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: k.ryan@beatson.gla.ac.uk

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

THE MOLECULAR MECHANISMS AND

TYPES OF AUTOPHAGY

utophagy is broadly defined as a mechanism by which intracellular and extracellular substrates are delivered to lysosomes
for degradation. This process is required for
the maintenance of cellular homeostasis (Mizushima et al. 2008), generation of amino acids
for sustained viability during periods of starvation (Cuervo 2004; Ciechanover 2005), and enhanced protection against pathogens (ShojiKawata and Levine 2009). On the basis of the delivery route and cargo specificity, three different
types of autophagy have been distinguished
macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA) (Mizushima
et al. 2008). Of these, macroautophagy, which
is often simply (and hereafter) referred to as autophagy, is the most characterized form and has
been extensively researched in yeast and mam-

mals. It is defined by the sequestration of bulk

cytoplasm and organelles in double-membrane
organelles termed autophagosomes (Fig. 1) (Eskelinen and Saftig 2009). In contrast, microautophagy is characterized by the direct uptake
of cytoplasmic substrates by the invagination
of the lysosomal membrane, and CMA by the
shuttling of soluble proteins into the lysosome
via lysosomal chaperone proteins (Mizushima
et al. 2008).
Autophagy regulators are conserved from
yeast to mammals, and they are the products of
AuTophaGy(Atg)-related genes (Xie and Klionsky 2007). The role of several Atg proteins in
autophagy is highlighted in this article and is
depicted in Figure 1, but for a more extensive
review of these factors, see Das et al. (2012).
An alternative form of macroautophagy has
also been described that does not rely on the
complete cascade of Atg signaling. This form
of autophagy has been termed non-canonical

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L.Y. Mah and K.M. Ryan

Lysosome
Beclin 1, UVRAG

Beclin 1,
UVRAG

Atg 5, Atg12,
Atg7,
LC3 (Atg8)

Beclin 1,
UVRAG

Beclin 1,
UVRAG

Endosome
Isolation membrane
formation

Nascent
autophagosome

Autophagosome

NUCLEATION

ELONGATION

MATURATION

Lysosome
Amphisome

Autolysosome
DEGRADATION

Figure 1. Cellular mechanism and molecular regulators of autophagy in eukaryotes. NUCLEATION: Beclin

1(Atg6) and UVRAG (UV irradiation resistance associated gene), are required for the formation of the isolation
membrane for sequestering the autophagic substrate. ELONGATION: The closure of the isolation membrane to
form autophagosomes causes sequestration/entrapment of cytoplasmic constituents. This requires the conjugation of Atg5 and Atg12 and is catalyzed by Atg7 (E1-like enzyme). Meanwhile, pro-LC3 (Atg8) is cleaved to
form LC3-I, which is then lipidated to form LC3-II. MATURATION: Autophagosomes dock and fuse with lysosomes to form autolysosomes. Although the molecular mechanism is not fully understood, Beclin 1 and UVRAG are thought to mediate this process. Alternatively, autophagosomes can fuse with endosomal vesicles, such
as endosomes and multivesicular bodies, to form amphisomes, which eventually dock with lysosomes. DEGRADATION: After fusion with lysosomes, autolysosomes are generated where the sequestered materials are hydrolyzed. The inner membrane of autophagosomes and the cargoes are degraded by lysosomal enzymes, and breakdown products are released back into the cytosol.

or alternative autophagy, and its relevance in

relation to classical autophagy is currently a
matter of debate (Scarlatti et al. 2008; Nishida
et al. 2009; Klionsky and Lane 2010). One possibility is that alternative autophagy is adopted
when cells fail to activate canonical autophagy
owing to mutations in the cluster of Atg genes.
Although autophagy was initially considered a nonselective cellular process, the specific
catabolism of cellular organelles like mitochondria, peroxisomes, endoplasmic reticulum, and
ribosomes has been documented and is termed
mitophagy (Kissova et al. 2004; Lemasters
2005), pexophagy (Sakai et al. 2006), ERphagy/reticulophagy (Bernales et al. 2007),
and ribophagy (Kraft et al. 2008), respectively.
In general, the role of autophagy to maintain cellular homeostasis requires the versatility
to recognize a diverse range of substrates and the
ability to regulate or respond to specific cellular
pathways and stimuli. This reflects a complex
signaling network in the regulation of autophagy. Collectively, this process is fundamental
and indispensable such that in response to a
2

