Physiol Genomics 46: 223–244, 2014.

First published February 11, 2014; doi:10.1152/physiolgenomics.00158.2013. Review

The wound healing, chronic fibrosis, and cancer progression triad

Brad Rybinski,* Janusz Franco-Barraza,* and Edna Cukierman
Cancer Biology Program, Fox Chase Cancer Center/Temple Health, Philadelphia, Pennsylvania
Submitted 8 October 2013; accepted in final form 4 February 2014

Rybinski B, Franco-Barraza J, Cukierman E. The wound healing, chronic

fibrosis, and cancer progression triad. Physiol Genomics 46: 223–244, 2014. First
published February 11, 2014; doi:10.1152/physiolgenomics.00158.2013.—For de-
cades tumors have been recognized as “wounds that do not heal.” Besides the
commonalities that tumors and wounded tissues share, the process of wound
healing also portrays similar characteristics with chronic fibrosis. In this review, we
suggest a tight interrelationship, which is governed as a concurrence of cellular and
microenvironmental reactivity among wound healing, chronic fibrosis, and cancer
development/progression (i.e., the WHFC triad). It is clear that the same cell types,
as well as soluble and matrix elements that drive wound healing (including
regeneration) via distinct signaling pathways, also fuel chronic fibrosis and tumor
progression. Hence, here we review the relationship between fibrosis and cancer
through the lens of wound healing.
wound healing; regeneration; fibrosis; cancer; tumor stroma; myofibroblasts; tu-
mor- or cancer-associated fibroblasts; desmoplasia; epithelial-to-mesenchymal
transition

THE SHEER COMPLEXITY OF THE tumor stroma constitutes a re-
markable discerning challenge for investigators. However, the
tumor niche resembles a site of chronic wound healing (16, 84,
317). Out of the many similarities between wound healing and
tumor progression, the mutual presence of myofibroblastic
cells has emerged as a particularly common hallmark (56).
Myofibroblasts are contractile spindle-shaped and stress fiber-
forming mesenchymal cells that are known to express alpha
smooth muscle actin (␣-SMA), contain excessive structural
rough endoplasmic reticulum, and produce copious amounts of
extracellular matrix (ECM) (56, 90, 183). Myofibroblasts are
also seen during fetal development (183) and are transiently
present at sites of acute wound healing to repair injured ECM
(i.e., to renew and/or to crosslink ECM fibers) and facilitate
wound closure. Nonetheless, their constant presence in tumoral-
activated stroma (i.e., desmoplasia) is known to encourage
neoplastic progression (16, 56). Interestingly, similar persistent
myofibroblastic populations are also common occurrences dur-
ing chronic tissue fibrosis (56, 317, 390). Hence, we propose to
review the triad “wound healing/chronic fibrosis/cancer”
(WHFC) through the lens of wound healing while highlighting
their numerous common and few dissimilar traits.
The wound healing response to injury is known to trigger
functional (i.e., proliferative) and phenotypic changes in fibro-
blasts, lymphocytes, and epithelial and endothelial cells (212).
For example, the changes in epithelial and stromal cells re-
spectively correspond to the epithelial-mesenchymal transition
(EMT) and myofibroblastic differentiation processes (212).
Both EMT and myofibroblastic differentiation are common
occurrences during wound healing (or tissue regeneration) but
* B. Rybinski and J. Franco-Barraza contributed equally to this work.
