Li Yen Mah

Autophagy and Cancer

Li Yen Mah and Kevin M. Ryan

Tumour Cell Death Laboratory, Beatson Institute for Cancer Research, Glasgow G61 1BD, United Kingdom

Correspondence: [email protected]

(Macro)autophagy is a cellular membrane trafficking process that serves to deliver cyto-plasmic constituents to lysosomes for degradation. At basal levels, it is critical for maintain-ing cytoplasmic as well as genomic integrity and is therefore key to maintaining cellularhomeostasis. Autophagy is also highly adaptable and can be modified to digest specificcargoes to bring about selective effects in response to numerous forms of intracellular andextracellular stress. It is not a surprise, therefore, that autophagy has a fundamental role incancer and that perturbations in autophagy can contribute to malignant disease. Wereview here the roles of autophagy in various aspects of tumor suppression including theresponse of cells to nutrient and hypoxic stress, the control of programmed cell death, andthe connection to tumor-associated immune responses.

THE MOLECULAR MECHANISMS ANDTYPES OF AUTOPHAGY

“Autophagy” is broadly defined as a mech-anism by which intracellular and extra-

cellular substrates are delivered to lysosomesfor degradation. This process is required forthe maintenance of cellular homeostasis (Mizu-shima et al. 2008), generation of amino acidsfor sustained viability during periods of starva-tion (Cuervo 2004; Ciechanover 2005), and en-hanced protection against pathogens (Shoji-Kawata and Levine 2009). On the basis of the de-livery route and cargo specificity, three differenttypes of autophagy have been distinguished—macroautophagy, microautophagy, and chaper-one-mediated autophagy (CMA) (Mizushimaet al. 2008). Of these, macroautophagy, whichis often simply (and hereafter) referred to as au-tophagy, is the most characterized form and hasbeen extensively researched in yeast and mam-

mals. It is defined by the sequestration of bulkcytoplasm and organelles in double-membraneorganelles termed autophagosomes (Fig. 1) (Es-kelinen and Saftig 2009). In contrast, microau-tophagy is characterized by the direct uptakeof cytoplasmic substrates by the invaginationof the lysosomal membrane, and CMA by theshuttling of soluble proteins into the lysosomevia lysosomal chaperone proteins (Mizushimaet al. 2008).

Autophagy regulators are conserved fromyeast to mammals, and they are the products ofAuTophaGy(Atg)-related genes (Xie and Klion-sky 2007). The role of several Atg proteins inautophagy is highlighted in this article and isdepicted in Figure 1, but for a more extensivereview of these factors, see Das et al. (2012).An alternative form of macroautophagy hasalso been described that does not rely on thecomplete cascade of Atg signaling. This formof autophagy has been termed “non-canonical”

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or “alternative autophagy,” and its relevance inrelation to “classical” autophagy is currently amatter of debate (Scarlatti et al. 2008; Nishidaet al. 2009; Klionsky and Lane 2010). One pos-sibility is that alternative autophagy is adoptedwhen cells fail to activate canonical autophagyowing to mutations in the cluster of Atg genes.

Although autophagy was initially consid-ered a nonselective cellular process, the specificcatabolism of cellular organelles like mitochon-dria, peroxisomes, endoplasmic reticulum, andribosomes has been documented and is termed“mitophagy” (Kissova et al. 2004; Lemasters2005), “pexophagy” (Sakai et al. 2006), “ER-phagy/reticulophagy” (Bernales et al. 2007),and “ribophagy” (Kraft et al. 2008), respectively.

In general, the role of autophagy to main-tain cellular homeostasis requires the versatilityto recognize a diverse range of substrates and theability to regulate or respond to specific cellularpathways and stimuli. This reflects a complexsignaling network in the regulation of autoph-agy. Collectively, this process is fundamentaland indispensable such that in response to a

block in the canonical signaling cascades, onecan imagine that cells adopt alternative routesto activate autophagy in response to intracellu-lar and extracellular cues that may not be equiv-alent, but are sufficient to sustain viability.

It is now well established that autophagy isconnected to tumor development, althoughthe exact roles played by the process at variousstages of cancer progression are not yet clearand in some cases are contradictory. In the fol-lowing sections, we outline the current knowl-edge regarding the regulation of autophagy incancer and its impact on various processes thatprotect against malignant disease. Finally, wespeculate asto newareas in cancer where autoph-agy may be important, and we discuss the possi-bility of targeting autophagy for cancer therapy.