block in the canonical signaling cascades, one

can imagine that cells adopt alternative routes
to activate autophagy in response to intracellular and extracellular cues that may not be equivalent, but are sufficient to sustain viability.
It is now well established that autophagy is
connected to tumor development, although
the exact roles played by the process at various
stages of cancer progression are not yet clear
and in some cases are contradictory. In the following sections, we outline the current knowledge regarding the regulation of autophagy in
cancer and its impact on various processes that
protect against malignant disease. Finally, we
speculate asto newareas in cancer where autophagy may be important, and we discuss the possibility of targeting autophagy for cancer therapy.
AUTOPHAGY: FROM MOLECULES
TO CANCER

The link between autophagy and cancer is now

broad-based (Rosenfeldt and Ryan 2011) but was
established based on two principal observations.

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Autophagy and Cancer

First, it was found that BECN1, the gene encoding Beclin 1 and the ortholog of yeast Atg6, is monoallelically deleted in breast, ovarian, and prostate cancers (Aita et al. 1999; Liang et al. 1999). In
addition, ectopic overexpression of BECN1 in
MCF7 cells, which have extremely low levels of
endogenous Beclin 1, resulted in activation of
autophagy coincident with decreased proliferation and inhibition of tumorigenesis (Liang
et al. 1999). Consistently, ectopic overexpression
of BECN1 in colon cancer cell lines with low expression of this gene results in growth inhibition
(Koneri et al. 2007). Subsequent to these studies,
mutations in other autophagy-related genes including Atg2B, Atg5, Atg9B, Atg12, and UVRAG,
have been documented in gastric and colorectal
cancers (Kim et al. 2008; Kang et al. 2009).
The second line of evidence, which consolidated a connection between autophagy and
cancer, came from a series of studies involving
genetically modified mouse models lacking autophagy regulators. It was found first in mice
hemizygous for BECN1, and later in mice lacking Atg4C and BIF1, that a deficiency in these
autophagic factors can lead to an increased incidence of tumor formation (Qu et al. 2003; Yue
et al. 2003; Marino et al. 2007; Takahashi et al.
2007). Interestingly, however, in the case of mosaic deletion of Atg5 and liver-specific deletion
of Atg7, only benign lesions were observed in
the liver. Moreover, the mosaic loss of Atg5 in
other tissues did not have any effect on tumor
formationeither benign or malignant (Takamura et al. 2011). This implies that certain autophagy regulatorsin this case, Atg5may
be redundant with respect to tumor suppression in many tissues and that in liver autophagy
might prevent tumor initiation, but is required
for tumor progression. Having said that, it
should be pointed out that some autophagy regulators also control other cellular processes. For
example, Beclin 1 also regulates endocytosis.
Thus, the resulting tumor phenotype associated
with mutation in these versatile regulators may
be caused by autophagy-independent mechanisms or by synergistic effects on autophagy
and other cellular mechanisms.
A plethora of genes, which are known to be
perturbed in cancer, have now also been re-

ported to modulate autophagy (for review, see

Rosenfeldt and Ryan 2009). For example, the
well-established tumor suppressor p53the
most frequently mutated gene in human cancerhas been reported to modulate autophagy both positively and negatively (Fig. 2)
(Ryan 2011). Its positive effects on autophagy
have been shown to occur via modulation of
mTOR and through transcriptional up-regulation of the autophagy promoters Sestrin-2
and damage-regulated autophagy modulator-1
(DRAM-1) (Feng et al. 2005; Crighton et al.
2006, 2007; Maiuri et al. 2009). DRAM-1 has
also been reported to be down-regulated in certain cancers indicating a direct role of this p53
target gene in tumor suppression (Crighton
et al. 2006, 2007).
p53 has, however, also been shown to be a
negative regulator of autophagy within the cytoplasm (Tasdemir et al. 2008). These dual effects on autophagy are not exclusive to p53.
The potent oncogene Ras has also been shown
to promote as well as inhibit autophagy (Furuta
et al. 2004; Elgendy et al. 2011). Although these
findings add to the connection between autophagy and cancer, the apparently conflicting reports may at first seem difficult to reconcile. It
must be remembered, however, that multiple
different forms of cellular stress occur during tumor development, and these observations may
simply reflect different positive and negative effects of autophagy at different stages of the disease.
Additionally, many of these observations
are conducted in transformed cell lines, which
differ biologically and may not represent what
happens in a genuine tumor microenvironment. As such, these results need to be consolidated through sophisticated and thorough
in vivo genetically modified mouse models of
cancer.
STIMULATING AUTOPHAGY IN CANCER

