed rats. Alcohol Clin ExpRes 2009;33:931–7.

24. Darko DF, Risch SC, Gillin JC, Golshan S. Association of beta-endor-phin with specific clinical symptoms of depression. Am J Psychiatry1992;149:1162–7.

25. Bernstein HG, Krell D, Emrich HM, Baumann B, Danos P, Diekmann S,et al. Fewer b-endorphin expressing arcuate nucleus neurons andreduced b-endorphinergic innervation of paraventricular neurons inschizophrenics and patients with depression. Cell Mol Biol 2002;48Online Pub:OL259-65.

26. Sarkar DK, Zhang C,Murugan S, Dokur M, Boyadjieva NI, Ortig€uelaM,et al. Transplantation of b-endorphin neurons into the hypothalamuspromotes immune function and restricts the growth and metastasis ofmammary carcinoma. Cancer Res 2011;71:6282–91.

27. SarkarDK,BoyadjievaNI,ChenCP,Ortig€uelaM,ReuhlK,ClementEM,et al. Cyclic adenosine monophosphate differentiated beta-endorphinneurons promote immune function and prevent prostate cancergrowth. Proc Natl Acad Sci U S A 2008;105:9105–10.

28. Wu L, Van Kaer L. Natural killer T cells in health and disease. FrontBiosci (Schol Ed) 2011;3:236–51.

29. Mantovani A, Sica A. Macrophages, innate immunity and cancer:balance, tolerance, and diversity. Curr Opin Immunol 2010;22:231–7.

30. Goldberg JE, Schwertfeger KL. Proinflammatory cytokines in breastcancer: mechanisms of action and potential targets for therapeutics.Curr Drug Targets 2010;11:1133–46.

Sarkar et al.

Cancer Res; 72(4) February 15, 2012 Cancer Research840

on March 7, 2021. © 2012 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

Published OnlineFirst January 27, 2012; DOI: 10.1158/0008-5472.CAN-11-3292

2012;72:836-840. Published OnlineFirst January 27, 2012.Cancer Res   Dipak K. Sarkar, Sengottuvelan Murugan, Changqing Zhang, et al.  

-Endorphin NeuronβRegulation of Cancer Progression by

  Updated version

  10.1158/0008-5472.CAN-11-3292doi:

Access the most recent version of this article at:

   

   

  Cited articles

  http://cancerres.aacrjournals.org/content/72/4/836.full#ref-list-1

This article cites 29 articles, 5 of which you can access for free at:

   

  E-mail alerts related to this article or journal.Sign up to receive free email-alerts

  Subscriptions

Reprints and

  .pubs@aacr.org

To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at

  Permissions

  Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)

.http://cancerres.aacrjournals.org/content/72/4/836To request permission to re-use all or part of this article, use this link

on March 7, 2021. © 2012 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

Published OnlineFirst January 27, 2012; DOI: 10.1158/0008-5472.CAN-11-3292