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Cancer: the Dark Side of Wound Healing

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STATE-OF-THE-ART REVIEW

Cancer: the dark side of wound healing

Gopinath M. Sundaram1, Shan Quah1 and Prabha Sampath1,2,3
1 Institute of Medical Biology, Agency for Science Technology & Research (A*STAR), Singapore City, Singapore
2 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore City, Singapore
3 Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore City, Singapore

Keywords Complex multicellular organisms have evolved sophisticated mechanisms to

angiogenesis; chronic wounds; growth
factors; invasion; metastasis; squamous cell
carcinoma; wound healing
Correspondence
P. Sampath, Institute of Medical Biology,
Agency for Science Technology & Research
(A*STAR), 8A Biomedical Grove, #05-41
Immunos, Singapore City, Singapore
138648
Fax: +65 6464 2049
Tel: +65 6407 0171
E-mail: prabha.sampath@imb.a-star.edu.sg
(Received 27 February 2018, revised 17
May 2018, accepted 13 June 2018)
doi:10.1111/febs.14586
rapidly resolve epithelial injuries. Epithelial integrity is critical to maintain-
ing internal homeostasis. An epithelial breach represents the potential for
pathogen ingress and fluid loss, both of which may have severe conse-
quences if not limited. The mammalian wound healing response involves a
finely tuned, self-limiting series of cellular and molecular events orches-
trated by the transient activation of specific signalling pathways. Accurate
regulation of these events is essential; failure to initiate key steps at the
right time delays healing and leads to chronic wounds, while aberrant initi-
ation of wound healing processes may produce cell behaviours that pro-
mote cancer progression. In this review, we discuss how wound healing
pathways co-opted in cancer lose their stringent regulation and become
compromised in their reversibility. We hypothesize on how the comman-
deering of wound healing ‘master regulators’ is involved in this process,
and also highlight the implications of these findings in the treatment of
both chronic wounds and cancer.

Introduction
Cancer is a leading cause of death worldwide, with 8.8
million attributable fatalities in 2015 alone (Source:
World Health Organization). Over 90% of cancers
originate in epithelial tissues, where the primary
tumour itself is rarely a significant cause of mortality.
Instead, the process of metastasis, whereby cells leave
the primary tumour and colonize distant organs, is
responsible for most cancer-related deaths. Under-
standing tumorigenesis and the metastatic process is
essential to the development of anticancer therapies.
One way in which this might be achieved is through
the study of epithelial wound healing. The physiology
underlying wound healing is highly similar to that
involved in cancer progression, especially in the case
of epithelial cancers. While this idea is not new, the
hypothesis of ‘cancer as an overhealing wound’ was
brought forward almost three decades ago, it has been
gaining traction in recent years [1–3]. Many signalling
pathways and molecular mechanisms which are critical
for wound healing have been implicated either in

Abbreviations
BCC, basal cell carcinoma; BMP, bone morphogenetic protein; CIS, carcinoma in situ; CSC, cancer stem cell; ECM, extracellular matrix;
EGF, epidermal growth factor; EMT, epithelial–mesenchymal transition; FAK, focal adhesion kinase; FGF, fibroblast growth factor; FSTL1,
follistatin like-1; HFSC, hair follicular stem cell; HGF, hepatocyte growth factor; HIF, hypoxia inducible factor; IFESC, interfollicular epidermal
stem cell; IFNc, interferon c; IL, interleukin; lncRNA, long noncoding RNA; miRNA, microRNA; MMP, matrix metalloproteinase; NET,
neutrophil extracellular traps; PDGF, platelet-derived growth factor; RTK, receptor tyrosine kinase; SCC, squamous cell carcinoma; SMAD,
mothers against decapentaplegic homologue; TAM, tumour-associated macrophage; TAN, tumour-associated neutrophil; TERT, telomerase
reverse transcriptase; TGF, transforming growth factor; TIMP, tissue inhibitor of metalloproteinase; TNF, tumour necrosis factor;
VEGF, vascular endothelial growth factor; ZEB, zing finger E-box binding homeobox.