AUTOPHAGY: FROM MOLECULESTO CANCER

The link between autophagy and cancer is nowbroad-based (Rosenfeldt and Ryan 2011) but wasestablished based on two principal observations.

Isolation membraneformation

NUCLEATION ELONGATION MATURATION DEGRADATION

Nascentautophagosome Autophagosome

Endosome Lysosome

Lysosome

Amphisome Autolysosome

Beclin 1,UVRAG

Beclin 1, UVRAG

Beclin 1,UVRAG

Atg 5, Atg12,Atg7,

LC3 (Atg8)Beclin 1,UVRAG

Figure 1. Cellular mechanism and molecular regulators of autophagy in eukaryotes. NUCLEATION: Beclin1(Atg6) and UVRAG (UV irradiation resistance–associated gene), are required for the formation of the isolationmembrane for sequestering the autophagic substrate. ELONGATION: The closure of the isolation membrane toform autophagosomes causes sequestration/entrapment of cytoplasmic constituents. This requires the conju-gation of Atg5 and Atg12 and is catalyzed by Atg7 (E1-like enzyme). Meanwhile, pro-LC3 (Atg8) is cleaved toform LC3-I, which is then lipidated to form LC3-II. MATURATION: Autophagosomes dock and fuse with ly-sosomes to form autolysosomes. Although the molecular mechanism is not fully understood, Beclin 1 and UV-RAG are thought to mediate this process. Alternatively, autophagosomes can fuse with endosomal vesicles, suchas endosomes and multivesicular bodies, to form amphisomes, which eventually dock with lysosomes. DEGRA-DATION: After fusion with lysosomes, autolysosomes are generated where the sequestered materials are hydro-lyzed. The inner membrane of autophagosomes and the cargoes are degraded by lysosomal enzymes, and break-down products are released back into the cytosol.

L.Y. Mah and K.M. Ryan

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First, it was found that BECN1, the gene encod-ing Beclin 1 and the ortholog of yeast Atg6, is mo-noallelically deleted in breast, ovarian, and pros-tate cancers (Aita et al. 1999; Liang et al. 1999). Inaddition, ectopic overexpression of BECN1 inMCF7 cells, which have extremely low levels ofendogenous Beclin 1, resulted in activation ofautophagy coincident with decreased prolifera-tion and inhibition of tumorigenesis (Lianget al. 1999). Consistently, ectopic overexpressionof BECN1 in colon cancer cell lines with low ex-pression of this gene results in growth inhibition(Koneri et al. 2007). Subsequent to these studies,mutations in other autophagy-related genes in-cluding Atg2B, Atg5, Atg9B, Atg12, and UVRAG,have been documented in gastric and colorectalcancers (Kim et al. 2008; Kang et al. 2009).

The second line of evidence, which consoli-dated a connection between autophagy andcancer, came from a series of studies involvinggenetically modified mouse models lacking au-tophagy regulators. It was found first in micehemizygous for BECN1, and later in mice lack-ing Atg4C and BIF1, that a deficiency in theseautophagic factors can lead to an increased inci-dence of tumor formation (Qu et al. 2003; Yueet al. 2003; Marino et al. 2007; Takahashi et al.2007). Interestingly, however, in the case of mo-saic deletion of Atg5 and liver-specific deletionof Atg7, only benign lesions were observed inthe liver. Moreover, the mosaic loss of Atg5 inother tissues did not have any effect on tumorformation—either benign or malignant (Taka-mura et al. 2011). This implies that certain au-tophagy regulators—in this case, Atg5—maybe redundant with respect to tumor suppres-sion in many tissues and that in liver autophagymight prevent tumor initiation, but is requiredfor tumor progression. Having said that, itshould be pointed out that some autophagy reg-ulators also control other cellular processes. Forexample, Beclin 1 also regulates endocytosis.Thus, the resulting tumor phenotype associatedwith mutation in these versatile regulators maybe caused by autophagy-independent mecha-nisms or by synergistic effects on autophagyand other cellular mechanisms.