Address for reprint requests and other correspondence: E. Cukierman,
Cancer Biology, Fox Chase cancer Center, 333 Cottman Ave. (W428), Phil-
adelphia, PA 19111 (e-mail: Edna.Cukierman@FCCC.edu).
also throughout development, inflammation, and fibrosis, as
well as during tumor progression. In EMT, epithelial cells
acquire a mesenchymal migratory phenotype, switching the
expression of known cell-cell adhesion molecules like E-
cadherin in favor of mesenchymal proteins such as N-cadherin
and vimentin (362). In cancer, EMT facilitates metastasis by
promoting ECM proteolysis and enhancing malignant cell
motility, thus conferring an ability to invade (362). EMT also
renders cancer cells a stem-like character, which is believed to
be responsible for therapeutic evasion, as well as a distinctive
prolonged latency/survival mechanism known as dormancy
(38). Myofibroblastic differentiation, also known as fibroblas-
tic activation, describes the process by which the mesenchy-
mal/fibroblastic components of the stroma (i.e., resident fibro-
blasts, recruited bone marrow-derived mesenchymal cells,
pericytes, endothelial cells, and others) acquire a myofibroblas-
tic phenotype (90). EMT and myofibroblast differentiation are
regulated by similar factors and signaling pathways (Supple-
mental Table S1).1 Moreover, some investigators believe that
stromal myofibroblasts arise also from epithelial cells via
EMT-like processes (56, 123). Importantly, the healing process
during acute injury involves four components: coagulation,
inflammation, cellular proliferation, and ECM repair (212).
Hence, wound healing (or regeneration) could be regarded as a
four-component process that constitutes the foundation for cell
proliferation, EMT, and myofibroblast differentiation in the
WHFC triad. Similarly to how Champollion deciphered hiero-
glyphs by understanding Greek and Coptic, wound healing
constitutes “the Rosetta Stone” needed for a better understand-
ing of the WHFC triad (Fig. 1).
Chronic fibrosis and tumorigenesis can both result from a
prolonged and exacerbated healing response that could stem
1
The online version of this article contains supplemental material.

1094-8341/14 Copyright © 2014 the American Physiological Society 223

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224 THE WHFC TRIAD

Fig. 1. The wound healing, chronic fibrosis, and cancer (WHFC) triad. Model depicting the WHFC triad commonalities based on wound healing. The cartoon
highlights the fact that if wound resolution (as in acute wound healing) is not attained then chronic wound healing facilitates a vicious cycle between fibrosis
and cancer. EMT, epithelial-mesenchymal transition.

from chronic injury (195, 317, 390), and as such the similari-
ties that tumors and their stroma have in common with chronic
fibrosis are intriguing. In fact, it is well known that chronic
fibrosis, such as in liver cirrhosis induced by persistent viral
infection (i.e., hepatitis), sustained alcohol consumption or
toxin-containing food, constitutes a direct cancer predisposi-
tion (86, 91, 117). The epithelia from both fibrotic and tumor
tissues are characterized by the presence of hyperproliferating
cells (219, 269, 288); however, carcinoma cells carry transfor-
mative mutations (as well as epigenetic changes) presumed to
be absent in the fibrotic tissue. Also intriguing is the stromal
element of both conditions, a dense myofibroblastic component
with an excessive deposition of ECM (56). The large popula-
tion of myofibroblasts at the tumor stroma is referred to as
cancer- or carcinoma-associated fibroblasts (i.e., known as
CAFs) and also, in this review, as tumor-associated fibroblasts
(TAFs). TAFs and fibrotic myofibroblasts drive tumor progres-
sion and chronic fibrosis, respectively, through both paracrine
effects on surrounding cells and exacerbated synthesis of ECM
(16, 56, 286, 389). TAFs express a plethora of protumorigenic
growth factors, inflammatory cytokines, proteolytic enzymes,
and ECM proteins such as collagen (Col)-I and -III as well as
a fibronectin spliced variant known as ED-A and more (56).