The FEBS Journal (2018) ª 2018 Federation of European Biochemical Societies 1

Parallels between wound healing and cancer
cancer cell proliferation or in metastasis [3,4]. There-
fore, elucidating the link between wound healing and
metastatic cancer progression may aid in the formula-
tion of better strategies to combat cancer.
Wound healing
The epithelium forms a protective barrier around the
organism, guarding it from external insults. The integ-
rity of epithelial tissues, such as skin, is critical to
maintaining a sterile internal environment. Multicellu-
lar organisms have therefore evolved sophisticated
means by which epithelial wounds may be rapidly
repaired, incorporating highly orchestrated pro-
grammes involving multiple cell and tissue types [5].
Wound healing occurs at the cellular, tissue and
organismal levels. As organismal complexity increases,
there is a correlated increase in the number of compo-
nents involved in the wound healing process [6]. This
is generally accompanied by a reduction in the organ-
ism’s regenerative capabilities. Morphologically simple
organisms such as planarians are capable of regenerat-
ing a large proportion of their bodies following ampu-
tation [7]. Vertebrate regeneration potential is
restricted to limbs and specific organs in amphibians,
while mammals have difficulty repairing all but the
smallest epithelial lesions without scarring [8,9].
Phases of wound healing
The cutaneous wound healing response is classically
subdivided into overlapping phases with distinct func-
tional objectives and biochemical events [10,11]. Hae-
mostasis is initiated immediately following injury. A
fibrin clot is formed at the wound site to minimize
blood loss. This fibrin plug serves as a provisional
matrix for the migration of various cell types such as
keratinocytes, macrophages and neutrophils, and a
trap for various growth factors in the wound milieu
[12]. The inflammatory phase is initiated with the infil-
tration of circulating neutrophils at the wound site.
Resident immune cells such as Langerhans, natural
killer (NK) and cd T cells are activated. These release
a plethora of cytokines and chemokines which serve as
alarm signals and actively recruit systemic immune
cells to combat infection at the wound site [13].
Re-epithelialization represents the most critical phase
of wound healing, whereby keratinocytes adjacent to the
wound edge initiate hyperproliferation and migration on
the wound bed to repair the wound. These cell behaviours
necessitate reciprocal interaction between keratinocytes,
dermal cells such as fibroblasts and immune cells. Re-
epithelialization is initiated rapidly; keratinocytes express
2 The FEBS Journal (2018) ª 2018 Federation of European Biochemical Societies
G. M. Sundaram et al.
markers associated with hyperproliferation and migration
as early as 6 h postinjury [14]. The time taken to achieve
wound closure depends on the severity of the injury.
Superficial wounds confined to epidermal tissue heal
within days without significant scarring. Full thickness
wounds involving dermal or subcutaneous tissue take
longer to heal and are often associated with significant
scarring in adult skin [15]. While restoration of barrier
function through the formation of neoepidermis occurs
quickly, reconstitution of dermal tissue may take several
months [16]. In this remodelling phase, dermal fibrob-
lasts/myofibroblasts actively reshape the dermal matrix
by secreting collagen fibres and metalloproteinases to
restore it to pre-injury conditions.
Cell behaviours involved in re-epithelialization are
very similar to those that occur during cancer initia-
tion and metastasis. One critical distinction between
wound repair and cancer progression is that the
promigratory, hyperproliferative behaviour demon-
strated by keratinocytes during wound healing is self-
limiting; keratinocytes return to a quiescent state when
epithelial repair is complete. In contrast, loss of con-
trol over tumour cell proliferation and migration is a
hallmark of malignant cancer.
Molecular similarities between wound
healing and cancer
The seminal link between wound healing and cancer
was first proposed nearly two centuries ago [17]. Over
the years, multiple lines of evidence have emerged in
support of the notion that wound healing and tumori-
genesis are two sides of the same coin. All the major
pathways implicated in wound healing are also active
in cancers [1,3]. Inflammation, an essential event in the
wound healing response, is a key driver for cancer
[18,19]. As mentioned above, enhanced proliferation
and migration of cancer cells is similar to the beha-
vioural profile of wounded epithelial cells [3,20]. Extra-
cellular matrix remodelling during later stages of
wound healing also has its parallels in tumours, where
cancerous tissue is capable of altering the surrounding
matrix to support its own growth and invasion [21].
The wound microenvironment is conducive to cancer
progression, as gleaned from a study performed on mice
by Stuelten et al. [22]. In this report, mice with a local
subcutaneous wound created adjacent to the site where
breast cancer cells were injected had higher incidences of
tumours and developed larger tumours relative to mice
with distally created wounds, implying that local injury
response may play a role in tumorigenesis. In a separate
study, biopsies performed on mouse mammary tumours
induced significant lung metastatic colonization. It was
G. M. Sundaram et al.
proposed that inflammation associated with the local
wound healing response at biopsy sites contributed to
metastasis [23]. This effect was abrogated in mice lack-
ing the proinflammatory cytokine IL-6. Injury-induced
tumour growth also occurs in nonmammalian verte-
brates. In a RasG12V -driven melanoma model of zebra-
fish, repeated wounding led to increased incidence of
melanoma formation compared to unwounded controls.
This process was mediated by inflammatory neutrophils
[24,25].
A relationship between wound healing and cancer
progression may also be inferred from studies on
chronic wounds in diabetics. In 2015, diabetes afflicted
400 million adults worldwide. About 15% of diabetic
patients develop nonhealing foot ulcers [26,27]. Met-
formin, an FDA-approved drug widely used in the
treatment of diabetes mellitus, significantly improves
the outcome of these wounds. Metformin also has a
negative effect on cancer progression [28,29]. However,
the relationship between chronic diabetic ulcers and
cancer is far from straightforward. Platelet derived
growth factor (PDGF-BB), marketed as Becaplermin,
is clinically approved for the treatment of chronic
ulcers. Diabetic patients treated with Becaplermin are
at increased risk of developing cancer, implying that
certain drugs which accelerate wound healing may
inadvertently induce cancer-promoting pathways [30].
Although wound healing and cancer are highly compli-
cated processes, both result from coordinated regulation
over two relatively simple cell behaviours – migration
and proliferation. These behaviours are shaped by inter-
actions between various cell types, including epithelial,
endothelial, mesenchymal and immune cells, through
growth factor/cytokine signalling networks. An example
of such coordination may be seen during re-epithelializa-
tion. Keratinocyte migration over the wound bed is
guided by intracellular mechanisms such as cytoskeletal
rearrangement, as well as extracellular events such as
cell–cell and cell–matrix interactions, basement mem-
brane remodelling and proteinase-mediated matrix alter-
ation. Many of these events also operate during cancer
progression [31–33]. A number of promigratory proteins
required for keratinocyte migration are also abundantly
expressed in epithelial cancers [34]. Here we provide a dis-
course into the commonalities between wound healing
and epithelial cancers, with a focus on invasive and meta-
static squamous cell carcinomas (SCCs).
Growth factor networks in wound
healing and cancer metastasis
A large number of growth factors influence wound
healing and metastasis, including the members of the
The FEBS Journal (2018) ª 2018 Federation of European Biochemical Societies
Parallels between wound healing and cancer
epidermal growth factor (EGF), fibroblast growth fac-
tor (FGF), transforming growth factor-b families
(TGF-b) and hepatocyte growth factor (HGF/c-MET).
Epidermal growth factor family
The epidermal growth factor (EGF) family is one of
the best-characterized growth factor signalling path-
ways involved in keratinocyte proliferation and migra-
tion [35]. This family of growth factors includes EGF,
heparin binding EGF (HB-EGF), transforming growth
factor-a (TGF-a), heregulin and amphiregulin [36] that
work in both autocrine and paracrine manners. EGFR
(otherwise known as ErbB11 or HER1) is a 170 kDa
transmembrane glycoprotein which belongs to the
receptor associated tyrosine kinase (RTK) family [36].
EGF can also induce heterodimerization across the
RTK family and activation of the mitogen-associated
protein kinase (MAPK) pathway, which promotes cell
proliferation and migration. EGFR is predominantly
expressed in the basal layer of the human epidermis.
Its expression is upregulated in wound edge ker-
atinocytes after injury [37].
The EGF pathway in wound healing,
tumour progression and metastasis
Cell proliferation and migration, the two vital processes
required for wound healing and cancer progression, are
activated by the EGFR pathway. This pathway is
essential for wound healing. EGFR!/! mouse skin
grafted onto nude mice displayed wound healing defects
after full thickness injury [38]. EGFR ligands such as
TGF-a, HB-EGF and amphiregulin are upregulated in
keratinocytes upon wounding [39,40]. In chronic ulcers,
EGFR signalling is reduced due to a number of factors
including cytoplasmic EGFR retention, as well as
decreased EGFR levels resulting from the protease-rich
milieu in the wound environment [41] (Fig. 1).
In cancer, one of the initial steps in metastasis is the
dissociation of cells from the primary tumour and
stromal invasion. This process is accompanied by
hemidesmosome disassembly, which results from the
disruption of a6b4 integrins in response to EGFR sig-
nalling [42]. Notably, this EGF-induced disassembly
process, which occurs during invasion and metastasis
of SCC cells in vitro and in vivo [43], also occurs dur-
ing normal epithelial cell migration. Thus, EGF-
mediated hemidesmosome disassembly represents a
function present in healthy epithelia which has been
co-opted by epithelial cancer cells for dissociation from
their site of origin. Nevertheless, cell dissociation from
the primary tumour alone is insufficient for stromal
3
Parallels between wound healing and cancer G. M. Sundaram et al.