A plethora of genes, which are known to beperturbed in cancer, have now also been re-

ported to modulate autophagy (for review, seeRosenfeldt and Ryan 2009). For example, thewell-established tumor suppressor p53—themost frequently mutated gene in human can-cer—has been reported to modulate auto-phagy both positively and negatively (Fig. 2)(Ryan 2011). Its positive effects on autophagyhave been shown to occur via modulation ofmTOR and through transcriptional up-regula-tion of the autophagy promoters Sestrin-2and damage-regulated autophagy modulator-1(DRAM-1) (Feng et al. 2005; Crighton et al.2006, 2007; Maiuri et al. 2009). DRAM-1 hasalso been reported to be down-regulated in cer-tain cancers indicating a direct role of this p53target gene in tumor suppression (Crightonet al. 2006, 2007).

p53 has, however, also been shown to be anegative regulator of autophagy within the cy-toplasm (Tasdemir et al. 2008). These dual ef-fects on autophagy are not exclusive to p53.The potent oncogene Ras has also been shownto promote as well as inhibit autophagy (Furutaet al. 2004; Elgendy et al. 2011). Although thesefindings add to the connection between auto-phagy and cancer, the apparently conflicting re-ports may at first seem difficult to reconcile. Itmust be remembered, however, that multipledifferent forms of cellular stress occur during tu-mor development, and these observations maysimply reflect different positive and negative ef-fects of autophagy at different stages of the dis-ease.

Additionally, many of these observationsare conducted in transformed cell lines, whichdiffer biologically and may not represent whathappens in a genuine tumor microenviron-ment. As such, these results need to be con-solidated through sophisticated and thoroughin vivo genetically modified mouse models ofcancer.

STIMULATING AUTOPHAGY IN CANCER

Autophagy occurs constitutively, but when cellsare exposed to unfavorable conditions, autoph-agy is activated above basal levels to counteract“stress” and to promote cellular homeostasis.This switch from default housekeeping to a


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specific cytoprotective role is triggered by vari-ous stimuli. In cancer, for example, a varietyof adverse and hostile conditions that resultin the production of reactive oxygen species(ROS) can lead to protein and DNA damagethat destabilizes cellular homeostasis (Dewaeleet al. 2010).

Under normal conditions, our cells are con-stantly breaking down macromolecules foundabundantly in the surrounding environmentfor the synthesis of new building blocks andto provide energy to sustain their survival. How-ever, under conditions in which nutrients arescarce, as occurs in the poorly vascularized re-gions of developing tumors, autophagy is acti-vated as a mechanism to provide nutrientsfrom within the cell in order to sustain viabilityfor a limited period until external nutrientsbecome available (Kuma et al. 2004; Lum et al.2005a,b). In fact, several evolutionarily con-served nutrient sensors such as mTOR, AMPK,and Sirtuins are regulators of autophagy (Ro-

senfeldt and Ryan 2009, 2011; Kroemer et al.2010; Mehrpouret al. 2010). In addition, cellularcompartments have recently been identified thatenable linkage between autophagy and mTOR(Narita et al. 2011). The importance of this re-sponse is exemplified by the fact that when cellsare deprived of amino acids, mature autophagicvacuoles have been reported to occupy �1% ofthe cytoplasm (Mizushima et al. 2001). Like-wise, under growth factor–limiting conditions,hematopoietic cells activate autophagy to pro-duce ATP for survival (Lum et al. 2005a). Usingsimilar measurements, glucose and serum with-drawal have also been shown to induce autoph-agy, although the net outcome in these situationsoften skews toward cell death (Aki et al. 2003;Steiger-Barraissoul and Rami 2009).

In addition to nutrient deprivation, meta-bolic stress is also caused by hypoxia. Solid tu-mors contain poorly vascularized regions thatare very hypoxic. Studies have now shown thatcells within these areas display high levels of

p53

BAX

PUMA

DRAM1

SESN2

SESN2BAX

PUMA

DRAM1

p53

p53

mTOR

Figure 2. p53 modulates autophagy in multiple ways. Basal levels of p53 target repression of autophagy fromwithin the cytoplasm. In response to cellular stress, the levels of p53 become elevated and accumulate in the nu-cleus. This results in activation of a series of target genes that positively regulate autophagy. PUMA and BAX alsolocalize to mitochondria. DRAM-1, in contrast, localizes to lysosomes, and Sestrin-2 modulates autophagy viamTOR. SESN2, the gene encoding Sestrin-2.