TAFs are also known to contribute to the degradation of
Col-IV, a protein associated with the epithelial ECM known as
basement membrane (158, 235). Alterations to mesenchymal
ECM deposition, together with the hyperproliferation of the
stromal compartment in the vicinity of neoplastic lesions, are
known as “desmoplasia” or “desmoplastic reaction.” As such,
the desmoplastic reaction bears a striking resemblance to the
modified ECM typical of chronic fibrosis, which is also char-
acterized by increased Col-I and -III deposition (390). Finally,
fibrotic myofibroblasts and TAFs both remodel the ECM fiber
distribution by physically contracting and pulling on ECM
proteins after engaging particular sets of integrins (140). Even
though it remains unclear whether TAFs and fibrotic myofi-
broblasts possess unique traits that differentiate them, similar-
ities, such as their contractile activity and the common expres-
sion of ␣-SMA and others, suggest numerous phenotypic
commonalities (56). Hence, it is only logical to assume that
effective targeting drugs that interfere with one (i.e., chronic
fibrosis) will also stall the other (i.e., desmoplasia). Supple-
mental Table S2 includes a list of drugs targeting both diseases.
While chronic fibrosis predisposes the affected tissues to
develop cancer (9, 30, 81, 91, 117, 232), a desmoplastic
reaction that correlates with poor prognosis (56, 125, 317) is
also believed to enhance tumor progression. In turn, trans-
formed tumor cells also promote TAF activation, thus support-
ing the desmoplastic reaction (16, 20, 56). Describing the
relationship between cancer and fibrosis in these terms implies
that fibrosis could be sparking tumorigenesis and tumor pro-
gression might be instigating chronic fibrosis. We suggest that
the relationship between cancer and fibrosis (i.e., the WHFC
triad) constitutes both correlation and causation (Fig. 1). There-
fore, here we review the mechanisms by which the prolonged
four component process of wound healing facilitates chronic
fibrosis and tumorigenesis through a common mechanistic link:
the WHFC triad.
THE COAGULATION CASCADE FUELS THE WHFC TRIAD
Wound healing begins with the process of coagulation where
platelets from circulating blood accumulate at the damaged site
and, together with increased levels of coagulation factors as

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THE WHFC TRIAD
well as with fibrinogen deposition and cleavage, result in the
formation of insoluble fibrin strands building up a clot (212).
The clot prevents blood loss and constitutes a short lived
scaffold or provisional ECM that serves both for cell migra-
tion/invasion and as a growth factor reservoir (212).
In chronic fibrosis as in cancer, a process resembling clotting
fuels disease progression. For example, fibrin bundles can
accumulate at the tumor stroma as a result of a leaky tumor
vasculature (260), and similar fibrin deposition has also been
reported in a variety of fibrotic tissues (151, 308). Although the
role of fibrin in chronic fibrosis remains rather unclear, it is known
that fibrinogen exerts a mitogenic effect on fibroblasts (337).
During tumor progression, fibrin facilitates angiogenesis (93);
meanwhile, fibrinogen also promotes angiogenesis as well as
oncogenic proliferation and antitumorigenic immune suppres-
sion (135). Moreover, elevated plasma fibrinogen correlates
with a poor cancer prognosis (110, 203, 225, 290, 296, 321,
356). Intriguingly, fibrinogen may induce a prolonged inflam-
matory state in several types of cancer and fibrosis (68),
suggesting a possible link between chronic inflammation and
persistent activity of the coagulation cascade.
The cleavage of fibrinogen is considered the end result of the
coagulation cascade signaling pathway (160). Thrombin di-
rectly cleaves fibrinogen into fibrin (95). Besides its role in the
coagulation cascade, thrombin promotes cancer progression
and fibrosis (47, 95). In cancer, thrombin induces cell prolif-
eration, tumor growth, angiogenesis, and metastasis (95). The
ability of thrombin to act as a mitogen is not limited to an
epithelial context. It also has been reported to enhance fibro-
blast proliferation in a model of bleomycin-induced pulmonary
fibrosis (358). Furthermore, thrombin inhibition reduces the
severity of both pulmonary (358) and liver fibrosis (83).