Fig. 1. Schematic representing common growth factor signalling pathways that regulate key cellular processes required for wound healing and
cancer. The effect of each growth factor on various physiological processes in a healing wound is listed above. The bottom panel elucidates the
role of growth factors in processes involved in cancer growth and metastasis. Note that TGF-b decreases the proliferation of epithelial cells in
both wound healing and cancer, while promotes keratinocyte migration in wound healing and tumour-promoting processes in cancer.

invasion. In order for metastasis to progress, cancer
cells must degrade the basement membrane delineating
the epithelial compartment from the stroma. Basement
membrane degradation requires dissolution of the
extracellular matrix (ECM), involving a remodelling
process highly similar to that which occurs during
wound healing. During re-epithelialization, wound
edge keratinocytes form an epithelial tongue that
migrates across the wound bed while constantly modi-
fying the wound ECM [33]. In both wound healing
and stromal invasion, ECM remodelling results from
the activities of matrix metalloproteases (MMPs).
MMPs are transcriptional targets of the EGFR path-
way [44] which degrade ECM components. Tissue inhi-
bitors of MMPs (TIMPs) exert spatiotemporal control
over MMP activity, and affect the healing status of an
acute or chronic wound [33]. The MMP2 and MMP9
proteins are present in wound fluids but virtually
absent from normal skin [45]. Increased MMP9
expression is associated with poor healing in chronic
wounds, and correlates with poor overall survival sta-
tus in HNSCC [46,47]. Stromal invasion of cutaneous
SCC is higher in patients with increased MMP2
expression [48]. These studies indicate that while EGF-
induced MMPs are a crucial requirement for wound
healing, uncontrolled expression of these proteases can
have pathological consequences including chronic
wounds and metastasis of SCC.
EGFR amplification, overexpression and gain-of-
function mutations are highly prevalent in cutaneous
and head and neck SCCs (cSCC & HNSCC) [49,50].
In cancer tissues, EGFR expression status is positively
correlated with lymph node involvement, tumour grade
and stage [21,51,52]. Recently, EGF has been shown to
induce EMT and confer stem cell-like properties to
oral cancer cells through the ‘Warburg effect’ [53].
EGFR activation may also activate multiple other
pathways such as PI3-AKT, JAK-STAT and nuclear
factor kappa B (NF-kB) [54]. Moderate success has
been attained using targeted therapies against EGFR
in the treatment of metastatic disease in multiple can-
cer types including HNSCC, oesophageal, gastric, col-
orectal and lung SCC [55–59].
TGF-b signalling pathway
TGF-b possesses three isoforms, all of which stimulate
the same intracellular signalling SMADs (SMAD2/3)
while performing different functions in development
and tissue homeostasis [60]. In the canonical TGF-b
pathway, TGF-b ligands bind to TGF-b receptor I
(TGFBRI, otherwise known as ALK-5) and cause it
to heterodimerize with TGF-b receptor II (TGFBRII).
This stimulates phosphorylation of the receptor regu-
lated SMAD2/3 (R-SMADs) complex. Phosphorylated
SMAD2/3 binds to SMAD4 (co-SMAD) and enters
the nucleus, where it transactivates transcriptional tar-
gets. In cutaneous wound healing, TGF-b is released
initially by platelets trapped in the fibrin clot, and at
later stages by keratinocytes [61–63].