Autophagy occurs constitutively, but when cells

are exposed to unfavorable conditions, autophagy is activated above basal levels to counteract
stress and to promote cellular homeostasis.
This switch from default housekeeping to a

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L.Y. Mah and K.M. Ryan

p53
BAX
PUMA

mTOR

DRAM1
SESN2
PUMA
BAX

p53

SESN2

p53
DRAM1

Figure 2. p53 modulates autophagy in multiple ways. Basal levels of p53 target repression of autophagy from

within the cytoplasm. In response to cellular stress, the levels of p53 become elevated and accumulate in the nucleus. This results in activation of a series of target genes that positively regulate autophagy. PUMA and BAX also
localize to mitochondria. DRAM-1, in contrast, localizes to lysosomes, and Sestrin-2 modulates autophagy via
mTOR. SESN2, the gene encoding Sestrin-2.

specific cytoprotective role is triggered by various stimuli. In cancer, for example, a variety
of adverse and hostile conditions that result
in the production of reactive oxygen species
(ROS) can lead to protein and DNA damage
that destabilizes cellular homeostasis (Dewaele
et al. 2010).
Under normal conditions, our cells are constantly breaking down macromolecules found
abundantly in the surrounding environment
for the synthesis of new building blocks and
to provide energy to sustain their survival. However, under conditions in which nutrients are
scarce, as occurs in the poorly vascularized regions of developing tumors, autophagy is activated as a mechanism to provide nutrients
from within the cell in order to sustain viability
for a limited period until external nutrients
become available (Kuma et al. 2004; Lum et al.
2005a,b). In fact, several evolutionarily conserved nutrient sensors such as mTOR, AMPK,
and Sirtuins are regulators of autophagy (Ro4

senfeldt and Ryan 2009, 2011; Kroemer et al.

2010; Mehrpour et al. 2010). In addition, cellular
compartments have recently been identified that
enable linkage between autophagy and mTOR
(Narita et al. 2011). The importance of this response is exemplified by the fact that when cells
are deprived of amino acids, mature autophagic
vacuoles have been reported to occupy 1% of
the cytoplasm (Mizushima et al. 2001). Likewise, under growth factor limiting conditions,
hematopoietic cells activate autophagy to produce ATP for survival (Lum et al. 2005a). Using
similar measurements, glucose and serum withdrawal have also been shown to induce autophagy, although the net outcome in these situations
often skews toward cell death (Aki et al. 2003;
Steiger-Barraissoul and Rami 2009).
In addition to nutrient deprivation, metabolic stress is also caused by hypoxia. Solid tumors contain poorly vascularized regions that
are very hypoxic. Studies have now shown that
cells within these areas display high levels of