macroautophagy (Degenhardt et al. 2006). Itwas concluded from this study that tumor cellsrely heavily on autophagy to survive. The mostdocumented hypoxic signaling pathway in-volves the activation of the hypoxia induciblefactor 1 (HIF), which is composed of a andb subunits. The HIF1a subunit is affected bychanges in oxygen concentration and modulatesgenes involved in regulating erythropoiesis, an-giogenesis, energy metabolism, pH regulation,cell migration, and tumor invasion (Mazureand Pouyssegur 2010). Another HIF familymember, HIF2a, is also stimulated by hypoxia,and both HIF1a and HIF2a, as well as the au-tophagy regulator Beclin 1, have been shownto be required for prosurvival hypoxia-inducedautophagy in normal and cancer cell lines(Zhang et al. 2008; Bellot et al. 2009; Wilkinsonet al. 2009). In tumor cells, this response is alsoenhanced by autocrine growth factor signalingvia PDGF receptors, leading to enhanced HIFactivity and a robust and selective autophagicresponse to promote cell survival (Wilkinsonand Ryan 2009; Wilkinson et al. 2009).

Several reports have also shown that hypoxiacan stimulate autophagy in an HIF-indepen-dent manner (Pursiheimo et al. 2009). Hyp-oxia-induced autophagy removes the autophagy“adaptor” and signaling protein p62/SQSTM1,a well-known autophagic substrate, suggesting alink between p62/SQSTM1 and the regulationof hypoxic cancer cell survival responses (Wil-kinson and Ryan 2009; Wilkinson et al. 2009).Furthermore, the lack of p62/SQSTM1 removalin autophagy-deficient cells has been shown tobe a contributing factor to tumor development(Mathew et al. 2009).

In short, autophagy is activated followingmetabolite deprivation and hypoxia, but alsoin response to a multitude of factors encoun-tered during the development of cancer thatperturb the equilibrated cellular environment.In addition, autophagy is also activated in re-sponse to a variety of chemotherapeutic drugs(Kondo et al. 2005). Thus, this draws us to thetentative conclusion that most, if not all, formsof stress stimulate autophagy, which when takentogether has been termed the “integrated stressresponse” (Kroemer et al. 2010).

AUTOPHAGY—NOT JUST CELLAUTONOMOUS IN CANCER

Tumor cells are thought to favor metabolism ofglucose via glycolysis, because they display highlevels of glucose uptake and lactate production,even when oxygen is abundant. This form ofaerobic glycolysis is termed the “Warburg Ef-fect” (Warburg 1956). Tumor cells that fail tokeep up with energy demands can die by ne-crosis, resulting in the production and accumu-lation of ROS (Lin et al. 2004). This induces ox-idative stress in the tumor microenvironment.As a result, bystander cells can switch on au-tophagy to remove ROS together with damagedcellular organelles, and tumor cells have hi-jacked this housekeeping program to fuel theirown growth. Martinez-Outschoorn et al. (2011)showed that cancer cells transmit oxidativestress to neighboring fibroblasts to down-regu-late Cav-1 (a marker often associated with earlytumor recurrence, lymph node metastasis, andtamoxifen resistance). They also showed thatcancer-associated fibroblasts are subsequentlyplagued with mitochondrial dysfunction, oxi-dative stress, and aerobic glycolysis. They pro-posed that these stromal cells activate autophagyto remove damaged organelles, and the resultingdegradation products are fed to tumor cells ina manner similar to what has been dubbed the“reverse Warburg effect” (Pavlides et al. 2009).Thus, not only is autophagy exploited intrinsi-cally by cancer cells for their benefit, but alsosignals for autophagy activation are transmittedto the surrounding untransformed cells, andtheir activity is used to fuel tumor cell growth.

AUTOPHAGY: GUARDIAN OF THE GENOMEIN ADDITION TO THE PROTEOME

Maintenance of genome integrity is critical toavoid tumorigenesis (Bartek et al. 2007). Oneof the main consequences of metabolic stressis the accumulation of ROS, which can causeDNA damage by inducing DNA base changesand strand breaks. This leads to the inactiva-tion of tumor-suppressor genes and enhancedexpression and/or activation of proto-oncogenes(Wiseman and Halliwell 1996). Consistently, ROS



has long been associated with human cancer de-velopment (Wiseman and Halliwell 1996), andthe role of autophagy in lowering ROS levels hasbeen confirmed by many studies (Rouschopet al. 2009). Given that ROS stimulate autophagy,we can summarize that when ROS are present athigh levels, autophagy is activated to scavengeROS, thus preventing DNA damage and tumori-genesis.