The ability of thrombin to promote cancer and fibrosis is
believed to be mediated in part through its ability to activate
the protease-activated receptor (PAR)-1 (47, 95). PAR-1 is
present in a variety of tumor types (89), and its activation
promotes cancer cell proliferation and angiogenesis (95). In the
clinic, PAR-1 signaling is suspected to facilitate melanoma
metastasis (416), and it correlates with poor prognosis of
gastric, prostate, and breast cancers (28, 100, 313). PAR-1 also
facilitates pulmonary fibrosis (143), while PAR-1-deficient
mice seem to resist bleomycin-induced pulmonary fibrosis
(142). PAR-1 is one of four PAR isoforms (PAR-1 to -4), and,
while thrombin induces many of its effects via PAR-1, PAR-3
and -4 are also suitable to be activated by thrombin (47).
However, PAR-2 can be activated by other molecules from the
coagulation cascade such as the tissue factor (TF) and activated
factor X (FXA) (47). TF is expressed by many types of cancer
cells (169), and TF or FXA-induced PAR-2 signaling has been
implicated in both chronic fibrosis and tumor progression (33,
34, 151, 169, 318, 347). Interestingly, TF, FXA, thrombin, and
activation of PAR-1 or PAR-2 may possibly promote myofi-
broblastic differentiation (Supplemental Table S1). This type
of common occurrence opens up the possibility that other
enzymes from the coagulation cascade could also induce/
sustain myofibroblastic populations during chronic fibrosis and
tumor desmoplasia.
To this end, the excess of fibrin deposition observed in
chronic fibrosis and desmoplastic stroma indicates a possible
enhancement in fibrin synthesis but also a likely decreased rate
of its degradation. The fibrin/platelet clot formed during wound
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225
healing is eventually broken down by plasmin, a cleaved
subproduct of plasminogen (111). Plasmin also plays a role in
the ECM context due to its proteolytic activity in Col degra-
dation, transforming growth factor beta (TGF-␤) activation
(see below) and release of other ECM-bound growth factors
(111). Urokinase-type plasminogen activator (uPA) and tissue-
type plasminogen activator (tPA) can each cleave plasminogen
to obtain plasmin, and both enzymes are inactivated by plas-
minogen activator inhibitor-1 (PAI-1)(111). Interestingly, uPA
has been reported to inhibit fibrosis (216, 334, 335) but also to
promote tumor progression(335). Similarly, the role of tPA is
also unclear as it has been reported both as promoter as well as
inhibitor of chronic fibrosis and cancer (62, 144, 196, 303,
405). Finally, PAI-1 has also been shown to either promote or
inhibit these two diseases (111, 155). The above-mentioned
facts together provide rationale to suggest that the coagulation
cascade constitutes a shared WHFC triad targetable pathway.
CHRONIC INFLAMMATION IS A DRIVER OF THE WHFC
TRIAD
Although overly simplified, it is generally agreed that, dur-
ing homeostatic disturbances (i.e., during wound healing), M1
type macrophages drive an inflammatory response known to be
tumor suppressive and antifibrotic, while M2 type macro-
phages promote profibrotic and protumorigenic effects (96,
390). In response to macrophages and to injured epithelial
cells, naïve CD4⫹ T-cells can differentiate into largely antifi-
brotic and antitumorigenic Th1 cells or profibrotic and protu-
morigenic Th2, Th17, and Treg cells, while CD8⫹ T-cells are
considered cytotoxic and constitute a positive neoplastic prog-
nostic marker (390). During the acute wound healing response,
immunity is triggered to prevent infection and to induce quick
healing. Hence, a plethora of acute inflammatory secreted
cytokines induce cellular proliferation, EMT, and myofibro-
blastic differentiation (56, 390).
Importantly, even though EMT has been proved to be
difficult to detect in many cancers, chronic inflammation asso-
ciated with fibrosis (389) and tumor progression (103) could
induce persistent EMT as well as myofibroblast differentiation,
both of which are known to further fuel the WHFC triad. It has
been shown that inflammatory responses promote tumor de-
velopment and progression including metastasis, and this axis
has been thoroughly reviewed (120). In the following sections
as well as in Supplemental Table S1, we highlight several
inflammatory factors that influence chronic fibrosis and tumor
progression because of their effects on cellular plasticity re-
lated to the WHFC triad. Please note that many of these factors
have also been reviewed elsewhere for their effects in regulat-
ing the plasticity of mesenchymal stem cells (343, 397, 406).