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Autophagy and Cancer

macroautophagy (Degenhardt et al. 2006). It

was concluded from this study that tumor cells
rely heavily on autophagy to survive. The most
documented hypoxic signaling pathway involves the activation of the hypoxia inducible
factor 1 (HIF), which is composed of a and
b subunits. The HIF1a subunit is affected by
changes in oxygen concentration and modulates
genes involved in regulating erythropoiesis, angiogenesis, energy metabolism, pH regulation,
cell migration, and tumor invasion (Mazure
and Pouyssegur 2010). Another HIF family
member, HIF2a, is also stimulated by hypoxia,
and both HIF1a and HIF2a, as well as the autophagy regulator Beclin 1, have been shown
to be required for prosurvival hypoxia-induced
autophagy in normal and cancer cell lines
(Zhang et al. 2008; Bellot et al. 2009; Wilkinson
et al. 2009). In tumor cells, this response is also
enhanced by autocrine growth factor signaling
via PDGF receptors, leading to enhanced HIF
activity and a robust and selective autophagic
response to promote cell survival (Wilkinson
and Ryan 2009; Wilkinson et al. 2009).
Several reports have also shown that hypoxia
can stimulate autophagy in an HIF-independent manner (Pursiheimo et al. 2009). Hypoxia-induced autophagy removes the autophagy
adaptor and signaling protein p62/SQSTM1,
a well-known autophagic substrate, suggesting a
link between p62/SQSTM1 and the regulation
of hypoxic cancer cell survival responses (Wilkinson and Ryan 2009; Wilkinson et al. 2009).
Furthermore, the lack of p62/SQSTM1 removal
in autophagy-deficient cells has been shown to
be a contributing factor to tumor development
(Mathew et al. 2009).
In short, autophagy is activated following
metabolite deprivation and hypoxia, but also
in response to a multitude of factors encountered during the development of cancer that
perturb the equilibrated cellular environment.
In addition, autophagy is also activated in response to a variety of chemotherapeutic drugs
(Kondo et al. 2005). Thus, this draws us to the
tentative conclusion that most, if not all, forms
of stress stimulate autophagy, which when taken
together has been termed the integrated stress
response (Kroemer et al. 2010).

AUTOPHAGYNOT JUST CELL

AUTONOMOUS IN CANCER

Tumor cells are thought to favor metabolism of

glucose via glycolysis, because they display high
levels of glucose uptake and lactate production,
even when oxygen is abundant. This form of
aerobic glycolysis is termed the Warburg Effect (Warburg 1956). Tumor cells that fail to
keep up with energy demands can die by necrosis, resulting in the production and accumulation of ROS (Lin et al. 2004). This induces oxidative stress in the tumor microenvironment.
As a result, bystander cells can switch on autophagy to remove ROS together with damaged
cellular organelles, and tumor cells have hijacked this housekeeping program to fuel their
own growth. Martinez-Outschoorn et al. (2011)
showed that cancer cells transmit oxidative
stress to neighboring fibroblasts to down-regulate Cav-1 (a marker often associated with early
tumor recurrence, lymph node metastasis, and
tamoxifen resistance). They also showed that
cancer-associated fibroblasts are subsequently
plagued with mitochondrial dysfunction, oxidative stress, and aerobic glycolysis. They proposed that these stromal cells activate autophagy
to remove damaged organelles, and the resulting
degradation products are fed to tumor cells in
a manner similar to what has been dubbed the
reverse Warburg effect (Pavlides et al. 2009).
Thus, not only is autophagy exploited intrinsically by cancer cells for their benefit, but also
signals for autophagy activation are transmitted
to the surrounding untransformed cells, and
their activity is used to fuel tumor cell growth.

AUTOPHAGY: GUARDIAN OF THE GENOME

IN ADDITION TO THE PROTEOME

Maintenance of genome integrity is critical to

avoid tumorigenesis (Bartek et al. 2007). One
of the main consequences of metabolic stress
is the accumulation of ROS, which can cause
DNA damage by inducing DNA base changes
and strand breaks. This leads to the inactivation of tumor-suppressor genes and enhanced
expression and/or activation of proto-oncogenes
(Wiseman and Halliwell 1996). Consistently, ROS

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L.Y. Mah and K.M. Ryan

has long been associated with human cancer development (Wiseman and Halliwell 1996), and
the role of autophagy in lowering ROS levels has
been confirmed by many studies (Rouschop
et al. 2009). Given that ROS stimulate autophagy,
we can summarize that when ROS are present at
high levels, autophagy is activated to scavenge
ROS, thus preventing DNA damage and tumorigenesis.
Despite being more sensitive to metabolic
stress, autophagy-deficient cancer cells are more
likely to accumulate genomic damage. Mathew
et al. (2007) showed that BECN1 /2 and
Atg5 2/2 immortalized baby mouse kidney
(iBMK) cells accumulate higher levels of mutation, chromosomal instability, and accelerated progression into aneuploidy (Mathew et
al. 2007). This finding is confirmed in an in
vivo mammary model. When immortalized
BECN1 / and BECN1 / mouse mammary
epithelial cells (iMMEC) were injected into
mice to form xenografts, BECN1 hemizygosity
resulted in genome damage under metabolic
stress and gene amplification (Karantza-Wadsworth et al. 2007).
The role of autophagy as the guardian of the
genome is multifaceted. The decision whether
to die via apoptosis or necrosis, or to stay alive
with unresolved damage, is not yet completely
understood. These variations may be governed
by the extent of damage, status of the affected
cells, or the type of drug, which might also stimulate other responses apart from DNA damage.
Either way, a defect in autophagy can be perceived as a road not only to impaired cytoplasmic homeostasis, but also to replication of cells
containing DNA damage that may be predisposed to tumor development.
AUTOPHAGY PROGRAMS CELL DEATH