Despite being more sensitive to metabolicstress, autophagy-deficient cancer cells are morelikely to accumulate genomic damage. Mathewet al. (2007) showed that BECN1þ/2 andAtg52/2 immortalized baby mouse kidney(iBMK) cells accumulate higher levels of mu-tation, chromosomal instability, and accelera-ted progression into aneuploidy (Mathew etal. 2007). This finding is confirmed in an invivo mammary model. When immortalizedBECN1þ/þ and BECN1þ/ – mouse mammaryepithelial cells (iMMEC) were injected intomice to form xenografts, BECN1 hemizygosityresulted in genome damage under metabolicstress and gene amplification (Karantza-Wads-worth et al. 2007).

The role of autophagy as the guardian of thegenome is multifaceted. The decision whetherto die via apoptosis or necrosis, or to stay alivewith unresolved damage, is not yet completelyunderstood. These variations may be governedby the extent of damage, status of the affectedcells, or the type of drug, which might also stim-ulate other responses apart from DNA damage.Either way, a defect in autophagy can be per-ceived as a road not only to impaired cytoplas-mic homeostasis, but also to replication of cellscontaining DNA damage that may be predis-posed to tumor development.

AUTOPHAGY PROGRAMS CELL DEATH

Apoptosis is long established as a form of pro-grammed cell death and is known to be a keycomponent of tumor suppression. The apop-totic pathways are well studied, and the role ofautophagy in modulating apoptosis has beenconvincingly documented in vivo. Autophagyhas been shown to be required for cell death insalivary glands during Drosophila development

(Berry and Baehrecke 2007)—we refer the read-er to the accompanying article in this collectionby Das et al. (2012). Similarly, overexpression ofwild-type Atg1 in Drosophila elicits a strong au-tophagic response, and cells that have high levelsof this protein are selectively and rapidly elimi-nated (Scott et al. 2007).

Although the exact mechanism(s) connect-ing autophagy and apoptosis as partners incell killing is still unclear, the cross talk betweenautophagy and apoptosis has been dissected bymany researchers (Fig. 3). Classical apoptoticregulators such as the antiapoptotic Bcl-2 familymembers Bcl-XL and Bcl-2 have been shown toregulate autophagy, and, reciprocally, a cleavedform of the essential autophagy protein Atg5has been shown to induce apoptosis directlyat mitochondria (Pattingre et al. 2005; Yousefiet al. 2006).

The coactivation of autophagy and apopto-sis has also been shown in cancercells. For exam-ple, DRAM-1 was found to have both proauto-phagic and proapoptotic roles downstreamfrom p53 (Crighton et al. 2006, 2007). Similarly,Yee et al. (2009) showed that another p53 targetgene, the potent proapoptotic Puma, inducesmitophagy and the subsequent release of cyto-chrome c, leading to apoptosis. The inhibitionof PUMA-induced autophagy diminishes theapoptotic response, thus highlighting a synergybetween autophagy and apoptosis in this celldeath response.

Although apoptosis and autophagy can oc-cur in a cooperative manner to elicit cell death,these processes are sometimes mutually antago-nistic (Fig. 3) (Boya et al. 2005). For example,caspases (the effectors of the apoptotic celldeath) have been shown to cleave and inacti-vate Atg6/Beclin 1, and the suppression of Atg6function increases apoptotic cell death (Choet al. 2009). These lines of evidence imply thatapoptosis is either inhibited or delayed whenautophagy is present, with the probable conclu-sion that autophagy is activated to protect cellsfrom dying (Fig. 3).

Other contrasting behaviors between apop-tosis and autophagy have been attributed tothe status of the cell, or stage of transforma-tion. Dominant-negative FADD invokes a death



stimulus involving autophagy in healthy cellsbut not in cancer cells and induces varying am-plitudes of death responses at different stages ofcancer progression (Thorburn et al. 2005). Inaddition, oncogenic Ras has also recently beenshown to cause autophagic cell death in the ab-sence of apoptosis (Elgendy et al. 2011), eventhough other reports have indicated that au-tophagy is required for Ras-driven tumorgrowth (Guo et al. 2011; Yang et al. 2011).

These lines of evidence suggest that the de-cision to activate, repress, or simply not to ma-nipulate autophagy, may be governed by the na-ture of the stimuli or the upstream regulator ofan autophagic and/or apoptotic protein, as wellas the health status of cells, and the net outcomeof these three possibilities is either to promoteor repress tumor survival, or both.