TGF-␤
The TGF-␤ superfamily of cytokines plays a notorious role
in the WHFC triad. TGF-␤ exerts a dual effect during cancer
progression, modulating the behavior of both epithelial and
stromal cells imparting both pro- and antitumorigenic effects
(238). For example, it has been described that TGF-␤ plays an
antitumoral role on preneoplastic liver lesions by inhibiting
epithelial cells’ growth and driving proapoptotic signaling
when induced by other cytokines such as interferon-␣ (70). On
the other hand, during more advanced tumorigenic stages,
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226 THE WHFC TRIAD
TGF-␤ has also been associated with increased invasion and
metastasis of malignant cells, correlating with enhanced activ-
ity and over expression of several integrins (238) as well as
triggering EMT (242). Regarding its effects on stromal cells,
TGF-␤ can also induce both myofibroblastic differentiation
(238) and altered ECM production (254). Of note and docu-
mented in several models of renal fibrosis (413), TGF-␤ can, in
addition, induce endothelial to mesenchymal transduction (16,
412). Although it acts through different cells and mechanisms
and clearly participates as a tumor suppressor at early tumor-
igenic stages, it is nevertheless clear that TGF-␤ also promotes
fibrosis (238) as well as tumor progression and metastasis
(242). Certainly more information is needed in this regard as
knockout of the TGF-␤ receptor II was shown to have tumor-
promoting consequences (271), while collective cell migration
was shown to improve under TGF-␤ signaling depletion (243).
Nonetheless, TGF-␤ is evidently the most dominant profibro-
genic factor known in all tissues, and anti-TGF-␤ agents (see
Supplemental Table S2) are highly effective in a variety of
fibrosis models. Latent TGF-␤ is secreted by various cell types,
such as lymphocytes, platelets, cancer cells, myofibroblasts,
and others, during the WHFC triad. For example, latent TGF-␤
can be secreted by cancer cells (242), inducing myofibroblastic
differentiation of stromal cells, contributing to enrich an inva-
sive TAF population (72, 211). Latent TGF-␤ is the inactive
form of TGF-␤ that is found linked to the ECM and is
sequestered by the latency-associated protein (LAP) and latent
TGF-␤-binding protein 1 (5). Latent TGF-␤ can be activated
by ECM damage and myofibroblastic engagement of LAP via
cell-matrix receptors such as integrins ␣v␤1, ␣v␤3, ␣v␤5,
␣v␤6, ␣v␤8, and others (257). TGF-␤ can be released and
activated via ECM contraction induced by myofibroblastic
cells (5). In fact, it has been suggested that changes in matrix
stiffness could regulate the equilibrium between storage and
release of matrix-bound factors such as TGF-␤ (383). In
addition, the integrin-mediated binding of LAP may trigger a
conformational change in the molecule, releasing the bioactive
form of this factor (5). It is noteworthy that myofibroblasts
secrete and activate TGF-␤, establishing a self-sustained feed-
back, contributing to expand their own population. In addition,
TGF-␤ effects are known to induce an increase in Col-I-rich
ECM production (254). Autocrine TGF-␤ signaling has been
shown to drive myofibroblast differentiation during tumor
progression (185), suggesting a similar operational process in
chronic fibrosis. Interestingly, the activation of TGF-␤ and
subsequent myofibroblast differentiation can be triggered in
vitro by a constant interstitial fluidic flow (265), suggesting the
possibility of a physical effect of augmented tissue pressure,
enhancing and expanding both myofibroblast and TAFs popu-
lations at the vicinity of the WHFC triad. To this end, it is not
surprising then to recognize that all the WHFC triad diseases
present changes in interstitial fluid flow.