Apoptosis is long established as a form of programmed cell death and is known to be a key
component of tumor suppression. The apoptotic pathways are well studied, and the role of
autophagy in modulating apoptosis has been
convincingly documented in vivo. Autophagy
has been shown to be required for cell death in
salivary glands during Drosophila development
6

(Berry and Baehrecke 2007)we refer the reader to the accompanying article in this collection
by Das et al. (2012). Similarly, overexpression of
wild-type Atg1 in Drosophila elicits a strong autophagic response, and cells that have high levels
of this protein are selectively and rapidly eliminated (Scott et al. 2007).
Although the exact mechanism(s) connecting autophagy and apoptosis as partners in
cell killing is still unclear, the cross talk between
autophagy and apoptosis has been dissected by
many researchers (Fig. 3). Classical apoptotic
regulators such as the antiapoptotic Bcl-2 family
members Bcl-XL and Bcl-2 have been shown to
regulate autophagy, and, reciprocally, a cleaved
form of the essential autophagy protein Atg5
has been shown to induce apoptosis directly
at mitochondria (Pattingre et al. 2005; Yousefi
et al. 2006).
The coactivation of autophagy and apoptosis has also been shown in cancer cells. For example, DRAM-1 was found to have both proautophagic and proapoptotic roles downstream
from p53 (Crighton et al. 2006, 2007). Similarly,
Yee et al. (2009) showed that another p53 target
gene, the potent proapoptotic Puma, induces
mitophagy and the subsequent release of cytochrome c, leading to apoptosis. The inhibition
of PUMA-induced autophagy diminishes the
apoptotic response, thus highlighting a synergy
between autophagy and apoptosis in this cell
death response.
Although apoptosis and autophagy can occur in a cooperative manner to elicit cell death,
these processes are sometimes mutually antagonistic (Fig. 3) (Boya et al. 2005). For example,
caspases (the effectors of the apoptotic cell
death) have been shown to cleave and inactivate Atg6/Beclin 1, and the suppression of Atg6
function increases apoptotic cell death (Cho
et al. 2009). These lines of evidence imply that
apoptosis is either inhibited or delayed when
autophagy is present, with the probable conclusion that autophagy is activated to protect cells
from dying (Fig. 3).
Other contrasting behaviors between apoptosis and autophagy have been attributed to
the status of the cell, or stage of transformation. Dominant-negative FADD invokes a death

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Autophagy and Cancer

Cellular stress

Mitophagy
Apoptosis

ROS
Autophagy

Necrosis

Cleavage
of beclin 1

ATP

Cell death
with autophagy
Cell death

Inflammation
tumor promotion
Cell survival

Cell death

Figure 3. Autophagy and the control of cell death. There is cross talk between apoptosis and autophagy in the

control 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 inflammation
can positively feed back to enhance the amplitude of these responses. Examples are shown to indicate how apoptosis and autophagy and necrosis and autophagy are connected.

stimulus involving autophagy in healthy cells

but not in cancer cells and induces varying amplitudes of death responses at different stages of
cancer progression (Thorburn et al. 2005). In
addition, oncogenic Ras has also recently been
shown to cause autophagic cell death in the absence of apoptosis (Elgendy et al. 2011), even
though other reports have indicated that autophagy is required for Ras-driven tumor
growth (Guo et al. 2011; Yang et al. 2011).
These lines of evidence suggest that the decision to activate, repress, or simply not to manipulate autophagy, may be governed by the nature of the stimuli or the upstream regulator of
an autophagic and/or apoptotic protein, as well
as the health status of cells, and the net outcome
of these three possibilities is either to promote
or repress tumor survival, or both.
AUTOPHAGY AND NECROSIS