AUTOPHAGY AND NECROSIS

Necrosis is a form of cellular demise character-ized by several features such as ATP depletion,the loss of cellular osmolarity, and release of var-ious factors such as HMGB1 and cell lysis, whichall lead to a strong inflammatory response (Ed-

inger and Thompson 2004). Although necrosisis often perceived as an unregulated form of celldeath, emerging evidence reveals that it can alsooccur as a form of caspase-independent pro-grammed cell death and is specifically termed“necroptosis” (Vandenabeele et al. 2010). Pro-grammed necrotic cell death is also known tobe the mediator of cell death in response to cer-tain classes of chemotherapeutic drugs (Zonget al. 2004).

As if contradicting the role of cell death intumor suppression, necrosis is generally consid-ered to be a tumor promoter and is often asso-ciated with poor prognosis (Swinson et al.2002). Necrotic cells in vivo cause a strong in-flammatory response, accompanied by the pro-duction of cytokines, chemokines, and otherinflammatory enzymes, which can, in turn, pos-itively feed back to cause further damage in sur-viving cells with enhanced tumorigenic poten-tial (Balkwill et al. 2005).

Necrosis and autophagy, like apoptosis andautophagy, often occur coincidently (Fig. 3).Therapeutic treatment of cancer cells triggersnecrosis due to bioenergetic compromise. Tu-mor cells can evade this ATP-limiting demise

Cell death

Inflammationtumor promotion

Cell survival

Cell deathwith autophagy

Cell death

Apoptosis NecrosisAutophagy

Cellular stress

Mitophagy

Cleavageof beclin 1

ROS

ATP

Figure 3. Autophagy and the control of cell death. There is cross talk between apoptosis and autophagy in thecontrol of cell death. The two pathways also repress one another, fighting for either cell survival or cell death.Autophagy also regulates necrosis. Both pathways can regulate each other, and the products of inflammationcan positively feed back to enhance the amplitude of these responses. Examples are shown to indicate how apop-tosis and autophagy and necrosis and autophagy are connected.



by activating the energy sensor LKB1/AMPKcomplex, which, in turn, inhibits the mam-malian target of rapamycin (mTOR), leadingto activation of autophagy (Amaravadi andThompson 2007). Although this seems to favorthe viability of cancer cells, the major role forautophagy activation in promoting tumor de-velopment lies in the repression of necrosis-associated inflammatory responses. These re-sponses can promote the release of prometa-static immune-modulatory factors such asHMBG1, and this may lead to increased meta-stasis (Thorburn et al. 2009a,b). Additionally,necrosis has been shown to be activated byAKT and Ras oncogenic signaling and is up-regulated when autophagy is compromised bymonoallelic deletion of BECN1 (Degenhardtet al. 2006). Thus, autophagy is perceived to pre-vent necrosis in order to limit further cellulardamage that may promote tumorigenesis andmetastasis. However, the situation is not entirelystraightforward because tumors that survivenecrotic stress via autophagy could obtain anadvantage to thrive under nutrient-limitingconditions and acquire mutations that causeresistance to cell death.

AUTOPHAGY AND SENESCENCE: A BARRIERTO TUMOR PROGRESSION?

Cellular senescence is a process in which cellsenter a state of irreversible cell cycle arrest (Kriz-hanovsky et al. 2008). The permanent with-drawal from the cell cycle can restrict tumorcell proliferation and is therefore considered animportant mechanism of tumor suppression.Senescent cells do, however, secrete a spectrumof proinflammatory cytokines, termed the senes-cence-associated secretory phenotype (SASP),causing inflammation that is, in turn, a vectorfor tumor cell growth (Davalos et al. 2010).

Recently, Young et al. (2009) reported thatseveral Atg genes—ULK3, Atg7, and LC3(Atg8)—are up-regulated during oncogene-induced senescence. They also showed thatautophagy is required for the transition of mi-totic to senescent phase, and genetic ablationof autophagy delays the onset of senescence.Since then, much thought has been put into

the “hows” and “whys” of the autophagy-regu-lated senescence program. Some researchers be-lieve that autophagy is evoked to break downspecific cellular components to enable physicalremodelling associated with senescence (Whiteand Lowe 2009). Additionally, autophagy maysupplement senescent cells with the monomersthat are required for the production and secre-tion of a plethora of growth factors, as wellas for restructuring the cellular cytoskeleton(Adams 2009).