4 The FEBS Journal (2018) ª 2018 Federation of European Biochemical Societies

G. M. Sundaram et al.
TGF-b in wound healing and cancer
The role of TGF-b in wound healing is complex, and
likely to vary temporally as well as by its distinct
effects on different cell types. TGF-b1 is secreted by
macrophages, stromal fibroblasts and keratinocytes
and its expression is stringently regulated during
wound healing [64,65]. Mice with a TGFBRII deletion
in dermal fibroblasts display severe defects in full
thickness wound healing and delayed re-epithelializa-
tion [66]. However, epidermal overexpression of TGF-
b1 also delays full thickness wound healing due to
excessive inflammation [67]. This is likely due to the
differential ability of TGF-b to orchestrate conflicting
pathways in wound healing. It is well known that
TGF-b exerts a negative effect on keratinocyte prolif-
eration, but promotes both in vitro and in vivo ker-
atinocyte migration [68]. Several studies have reported
defective TGF-b signalling in chronic wounds due to
lack of TGFBR1, TGFBR2 or TGF-b ligand expres-
sion [69–71]. In such wounds, TGF-b treatment was
met with limited success, perhaps due to the lack of
TGFBR expression and the protease-rich environment
[72].
TGF-b has gained considerable attention in past
years for its puzzling role in cancer progression and
metastasis. Some authors argue that TGF-b1 and its
receptors are downregulated in SCC [73,74], while
others presenting evidence for aberrant TGF-b1 over-
expression in head and neck tumours [75]. It is possi-
ble that TGF-b initially exerts growth suppression on
epithelial cells, while also promoting EMT at later
stages. In transgenic mice, induction of TGF-b1 over-
expression at papilloma stage induced rapid metastasis,
while induction of TGF-b1 at earlier stages led to
tumour suppression [76]. Similarly, mice expressing
dominant-negative TGFBRII (DbRII) in the epidermis
exhibit faster tumour formation and malignant pro-
gression, but reduced EMT. This suggests that TGF-
b1 has distinct effects on keratinocyte proliferation
and metastasis, and that normal TGFBRII exerts a
tumour-suppressive effect in the epidermis. In support
of these findings, Han et al. showed increasing TGF-
b1 expression in stage wise SCC progression from acti-
nic keratosis (epidermal hyperplasia), carcinoma
in situ (CIS) towards metastatic SCC, while TGFBRII
showed an opposite trend [77]. Thus, TGF-b signalling
is activated in a cancer stage specific manner. This
may explain why TGF-b and TGFBR were not identi-
fied as hot spots for SCC risk, unlike EGF/EGFR
[78].
The dissociation of cell–cell junctions to facilitate
keratinocyte migration is a prerequisite for both
The FEBS Journal (2018) ª 2018 Federation of European Biochemical Societies
Parallels between wound healing and cancer
wound healing and cancer cell invasion [79] (Fig. 1).
Downregulation of E-cadherin in epithelial cells, a
classical marker of EMT, also occurs during ker-
atinocyte migration in wound healing [80]. Transcrip-
tional targets of TGF-b1 are often involved in cell
migration, invasion and EMT. TGF-b1 activates sev-
eral EMT-associated master transcription factors
which are Snail 1, Snail 2 (Slug), and zinc finger E-box
binding homeobox (ZEB) 1, ZEB2 and TWIST [81].
During EMT, TGF-b1-mediated Snail activation leads
to direct suppression E-cadherin gene expression, via
HDAC recruitment to the E-cadherin promoter, or
through activating ZEB-1 [82,83].
Fibroblast growth factor family in
wound healing and cancer
The FGF family includes over 22 structurally related
FGF ligands, most of which interact with four FGF
receptors (FGFR1, FGFR2, FGFR3 and FGFR4).
FGFs function primarily as mitogens controlling pro-
liferation and differentiation of various tissues, and
also regulate wound healing and angiogenesis [84].
Several FGF ligands such as FGF7, FGF10 and
FGF22 are transcriptionally induced upon injury in
mice, although only FGFR1 is upregulated in similar
conditions [85]. FGF2 stimulates keratinocyte migra-
tion in vitro through Rac activation and lamellipodia
formation, and its loss causes delayed wound healing
in mice [86]. FGF7, otherwise known as keratinocyte
growth factor, is critical to keratinocyte proliferation.
Inhibiting FGF7 signalling in mice causes epidermal
atrophy and substantial delays in re-epithelialization
[87]. In addition to its effects on proliferation, FGF7
is a more potent stimulator of keratinocyte migration
than FGF2 [88].
Fibroblast growth factor pathways utilized in wound
healing also feature in cancer progression. FGFR1
expression correlates with the epithelial–mesenchymal
transition (EMT) status of cell lines in vitro. Treatment
of high EMT cell lines with the FGFR inhibitor
PD173074 induces mesenchymal–epithelial transition,
suggesting a potent role of FGF signalling in cancer
metastasis [89] (Fig. 1). FGFR1 was recently shown to
be a part of a molecular signature network with b3-
integrin and focal adhesion kinase (FAK) which drives
EMT and metastasis of breast cancer [90]. Oncogenic
driver mutations and copy number changes in FGFR
and ligands occur in a subset of HNSCC patients [91].
Aberrant FGF signalling may promote both angiogen-
esis and the acquisition of chemoresistance against
tyrosine kinase inhibitors [92].
5
Parallels between wound healing and cancer
Hepatocyte growth factor/c-MET
receptor signalling in wound healing
and cancer
Hepatocyte growth factor (HGF), also known as scat-
ter factor (SF), is another growth factor involved in
wound healing and cancer. It is mostly secreted by
mesenchymal cells, although injury can upregulate
HGF and its receptor in murine epidermal ker-
atinocytes [93]. The HGF receptor c-MET controls
proliferation and also promotes keratinocyte migration
by coordinating the formation and orientation of focal
adhesions [93]. In diabetic rats, exogenous HGF
administration accelerates wound healing by inducing
cell adhesion molecules b1-integrin and integrin-linked
kinase both in vivo and in vitro [94].
An association of c-MET with migration, invasion
and angiogenesis is frequently observed in cancers.
While genetic mutations or amplifications are rare at
the c-MET locus in cancer, an activating point muta-
tion, Y1253D, in the MET gene is tightly linked to
distant metastasis in HNSCC patients [95]. c-MET
overexpression is seen in HNSCC, cSCC and cuta-
neous melanoma patients, with elevated serum HGF
levels also observed in oral SCC [96,97]. In conjunc-
tion with its promigratory role, overexpression of
c-MET in oral SCC disrupts cadherin junctions and
significantly augments invasion [98]. Interestingly,
c-MET is also secreted in exosomes. This increases
metastasis frequency in melanoma, perhaps by precon-
ditioning possible metastasis niches such as bone mar-
row for cancer cells to thrive after colonization [99]. A
role for HGF/c-MET signalling in conveying stem cell
properties and drug resistance has been recently
demonstrated [100,101]. The HGF/c-MET pathway is
currently an attractive therapeutic target in multiple
cancers [102].
Inflammation and the immune system
in tumour metastasis and wound
healing
Inflammation is the body’s natural response to infec-
tion, wounds and foreign body infiltration, and is
mainly mediated by immune cells via cytokines and
chemokines (Fig. 2). Inflammation is prevalent in both
healing wounds and tumours [19]. Several studies have
reported a low but significantly reduced risk of SCC in
people taking nonsteroidal anti-inflammatory drugs
such as aspirin or ibuprofen, suggesting a role for
inflammation in cancer [103,104]. Multiple cell types
contribute to inflammation including platelets, mast
cells, neutrophils, macrophages, dendritic cells and
6 The FEBS Journal (2018) ª 2018 Federation of European Biochemical Societies
G. M. Sundaram et al.
keratinocytes. Both macrophages and neutrophils pre-
dominate the tumour mass and play pivotal roles in
injury and cancer. Metastatic tumours often show infil-
tration of tumour-associated macrophages and neu-
trophils (TAMs and TANs respectively) which provide
an abundant supply of proangiogenic factors in the
tumour microenvironment [105]. Adaptive immune
cells such as T- and B-lymphocytes may also have
tumour-promoting properties [105].
Neutrophils in wound healing and
cancer
Neutrophils contribute to the innate immune response
against infection following a barrier breach (Fig. 2).
Platelet degranulation provides chemo-attractants
which recruit circulating neutrophils to the injury site
[106], where they perform antimicrobial functions.
Neutrophil infiltration is also seen in epithelial
tumours. Although tumour-associated neutrophils
(TANs) are expected to be antitumorigenic, TAN-asso-
ciated tumours show poor clinical outcome and
increased metastasis frequency. This is likely due to
inflammation associated with neutrophil infiltration,
which promotes tumour growth [107]. In addition to
killing foreign pathogens through engulfing and the
use of antimicrobial peptides, neutrophils form web-
like structures known as neutrophil extracellular traps
(NETs). NETs consist of chromatin fibres and antimi-
crobial proteins and form a mesh-like structure used
to trap pathogens. In mouse breast cancer, NET for-
mation occurs in the absence of infection and enhances
lung metastasis. This clearly demonstrates the capacity
for cancers to seize neutrophil-mediated innate immu-
nity to promote cancer progression [108].
Macrophages in wound healing and
cancer
Following neutrophil recruitment, circulating mono-
cytes transmigrate through endothelial cells, enter the
injury site and differentiate into macrophages. Macro-
phages perform several key tasks in regulating inflam-
mation during both wound healing and cancer
metastasis, and are subdivided based on their cytokine
expression profiles [109]. M1 macrophages are proin-
flammatory, activated by IFN-c, and secrete IL-1b,
TNF-a and MMP9. M2 macrophages, activated by
IL-4, are anti-inflammatory and secrete higher levels of
TGF-b and IL-10 [110,111]. The presence of M1
macrophages is associated with a chronic wound phe-
notype in mouse models. Antagonizing IL-1b with a
neutralizing antibody causes proinflammatory, chronic
G. M. Sundaram et al. Parallels between wound healing and cancer