Necrosis is a form of cellular demise characterized by several features such as ATP depletion,
the loss of cellular osmolarity, and release of various factors such as HMGB1 and cell lysis, which
all lead to a strong inflammatory response (Ed-

inger and Thompson 2004). Although necrosis

is often perceived as an unregulated form of cell
death, emerging evidence reveals that it can also
occur as a form of caspase-independent programmed cell death and is specifically termed
necroptosis (Vandenabeele et al. 2010). Programmed necrotic cell death is also known to
be the mediator of cell death in response to certain classes of chemotherapeutic drugs (Zong
et al. 2004).
As if contradicting the role of cell death in
tumor suppression, necrosis is generally considered to be a tumor promoter and is often associated with poor prognosis (Swinson et al.
2002). Necrotic cells in vivo cause a strong inflammatory response, accompanied by the production of cytokines, chemokines, and other
inflammatory enzymes, which can, in turn, positively feed back to cause further damage in surviving cells with enhanced tumorigenic potential (Balkwill et al. 2005).
Necrosis and autophagy, like apoptosis and
autophagy, often occur coincidently (Fig. 3).
Therapeutic treatment of cancer cells triggers
necrosis due to bioenergetic compromise. Tumor cells can evade this ATP-limiting demise

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L.Y. Mah and K.M. Ryan

by activating the energy sensor LKB1/AMPK

complex, which, in turn, inhibits the mammalian target of rapamycin (mTOR), leading
to activation of autophagy (Amaravadi and
Thompson 2007). Although this seems to favor
the viability of cancer cells, the major role for
autophagy activation in promoting tumor development lies in the repression of necrosisassociated inflammatory responses. These responses can promote the release of prometastatic immune-modulatory factors such as
HMBG1, and this may lead to increased metastasis (Thorburn et al. 2009a,b). Additionally,
necrosis has been shown to be activated by
AKT and Ras oncogenic signaling and is upregulated when autophagy is compromised by
monoallelic deletion of BECN1 (Degenhardt
et al. 2006). Thus, autophagy is perceived to prevent necrosis in order to limit further cellular
damage that may promote tumorigenesis and
metastasis. However, the situation is not entirely
straightforward because tumors that survive
necrotic stress via autophagy could obtain an
advantage to thrive under nutrient-limiting
conditions and acquire mutations that cause
resistance to cell death.
AUTOPHAGY AND SENESCENCE: A BARRIER
TO TUMOR PROGRESSION?

Cellular senescence is a process in which cells

enter a state of irreversible cell cycle arrest (Krizhanovsky et al. 2008). The permanent withdrawal from the cell cycle can restrict tumor
cell proliferation and is therefore considered an
important mechanism of tumor suppression.
Senescent cells do, however, secrete a spectrum
of proinflammatory cytokines, termed the senescence-associated secretory phenotype (SASP),
causing inflammation that is, in turn, a vector
for tumor cell growth (Davalos et al. 2010).
Recently, Young et al. (2009) reported that
several Atg genesULK3, Atg7, and LC3
(Atg8)are up-regulated during oncogeneinduced senescence. They also showed that
autophagy is required for the transition of mitotic to senescent phase, and genetic ablation
of autophagy delays the onset of senescence.
Since then, much thought has been put into
8

the hows and whys of the autophagy-regulated senescence program. Some researchers believe that autophagy is evoked to break down
specific cellular components to enable physical
remodelling associated with senescence (White
and Lowe 2009). Additionally, autophagy may
supplement senescent cells with the monomers
that are required for the production and secretion of a plethora of growth factors, as well
as for restructuring the cellular cytoskeleton
(Adams 2009).
AUTOPHAGY AND TUMOR IMMUNITY