AUTOPHAGY AND TUMOR IMMUNITY

Cellular immunity can be generally classifiedinto two categories; innate and adaptive. Innateimmunity, analogous to the body’s first line ofdefense, is almost always engaged in trigger-ing the complement system and inflammation.Adaptive immunity, on the other hand, resultsin a more specific and stronger response. Thisinvolves the surveillance, capture, and presenta-tion of pathogens or pathogenic/non-self pep-tides by antigen-presenting cells (APCs) suchas macrophages, B-cells, and dendritic cells(DCs), which then stimulate T-lymphocytes toinvoke cell death, among other responses. Au-tophagy and immunity have long been consid-ered as two inseparable entities (Schmid et al.2007; Shoji-Kawata and Levine 2009). The rolesof autophagy in regulating inflammation andadaptive immunity, ranging from lymphocytedevelopment (Nedjic et al. 2008), pathogen rec-ognition and destruction, to antigen presenta-tion have been shown (Schmid et al. 2007).

Over the last few decades, neoplastic cellshave been shown to express a panel of uniqueantigens that are recognized by T cells (Sensiand Anichini 2006). Hence, tumor antigen pre-sentation is an important aspect of antitumorresponses, and a defect in this system can resultin tumor escape from immune surveillance—afacet often associated with cancer progression(Garcia-Lora et al. 2003; Hanahan and Wein-berg 2011). DCs are one of the most effectiveprofessional APCs. One of the many contribu-tors that impede DC function in tumor defenseis the buildup of ROS, which are present abun-dantly in the tumor microenvironment (Fricke



and Gabrilovich 2006). High levels of ROS havebeen shown to induce oxidative stress, resultingin JNK-mediated denditric cell death (Handleyet al. 2005). Because autophagy has a major rolein buffering ROS, a defect in this lysosomal deg-radation pathway would handicap DCs due tothe accumulation of ROS.

Autophagy is also intrinsically connected tothe process of antigen presentation. Classically,antigens derived from outside the cell are de-graded in lysosomes, and autophagy has impor-tant roles in trafficking antigens destined fordegradation, as well as trafficking peptidesfrom degraded antigen back to the cell surfacefor presentation on the class II major histocom-patibility complex (MHC). Most tumor anti-gens are, of course, derived from within thecell, and degradation in this context is primarilyvia proteasomes, resulting in presentation onclass I MHC. Autophagy, however, stills plays amajor role in the presentation of tumor antigenson APCs directly on class II MHC or via a proc-ess termed “cross-presentation” on class I MHC(Munz 2010). With respect to this, priming ofCD8þ T cells APCs presenting the melano-cyte-derived tumor antigen gp100 is greatly en-hanced when autophagy is pharmacologicallyinduced in the melanocytes with rapamycin,and this is reversed when autophagy is blockedwith 3-methyladenine (3-MA) (Li et al. 2008).The investigators also found that blockingautophagy at later stages by inhibiting autoph-agosome turnover facilitated antigen cross-pre-sentation, subsequently revealing that autoph-agosomes are efficient transporters of antigenfrom antigen-presenting cells to T cells. Thissuggests that the stabilization of autophago-somes, rather than the initiation and comple-tion of autophagy itself, is required for effectivepriming of cytotoxic T cells. Elegant in vivostudies by Lee et al. (2010) have confirmed thatautophagy is particularly required to enhanceclass I antigen presentation by DCs. They showedthat Atg52/2 DCs present antigen on class IImolecules but have a reduced ability to activateCD4þ lymphocytes by promoting antigen deg-radation in autolysosomes. No differences wereobserved in DC migration or DC antigen cap-ture via endocytosis and phagocytosis, as well

as cross-presentation on class I. They also dis-covered that autophagy induced by starvationand rapamycin treatment decreases class II pre-sentation.

Albeit varying in the mode of action, au-tophagy initiation is required for both class Iand II MHC processing. Evidence indicatesthat the synthesis, but not degradation, of auto-phagosomes is the determining factor for class I,whereas for class II, both synthesis and degrada-tion of autophagosomes are crucial (Dorfelet al. 2005). Aside from macroautophagy, chap-erone-mediated autophagy has also been shownto play a role in antigen presentation, particu-larly in the presentation of endogenous antigenof cytoplasmic origin (Deretic 2005). It is con-ceivable, therefore, that more than one formof autophagy operates in antigen processing,and the dissection of this network, particularlyin the context of tumor antigen presentation,may represent an encouraging step towardnew, rationally designed tumor therapies.