Fig. 2. Illustration showing the three important cell types that play an integral role in both wound healing and cancer. Depending on the
cytokine milieu in the micro environment, macrophages differentiate into either the M1 or M2 subtype with opposing functions in regulating
inflammation in both wound and cancer niches. Macrophages also regulate angiogenesis and extracellular matrix composition in tumour
stroma making the tumour environment conducive for tumour growth. Even though the main function of neutrophils in the wound bed to
promote inflammation and defence, tumour-associated neutrophils (TANs) perform functions akin to macrophages. Both interfollicular
epidermal (IFESC) and hair follicular (HFSC) stem cells contribute to re-epithelialization. Recent evidence indicates their active role in
conferring drug resistance and EMT properties via acting as cancer stem cells.

wounds to adopt a healing phenotype containing M2
macrophages [110]. In cancer, M1 macrophages antag-
onize tumour growth, while the M2 phenotype is con-
ducive to tumour progression. M2 macrophages are
also known as tumour-associated macrophages
(TAMs) [112]. Hypoxia, which is common in tumour
microenvironments, is a major inducer of intratumoral
macrophage recruitment through chemo-attractants
such as EMAPII, endothelin and VEGF-A. Macro-
phages in turn modulate the tumour microenvironment
to favour invasion by secreting proteases and growth
factors [113].
Angiogenesis in wound healing and
cancer
Both wound repair and metastasis involve the coordi-
nation of cell movement and proliferation. These pro-
cesses require an energy supply, which is obtained
from the vasculature. Angiogenesis, referring to the
growth of new blood vessels, is essential to the pro-
gression of cancer and wound healing. Wound angio-
genesis involves multiple steps with striking parallels
to metastasis, including endothelial cell activation, pro-
liferation, invasion through the basement membrane,
and migration into the surrounding ECM (reviewed in
[114]).
Hypoxia is a key trigger for angiogenesis in the
wound environment and in tumours [115]. Reduced
oxygen tension is detected by hypoxia inducible factor,
HIF1a, which stimulates production of the proangio-
genetic factor VEGF [116,117]. VEGF and HIF1a
mRNAs are absent in unwounded skin, upregulated
upon wounding and restored to basal levels after re-
epithelialization [117]. Neovascularization of the
wound bed permits adequate supply of nutrients, oxy-
gen and immune cells for proper wound healing [118];
vascular insufficiency is a common causative factor in
chronic wounds, which also exhibit reduced levels of
VEGF secretion [116,119]. Angiogenesis in the wound
environment, like keratinocyte migration during re-
epithelialization, is self-limiting and terminates upon
healing. Stringent regulation of angiogenesis during
pre- and post-wound healing is orchestrated through
controlled expression of negative (CXCL4 and Throm-
bospondin-1) and positive (FGF-2, VEGF and PDGF-
BB) regulators of angiogenesis [120]. During solid
tumour progression, hypoxia develops at the centre of
the tumour mass. Both HIF1a and VEGF mRNAs
increase in abundance from simple hyperplasia to