Cellular immunity can be generally classified

into two categories; innate and adaptive. Innate
immunity, analogous to the bodys first line of
defense, is almost always engaged in triggering the complement system and inflammation.
Adaptive immunity, on the other hand, results
in a more specific and stronger response. This
involves the surveillance, capture, and presentation of pathogens or pathogenic/non-self peptides by antigen-presenting cells (APCs) such
as macrophages, B-cells, and dendritic cells
(DCs), which then stimulate T-lymphocytes to
invoke cell death, among other responses. Autophagy and immunity have long been considered as two inseparable entities (Schmid et al.
2007; Shoji-Kawata and Levine 2009). The roles
of autophagy in regulating inflammation and
adaptive immunity, ranging from lymphocyte
development (Nedjic et al. 2008), pathogen recognition and destruction, to antigen presentation have been shown (Schmid et al. 2007).
Over the last few decades, neoplastic cells
have been shown to express a panel of unique
antigens that are recognized by T cells (Sensi
and Anichini 2006). Hence, tumor antigen presentation is an important aspect of antitumor
responses, and a defect in this system can result
in tumor escape from immune surveillancea
facet often associated with cancer progression
(Garcia-Lora et al. 2003; Hanahan and Weinberg 2011). DCs are one of the most effective
professional APCs. One of the many contributors that impede DC function in tumor defense
is the buildup of ROS, which are present abundantly in the tumor microenvironment (Fricke

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Autophagy and Cancer

and Gabrilovich 2006). High levels of ROS have

been shown to induce oxidative stress, resulting
in JNK-mediated denditric cell death (Handley
et al. 2005). Because autophagy has a major role
in buffering ROS, a defect in this lysosomal degradation pathway would handicap DCs due to
the accumulation of ROS.
Autophagy is also intrinsically connected to
the process of antigen presentation. Classically,
antigens derived from outside the cell are degraded in lysosomes, and autophagy has important roles in trafficking antigens destined for
degradation, as well as trafficking peptides
from degraded antigen back to the cell surface
for presentation on the class II major histocompatibility complex (MHC). Most tumor antigens are, of course, derived from within the
cell, and degradation in this context is primarily
via proteasomes, resulting in presentation on
class I MHC. Autophagy, however, stills plays a
major role in the presentation of tumor antigens
on APCs directly on class II MHC or via a process termed cross-presentation on class I MHC
(Munz 2010). With respect to this, priming of
CD8 T cells APCs presenting the melanocyte-derived tumor antigen gp100 is greatly enhanced when autophagy is pharmacologically
induced in the melanocytes with rapamycin,
and this is reversed when autophagy is blocked
with 3-methyladenine (3-MA) (Li et al. 2008).
The investigators also found that blocking
autophagy at later stages by inhibiting autophagosome turnover facilitated antigen cross-presentation, subsequently revealing that autophagosomes are efficient transporters of antigen
from antigen-presenting cells to T cells. This
suggests that the stabilization of autophagosomes, rather than the initiation and completion of autophagy itself, is required for effective
priming of cytotoxic T cells. Elegant in vivo
studies by Lee et al. (2010) have confirmed that
autophagy is particularly required to enhance
class I antigen presentation by DCs. They showed
that Atg5 2/2 DCs present antigen on class II
molecules but have a reduced ability to activate
CD4 lymphocytes by promoting antigen degradation in autolysosomes. No differences were
observed in DC migration or DC antigen capture via endocytosis and phagocytosis, as well

as cross-presentation on class I. They also discovered that autophagy induced by starvation

and rapamycin treatment decreases class II presentation.
Albeit varying in the mode of action, autophagy initiation is required for both class I
and II MHC processing. Evidence indicates
that the synthesis, but not degradation, of autophagosomes is the determining factor for class I,
whereas for class II, both synthesis and degradation of autophagosomes are crucial (Dorfel
et al. 2005). Aside from macroautophagy, chaperone-mediated autophagy has also been shown
to play a role in antigen presentation, particularly in the presentation of endogenous antigen
of cytoplasmic origin (Deretic 2005). It is conceivable, therefore, that more than one form
of autophagy operates in antigen processing,
and the dissection of this network, particularly
in the context of tumor antigen presentation,
may represent an encouraging step toward
new, rationally designed tumor therapies.
CONCLUSIONS AND PERSPECTIVES

Autophagy is not only a critical degradation

process for housekeeping purposes in normal
tissues, but it also affects various cellular mechanisms that are critical, or altered in cancer cells
(Fig. 4). There may, however, be additional
mechanisms relevant to tumor development
where a role for autophagy is yet to be defined.
For example, in addition to genetic alterations,
cancer cells usually have tremendous changes
in their epigenetic landscape (Sharma et al.
2010). Given that autophagosomes can sequester chromosomes (Sit et al. 1996) and autophagic breakdown of the nucleus is well documented in yeast (Kvam and Goldfarb 2007), it
might be possible for autophagy to regulate
epigenetic regulatory factors such as histone
methyltransferases and deacetylases in the nucleus of mammalian cells. Could this be an additional role for autophagy in cancer?
It is a defining feature of cancer that tumor
cells show uncontrolled proliferation compared
with normal cells. Because autophagy is often
deregulated in transformed cells, is there a link
between autophagy and cell cycle deregulation?