Interleukin-6
An important acute phase mediator, interleukin-6 (IL-6), is
also a proinflammatory factor that has a prominent role in
stromal activation. IL-6 null mice exhibit delayed wound
healing related to a diminished myofibroblast differentiation
(105). Moreover, IL-6 null mice exhibit an attenuated lung
fibrosis phenotype in response to radiation (311), suggesting a
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role for IL-6-induced myofibroblast differentiation in fibrosis.
In addition, IL-6 induces epithelial cancer cell proliferation
(315) while also activating the EMT program (145, 348) and
contributing to a preference for bone metastasis (8, 327). It is
well documented that IL-6 promotes colitis-associated cancer
via a STAT3-dependent mechanism (119). Finally, myofibro-
blasts from a variety of tissues are known to produce IL-6 (46,
330, 361), suggesting that mesenchymal IL-6 may participate
in the WHFC triad by facilitating tissue fibrosis, tumoral
desmoplasia, epithelial growth, and metastasis.
IL-17
IL-17 is a cytokine that is upregulated in response to Th17
effector cytokine IL-23 (121, 379). IL-17 upregulation has
been associated, together with other cytokines such as IL-6 and
IL-22, as proinflammatory (394) as well as protumorigenic
(379). IL-17 is known to act on myeloid and mesenchymal
cells to induce expression of IL-6 (and others) (394). In
addition, IL-17 is believed to induce expression of CXC
chemokines known for their neurophil chemo-attractive capa-
bilities (394). Interestingly, IL-17 has also been associated with
the expression of ECM remodeling enzymes such as matrix
metalloproteinases (MMPs) MMP1, MMP3, MMP9, and
MMP13, which are linked to both chronic inflammation and
cancer (394). In particular, IL-17 has been shown to be acti-
vated by local microbial factors that can particularly penetrate
neoplastic but not normal tissues. For example, a deterioration
of the colorectal cancer tumoral barrier is induced in early
lesions, allowing microbial factors to promote local IL-17-
dependent inflammation to further drive tumor growth (121).
Interestingly, IL-17 has an ability to activate fibroblasts in
autoimmunity, liver fibrosis, and cancer (246). Together these
facts emphasize an important role for IL-17 in the WHFC triad.
Chemokines
For the success of a wound resolution, it is necessary to
coordinate the recruitment of several types of cells (e.g.,
inflammatory cells, macrophages, fibroblasts, and endothelial
and epithelial cells) to the insulted tissue. This recruitment is
mediated by chemotactic cytokines (chemokines), which are
diffusible molecules that activate cell proliferation and direct
cell migration toward the wound (21). The cytokines and
chemokines involved in wound healing and their influence in
tumor microenvironment (370) have been listed in several
publications (21, 191, 411). In this review, we highlight some
chemokines that are especially relevant to the WHFC triad.
During wound healing, the CXC chemokine family facili-
tates angiogenesis as well as lymphocyte recruitment (411).
CXC receptors (CXCRs), in combination with chemokine
ligands such as CXCL8 (184), play a key role during various
cellular key responses (76, 253, 411). Therefore, it is not
surprising that deregulation of the CXCRs/CXCL8 axis leads
to fibrotic pathologies affecting lung (237, 340), kidney (351),
and liver (417). Moreover, CXCR receptors have been pro-
posed as therapeutic targets in some fibrotic conditions such as
asthma (48, 175). In cancer, CXCRs/CXCL8 seem to be
responsible for driving cancer cell proliferation, survival, and
metastasis (104). Stromal CXCL8 potentiates the metastatic
phenotype of cancer cells (104). More recently, CXCR2 has
been implicated in sustaining a protumor inflammatory envi-

THE WHFC TRIAD
ronment in colon cancer not only by recruiting inflammatory
cells but also by recruiting myeloid-derived suppressor cells
into the tumor milieu and therefore obstructing antitumor
immune responses (170). The broad spectra of CXCRs/CXCL8
effects on cancer progression remains unclear, and yet CXCL8
expression has been proposed as a chemotherapy effectiveness
marker (104).