The FEBS Journal (2018) ª 2018 Federation of European Biochemical Societies 7

Parallels between wound healing and cancer
invasive SCC in multistage carcinogenesis mouse mod-
els [117]. Notably, the first report showing the ability
of endothelial cells to form capillary tubes in vitro
demonstrated the dependency of this process on
tumour conditioned media, suggesting that cancer cells
can induce angiogenesis [121]. Tumour cells secreted
FGFs stimulate migration of vascular endothelial cells
towards the tumour mass and work in synergy with
VEGF [122]. VEGF directly stimulates the secretion of
matrix metalloproteinases (MMP-1 and MMP-2) by
endothelial cells [123]. MMPs degrade the basement
membrane and allow for endothelial cell invasion.
Basement membrane degradation also allows tumour
cells to escape the epithelial compartment boundary,
thereby facilitating metastasis.
Angiogenesis in epithelial wounds and carcinoma is
also stimulated by inflammation. Epidermal injury trig-
gers rapid recruitment of leucocytes and initiates the
inflammatory response. Neutrophils, macrophages,
endothelial cells and keratinocytes in acute wounds
secrete VEGF-A and promote angiogenesis [124–126].
Although tumour angiogenesis does not guarantee
metastasis, it is permissive for malignancy. The initia-
tion of angiogenesis is cited as a pivotal point in tumour
progression (the ‘angiogenic switch’), following which
tumours can more readily expand in size as well as allow
for intravasation of cancer cells into the bloodstream.
Angiogenesis at secondary sites also facilitates the
growth of metastases. The importance of angiogenesis
to cancer progression has made it the subject of much
research into anticancer drugs. Insights into candidate
antiangiogenics have been gleaned from the understand-
ing of angiogenesis in wound healing, and strategies are
being developed to either target endothelial cells
directly, or to block key growth factors and proangio-
genic pathways involved in cancer progression [127].
Role of stem cells in wound healing
and cancer metastasis
Stemness, the ability of a cell to perform self-renewal, is
important for the provision of material for wound clo-
sure, and is also essential to tumour formation and the
repopulation of tumours following treatment. Stem cells
are present in several reservoirs within the skin, includ-
ing the interfollicular epidermis (IFESC) and hair folli-
cles (HFSC) [128]. Stem cells in both niches participate
in wound healing and in skin homeostasis, though their
relative contributions may differ based on the wound
niche [129–131]. In mice, the absence of hair follicles
results in delayed re-epithelialization, followed by com-
plete wound closure [132]. The addition of purified
CD34+ HFSCs to full thickness wounds accelerates
8 The FEBS Journal (2018) ª 2018 Federation of European Biochemical Societies
G. M. Sundaram et al.
healing time in rats [133]. Composite skin grafts con-
taining stem cells derived from IFE or HF has been suc-
cessfully used to treat chronic wounds [134].
Both IFESCs and HFSCs contribute to skin cancers
[135]. LGR6 is a marker associated with stem/progeni-
tor cells within the IFE or HF niche [136]. Unsurpris-
ingly, LGR6 was also found to be a specific CSC
marker in mouse SCC models [137]. The contribution
of injury-induced HFSC migration to cancer is demon-
strated in two contiguous articles published in 2011 on
transgenic BCC mouse models. In these models, injury
increased the frequency of BCC lesions by recruiting
HFSCs to tumours, implicating a link between wound-
ing, stem cells and cancer [138,139]. Cancer stem cells
(CSCs) may be derived from tissue-resident stem cells,
or from cells which acquire the capability to self-
renew. They contribute to drug resistance and closely
associate with tumour recurrence [140].
The contribution of epithelial stem cells to cancer
metastasis is currently an active area of investigation. Sev-
eral studies have highlighted that the EMT and stemness
properties are probably linked. For example, TWIST is a
classical EMT marker in epithelial cancers. Conditional
ablation of TWIST at different stages of carcinogenesis
revealed its role in CSC maintenance independent of its
EMT related functions. [141]. Forced expression of other
EMT drivers such as Snail led to the development of stem
cell-like traits in mammary epithelium. Further suggest-
ing EMT transition and CSC emergence may be coupled
in cancers [142]. Counterintuitively, EMT transition is a
reversible process in both wound healing and cancers.
EMT is only transiently activated during the re-epithelia-
lization phase of wound healing. [143]. In cancers, EMT
is an early event and once cells reach the metastatic
organs, a mesenchymal–epithelial transition (MET)
appears to be imperative for successful colonization [144].
Indeed, in mouse tumours derived from bladder and
prostate cancer cell lines, the tumour initiating cells
(TICs) isolated from metastatic sites had highly enriched
epithelial gene programme, while overexpression of Snail
in these cells led to reduced TIC attributes and less meta-
static potential [145]. Taken together, the link between
cancer stem cells and metastasis is highly plastic. Multiple
factors such as tumour microenvironment and contextual
dependences decide its nature [146].
Noncoding RNAs in wound healing
and cancer
Noncoding RNAs (ncRNA) have received remarkable
attention in recent years due to their pivotal and pleo-
tropic role in the regulation of proteome output of the
cell. They can be broadly classified based on their size,
G. M. Sundaram et al.
namely, small; microRNAs (miRNAs), piRNAs and
endosiRNAs, medium sized; snRNA, snoRNA, tRNA
and large ncRNAs; intergenic/intragenic long noncod-
ing RNA (lncRNAs) and circular RNAs (cRNAs) [147].
A number of microRNAs help to regulate the intri-
cate wound healing cascade in mammals, some of
which also have well-defined roles in cancer progres-
sion [148]. During cutaneous injury, miR-21 is upregu-
lated in both the epithelial and mesenchymal
compartments of skin, where it actively promotes
wound healing. AntagomiR inhibition of miR-21 in
wounds reduces wound contraction and re-epitheliali-
zation [149,150]. miR-21 is a direct target of the
TGF-b signalling pathway, and is essential for TGF-
b-driven keratinocyte migration [150]. miR-21 is also
considered to be an oncomiR in multiple cancers and
a prognostic biomarker in HNSCC, where its expression