Cite this article as Cold Spring Harb Perspect Biol 2012;4:a008821

L.Y. Mah and K.M. Ryan

Remove
damaged
mitochondria

Mitigate
ROS

INITIATION

Facilitate
senescence

Suppress
growth

Facilitate
tumor antigen
presentation

Facilitate
apoptosis

TUMOR
DEVELOPMENT

Suppress necrosis/
inflammation?

METASTASIS

RECURRENT
DISEASE

Promote
inflammation

Promote survival
of damaged cells
Adaptation to nutrient
and oxygen depletion

Resistance
to treatment

Figure 4. The contrasting roles of autophagy in cancer. Activating autophagy at different stages of cancer yields

multiple opposing effects. In healthy cells, autophagy prevents cellular transformation by removing ROS and
damaged mitochondria. However, following transformation, activation of autophagy can promote and suppress
cancer 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.

In this regard, autophagy has been reported to

be activated in response to TGF-b, resulting in
enhancement of TGF-b-mediated growth inhibition in human hepatocellular carcinoma
cells (Kiyono et al. 2009). Would this imply
that autophagy could attenuate the cell cycle
and limit cancer cell proliferation?
Because of these extensive links, autophagy
is a very attractive target for cancer therapeutics.
In fact, most existing drugs designed to kill cancer cells also induce autophagy (Kondo et al.
2005). Whether autophagy is activated to enhance cell killing or as a counterstress mechanism is governed by many factors, ranging
from the nature of the stimulus to the health status of the cell. Recently, the role of autophagy in
the interplay of stromal cells within the tumor
niche has also been acknowledged (MartinezOutschoorn et al. 2010, 2011). This adds another level of complexity to the existing theory
whereby the induction of autophagy at different
stages of cancer yields different effects (Fig. 4).
10

With this knowledge, treatments, or at least adjuvants that modulate autophagy, could be incorporated into the cancer treatment regime
(Amaravadi and Thompson 2007). Perhaps the
delivery of autophagic modulators either positive or negative should also be tailored to the
stage and type of cancer. In addition, would
the modulation of autophagy be a strategy for
both initial treatment and for treatment of relapsed disease?
These are all questions that remain to be answered. Nevertheless, the roles of autophagy in
modulating various cellular processes involved
in cancer progression are now without question. As a result, much excitement currently surrounds the possibility of targeting autophagy
for tumor therapy. The issue, however, is not
straightforward. As we have highlighted here,
autophagy can have both positive and negative
effects on tumor development, thus making
it difficult to know whether to positively or negatively modulate autophagy in any given

Cite this article as Cold Spring Harb Perspect Biol 2012;4:a008821

Autophagy and Cancer

scenario. Moreover, it must be remembered that

autophagy is not only serving to protect us
against cancer, but also has major roles in protecting us against many other forms of disease
(Ravikumar et al. 2010). Systemic modulation
of autophagy, although beneficial for tumor
therapy, may therefore have detrimental roles
in normal tissues. Ultimately, however, with
an optimistic view, it may be that transient
modulation of autophagy may be sufficient
for therapy without impact in normal tissues
or that ways to selectively target tumor-associated autophagy may be devised. Numerous laboratories are currently addressing these issues,
and the exciting answers should be revealed in
the not-too-distant future.
ACKNOWLEDGMENTS

We apologize to those researchers whose studies

on autophagy we were unable to cite because of
the length of this article. We thank Simon Milling and members of the Tumour Cell Death
Laboratory for critical reading of the manuscript. Work in the Tumour Cell Death Laboratory is supported by Cancer Research UK and
the Association for International Cancer Research.
CONFLICT OF INTEREST STATEMENT

The authors declare that they have no conflicts

of interest in relation to this article.
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