CONCLUSIONS AND PERSPECTIVES

Autophagy is not only a critical degradationprocess for housekeeping purposes in normaltissues, but it also affects various cellular mech-anisms that are critical, or altered in cancer cells(Fig. 4). There may, however, be additionalmechanisms relevant to tumor developmentwhere a role for autophagy is yet to be defined.For example, in addition to genetic alterations,cancer cells usually have tremendous changesin their epigenetic landscape (Sharma et al.2010). Given that autophagosomes can seques-ter chromosomes (Sit et al. 1996) and autopha-gic breakdown of the nucleus is well docu-mented in yeast (Kvam and Goldfarb 2007), itmight be possible for autophagy to regulateepigenetic regulatory factors such as histonemethyltransferases and deacetylases in the nu-cleus of mammalian cells. Could this be an ad-ditional role for autophagy in cancer?

It is a defining feature of cancer that tumorcells show uncontrolled proliferation comparedwith normal cells. Because autophagy is oftenderegulated in transformed cells, is there a linkbetween autophagy and cell cycle deregulation?



In this regard, autophagy has been reported tobe activated in response to TGF-b, resulting inenhancement of TGF-b-mediated growth in-hibition in human hepatocellular carcinomacells (Kiyono et al. 2009). Would this implythat autophagy could attenuate the cell cycleand limit cancer cell proliferation?

Because of these extensive links, autophagyis a very attractive target for cancer therapeutics.In fact, most existing drugs designed to kill can-cer cells also induce autophagy (Kondo et al.2005). Whether autophagy is activated to en-hance cell killing or as a counterstress mecha-nism is governed by many factors, rangingfrom the nature of the stimulus to the health sta-tus of the cell. Recently, the role of autophagy inthe interplay of stromal cells within the tumorniche has also been acknowledged (Martinez-Outschoorn et al. 2010, 2011). This adds an-other level of complexity to the existing theorywhereby the induction of autophagy at differentstages of cancer yields different effects (Fig. 4).

With this knowledge, treatments, or at least ad-juvants that modulate autophagy, could be in-corporated into the cancer treatment regime(Amaravadi and Thompson 2007). Perhaps thedelivery of autophagic modulators either posi-tive or negative should also be tailored to thestage and type of cancer. In addition, wouldthe modulation of autophagy be a strategy forboth initial treatment and for treatment of re-lapsed disease?

These are all questions that remain to be an-swered. Nevertheless, the roles of autophagy inmodulating various cellular processes involvedin cancer progression are now without ques-tion. As a result, much excitement currently sur-rounds the possibility of targeting autophagyfor tumor therapy. The issue, however, is notstraightforward. As we have highlighted here,autophagy can have both positive and negativeeffects on tumor development, thus makingit difficult to know whether to positively or neg-atively modulate autophagy in any given

Removedamaged

mitochondriaFacilitate

senescence Facilitatetumor antigenpresentation

Facilitateapoptosis

SuppressgrowthMitigate

ROS

Promote survivalof damaged cells

INITIATIONTUMOR

DEVELOPMENTMETASTASIS

RECURRENTDISEASE

Adaptation to nutrientand oxygen depletion

Promoteinflammation

Resistanceto treatment

Suppress necrosis/inflammation?

Figure 4. The contrasting roles of autophagy in cancer. Activating autophagy at different stages of cancer yieldsmultiple opposing effects. In healthy cells, autophagy prevents cellular transformation by removing ROS anddamaged mitochondria. However, following transformation, activation of autophagy can promote and suppresscancer progression, depending on the timing or stage of disease. Autophagy either mediates its effects directly or“communicates” with other cellular pathways such as senescence, apoptosis, necrosis, and inflammation.



scenario. Moreover, it must be remembered thatautophagy is not only serving to protect usagainst cancer, but also has major roles in pro-tecting us against many other forms of disease(Ravikumar et al. 2010). Systemic modulationof autophagy, although beneficial for tumortherapy, may therefore have detrimental rolesin normal tissues. Ultimately, however, withan optimistic view, it may be that transientmodulation of autophagy may be sufficientfor therapy without impact in normal tissuesor that ways to selectively target tumor-associ-ated autophagy may be devised. Numerous lab-oratories are currently addressing these issues,and the exciting answers should be revealed inthe not-too-distant future.

ACKNOWLEDGMENTS

We apologize to those researchers whose studieson autophagy we were unable to cite because ofthe length of this article. We thank Simon Mil-ling and members of the Tumour Cell DeathLaboratory for critical reading of the manu-script. Work in the Tumour Cell Death Labora-tory is supported by Cancer Research UK andthe Association for International Cancer Re-search.

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no conflictsof interest in relation to this article.

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