correlates negatively with patient survival [151,152].
Specific upregulation of miR-21 occurs during the pro-
gression from carcinoma in situ to invasive SCC,
implying that its promigratory role in wound healing
also occurs in cancer [153]. miR-31 is upregulated in
wound edge keratinocytes, where it stimulates migra-
tion and proliferation in wound healing [154]. It is also
upregulated in oral SCC and has oncogenic roles in
oral epithelial carcinogenesis [155,156]. miR-424 is
induced in response to hypoxia in wounds, where it
stimulates angiogenesis [157]. Hypoxia-driven induc-
tion of miR-424 also promotes chemoresistance in can-
cer by inhibiting apoptosis [158]. In pancreatic cancer,
miR-424-5p enhances proliferation and invasion in
addition to its antiapoptotic effects [159]. MicroRNAs
which delay wound healing also inhibit cancer progres-
sion. miR-203 is an antiproliferative miRNA with piv-
otal roles in epidermal homeostasis. It is specifically
downregulated in the hyperproliferative compartment
of the migrating tongue in healing wounds [160]. In
the context of cancer, miR-203 exerts tumour-suppres-
sive characteristics at multiple stages of epithelial
tumour progression; by targeting c-Myc leading to dif-
ferentiation, suppressing tumour initiating cells and by
promoting mesenchymal–epithelial transition (MET) in
SCC. miR-200c suppresses keratinocyte migration and
delays re-epithelialization in human ex vivo wound
models [161]. In epithelial cancers, miR-200c exerts
tumour-suppressive effects by targeting key mediators
of EMT and angiogenesis such as ZEB1, ZEB2,
MMP2 and VEGF [162,163]. The restoration of epi-
dermal homeostasis after wound closure, involving
reversion of cells to a nonmigratory state, is also under
miRNA regulation. miR-483-3p restricts keratinocyte
proliferation by inducing cell cycle arrest, and is specif-
ically upregulated during later stages of wound
The FEBS Journal (2018) ª 2018 Federation of European Biochemical Societies
Parallels between wound healing and cancer
healing. Ectopic miR-483-3p expression suppresses the
in vitro and in vivo growth of HNSCC cells [164].
miR-132, cited as a potential therapeutic for chronic
wounds, is expressed at significantly lower levels in
diabetic ulcers relative to normal wounds. Diabetic
mice also have reduced wound expression of miR-132
relative to wild-type mice; topical replenishment of
miR-132 in these mice stimulates keratinocyte prolifer-
ation and accelerates wound closure [165]. However,
the clinical use of miR-132 in chronic wound manage-
ment should be approached with caution as it has
known oncogenic functions in laryngeal SCC [166].
Unlike miRNAs, lncRNAs and the roles they play
in wound healing and epithelial cancers (excluding
melanoma) are less well understood [167]. Both wound
healing and cancer progression are associated with
dedifferentiation of epidermal cells and their concomi-
tant re-entry into cell cycle [94]. Differentiation antag-
onizing noncoding RNA (DANCR) and terminal
differentiation induced noncoding RNA (TINCR)
have opposing effects on epidermal differentiation
[168,169]. TINCR has prodifferentiation functions and
may act as a tumour suppressor in cSCC, where it is
suppressed [168]. Lee et al. identified eight novel
lncRNAs dysregulated in SCC – SCC misregulated
transcripts (SMRT). The reciprocal link between neo-
plasia and differentiation status is apparent in the case
of SMRT-2, which is significantly downregulated in
SCC tissues. SMRT-2 is also essential for terminal ker-
atinocyte differentiation in healthy skin. [170]. H19, a
maternally imprinted lncRNA, has dual functions. It
acts either as a reservoir for the controlled release of
miR-675, or as a sponge for let-7 family microRNAs
[171,172]. H19 is implicated in several aspects of can-
cer progression such as genome instability, cell sur-
vival, hypoxia response, proliferation and EMT [173].
H19 also promotes angiogenesis during wound healing;
its downregulation in diabetic patients is correlated
with impaired angiogenesis. Targeted delivery of H19
lncRNA accelerates wound healing in diabetic rat
models [174].
Cancer cells adopt multiple signalling pathways,
growth factors and molecular processes, ordinarily
used in wound healing, for their own benefit. We spec-
ulate that this is more likely to be achieved through
the hijacking of specific ‘master switches’ at the top of
each pathway, rather than co-option of individual
pathway components. One clear example by which a
wound healing master regulator has been comman-
deered can be seen in miR-198, a microRNA derived
from the 30 UTR of the follistatin-like-1 (FSTL1) tran-
script (Fig. 3). FSTL1 is capable of switching func-
tions under different physiological contexts, acting
9
Parallels between wound healing and cancer
either as a noncoding RNA (pri-miR-198), or a mes-
senger RNA encoding the FSTL1 protein [63]. This
change in function is reversible and forms the basis of
a bistable molecular switch controlling production of
either miR-198 or FSTL1. Crucially, the state of the
switch governs the migratory status of epidermal ker-
atinocytes. In healthy epidermis, exclusive expression
of miR-198 suppresses promigratory targets, blocking
keratinocyte migration. Upon injury, TGF-b signalling
flips the switch, causing wound edge keratinocytes shut
down miR-198 synthesis in favour of FSTL1 produc-
tion. In addition to the derepression of promigratory
targets caused by the absence of miR-198, FSTL1 also
stimulates keratinocyte migration. Thus, a single
molecular switch regulates the expression of whole
suite of migration associated genes. In epithelial can-
cers, EGF signalling hijacks the switch to promote
oncogenesis. Processing of the tumour-suppressive
miR-198 is abnormally suppressed, leading to sus-
tained FSTL1 expression. The loss of miR-198 allows
for expression of its downstream promigratory targets,
while FSTL1 is a promigratory, proinflammatory
secreted protein which also stimulates EGF signalling.
This creates a feed-forward loop which locks the
switch in its defective position [175], creating a cellular
state resembling a prolonged wound healing phase. In
this state, uncontrolled cell migration is highly con-
ducive to metastasis [34]. The effects of this faulty
switch may not be limited to epithelial cancers. The
tumour-suppressive role of miR-198 has been
10
G. M. Sundaram et al.
Fig. 3. A wound healing process hijacked in
cancer. Graphical representation of a dual
state molecular switch in wound healing
and cancer. MicroRNA-198 and FSTL1
protein are derived from the same primary
transcript. In physiological wound healing,
TGF-b triggers the switch from expression
of antimigratory miR-198 to FSTL1 to
initiate keratinocyte migration. In chronic
wounds, due to lack of TGF-b signalling, a
defective switch leads to persistent
expression miR-198 coupled with lack of
FSTL1 suppresses migration. On the other
hand, SCCs hijack this molecular switch
using EGF signalling as a surrogate for TGF-
b to turn off tumour-suppressive miR-198
and gain FSTL1 to promote cancer invasion
and metastasis.
demonstrated in several other cancers such as pancre-
atic, colorectal, liver and lung cancer [144,176–178].
FSTL1 promotes cell survival, invasion and metastasis
in glioma, liver, oesophageal SCC and lung cancer
[179–183]. Given the wide range of miR-198 targets
being distinct in different tissues and the modulation
of various signalling pathways by FSTL1 in different
cancers, miR-198/FSTL1 molecular switch may be a
master controller in physiological wound healing and
cancer. It is also likely that other master switches exist
and sit atop the various wound healing pathways and
processes which are seized for the progression of can-
cer.
Conclusion and future perspectives
The need to demarcate the self from the surroundings
through maintenance of an intact barrier between the
internal and external environments is universal to all
cellular life. It is therefore unsurprising that wound
healing exists in one form or another, even in the sim-
plest animals. These basally branching metazoans
often possess immense regenerative potential such that
much of the body can be regrown after injury. In ver-
tebrates, retention of a limited capacity for limb regen-
eration is observed in some amphibian species.
Mammals have very restricted capabilities for tissue
replacement; most limbs and organs do not regenerate,
and even epithelial wound repair is accompanied by
some degree of scarring [9]. The evolutionary origin of
The FEBS Journal (2018) ª 2018 Federation of European Biochemical Societies
G. M. Sundaram et al.
tumours is likely to be linked to that of wound heal-
ing; spontaneous tumour formation is known to occur
in Hydra (Cnidaria), at the base of the animal evolu-
tionary tree. It is therefore possible that co-option of
wound repair pathways in tumourigenesis was present
at the dawn of animal life, and that the two processes
remained linked till the present day [184].
In mammals, the literature is replete with studies on
the occurrence of common molecular ground between
wound healing and tumour progression. Mice with
basal keratinocyte-specific telomerase (TERT) overex-
pression show increased tumour incidence as well as
accelerated wound healing [185]. Growth-promoting
molecular pathways, such as mTOR activation, are
associated with both improved wound healing and
increased cancer incidence [186,187]. The use of BRAF
inhibitors in melanoma represents an interesting
demonstration of the integral link between cancer and
wound healing. BRAF inhibitors enhance patient sur-
vival, but also stimulate metastasis through ERK/
MAPK activation in RAS mutant melanoma cells
[188]. This same drug-induced MAPK activation
improves wound healing in mouse models by stimulat-
ing keratinocyte hyperproliferation [189].
Given this degree of overlap between cellular pro-
cesses and signalling pathways used in wound healing
and cancer, and the effects of chronic wound therapy
on cancer risk noted at the start of this review, the
possibility that anticancer treatment could interfere
with wound healing should not be discounted. This is
particularly relevant in the management of surgical
wounds incurred during tumour removal or resection
procedures. Therapeutic strategies targeted at rapidly
proliferating tumour cells tend to have side effects on
wound healing. Radiotherapy, for example, delays
wound healing due to cytotoxic effects on skin, con-
nective tissue and surrounding vasculature [190]. The
effects of chemotherapy have mainly been studied in
animal models; in humans, cutaneous side effects
including alopecia and pigment changes are well
known but wound healing studies tend to yield con-
flicting results. Alkylating agents such as cisplatin sig-
nificantly affect rat wound healing, but human studies
using therapeutic doses of cisplatin have not produced
conclusive findings [191]. Gefitinib and cetuximab,
both EGFR inhibitors, do not compromise surgical
wound healing in HNSCC patients [192,193]. Antian-
giogenics such as the systemic VEGF inhibitor Beva-
cizumab, on the other hand, may have adverse effects
including wound dehiscence, subcutaneous bleeding
and infection [194,195]. Again, data on this are incon-
clusive; other studies report negligible effects of Beva-
cizumab on surgical wound healing in patients
The FEBS Journal (2018) ª 2018 Federation of European Biochemical Societies
Parallels between wound healing and cancer
undergoing colorectal and pancreatic cancer resection
[196]. It is likely that multiple factors affect the rela-
tionship between anticancer treatment and wound
healing. Thus, careful consideration of conditions such
as wound aetiology, drug dosage and timing of treat-
ment relative to surgery may help to minimize wound
healing complications [190].
Humanity’s understanding of the interrelationship
between epithelial wound healing and cancer has a
long and extensive history, just as the two processes
themselves have evolved and intertwined over phyloge-
netic time. While we are clear on the broad parallels
between both events, the literature is far less certain
on their distinctions. What makes cancer different
from wound healing? What molecular processes govern
self-limitation at each step in the intricate series of
events in the mammalian wound healing cascade?
How, over the course of cancer progression, do
tumour cells gradually erode away these molecular
controls and commandeer the relevant pathways for
their own benefit? To understand how cancer differs
from wound healing in healthy epithelia is to gain a
glimpse into the restorative processes required to limit
the progression of cancer.
Acknowledgements
This work was supported by National Medical
Research Council (NMRC) Individual Research Grant
(IRG) to PS and Biomedical Research Council of Sin-
gapore, A*STAR.
Conflict of interest
The authors declare no competing financial interests.
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