Additional chemotactic axes relevant to the WHFC triad,
which present contentious roles in fibrosis, are CXCR3 and
their relevant ligand chemokines such as CXCL10 (411).
Activity of CXCL10/CXCR3 promotes fibroblastic maturation,
and it also inhibits endothelial cell proliferation and migration
into the wound, a crucial step for wound tissue remodeling and
maturation (21). Since CXCR3 activity has been associated
with myofibroblastic differentiation and ECM maturation, it is
expected that CXCR3-associated chemokines will be impli-
cated in fibrosis. Indeed, in liver, CXCR3 is upregulated and is
believed to play a profibrotic role in chronic hepatitis C (414).
In fact, serological levels of CXCR3-associated chemokines
have been proposed to help monitor the progression and
complications of chronic liver diseases (352). In contrast,
studies in chronic pancreatitis have proposed an anti-fibrotic
role for CXCR3 and its associated chemokine CXCL9 via
downregulation of Col-1-␣1 and TGF-␤ (329). Additionally in
the pancreas, the blockade of CXCL10/CXCR3 promotes a
fibrotic condition in renal disease by upregulation of TGF-␤
(262). Disparities in the CXCR3 activity on different organs
during a fibrotic response suggest a more complicated interplay
of immune cells for a balanced regulation between pro- and
antifibrotic cytokines/chemokines, which needs more investi-
gation.
CXCL10/CXCR3 plays important roles in cancer as well.
For example, in murine models of breast cancer, hypoxia
inducible factor (HIF)-1␣ mediates the expression of CXCL10
and CXCR3 in mesenchymal stem cells and breast cancer cells,
respectively, promoting metastasis (50). Moreover, in mela-
noma murine models as well as in colon cancer patients,
CXCR3 promotes metastasis to lymph nodes (172, 173), and
recent findings have demonstrated a synergism between
CXCR3 and CXCR4 to promote metastasis to liver and lungs
(258).
Perhaps the best-known chemokine reported in the WHFC
triad is CXCL12, also known as stromal-derived factor
(SDF)-1, which together with its main receptor CXCR4 in-
duces migration of endothelial cells during wound-induced
angiogenesis (411). The chemotactic properties of CXCL12
have also been documented during mobilization of fibrocytes
from the bone marrow to the lungs (284), which in concert with
other chemokines contribute to aggravate pulmonary fibrosis
(230). Moreover, the SDF-1/CXCR4 axis has been shown to
trigger prostate myofibroblastic differentiation in vitro, sug-
gesting a role in fibrosis (109).
In cancer, the SDF-1/CXCR4 axis has been implicated in the
progression of several types of malignancies, and its expres-
sion is associated with poor prognosis (66, 132, 387, 393, 395).
An important study almost a decade ago demonstrated that
SDF-1 secreted by TAFs (but not normal fibroblastic cells)
triggers both angiogenesis and tumor growth via CXCR4
(275). SDF-1/CXCR4 activity is known to induce EMT and
promote cell motility, invasion, and metastasis (299, 336),
demonstrating a strong relationship between stromal and tu-
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227
moral components (298). Moreover, in breast cancer cells in
vitro, CXCR4 signaling has been found to induce endocrine
therapy resistance (300).
Several inflammatory stimuli are responsible for the expres-
sion of particular sets of chemotactic receptors in cancer cells
(371), and more recently we have started to learn about the
cooperation between diverse chemotactic receptors driving the
metastatic phenotype as in the case of induction of CXCR2
expression via CXCR4 activation in breast cancer (336). The
complexity in the chemokines receptor/ligand networks calls
for a better understanding of the role of inflammatory signals
modulating the evolution of the WHFC triad to develop better
therapeutic strategies.
Cyclo-oxygenase-2
The enzyme cyclo-oxygenase-2 (COX-2) converts arachi-
donic acid to prostaglandin endoperoxide H2 (PGE2), and its
expression triggers an inflammatory response (6). Neverthe-
less, the function of COX-2 and PGE2 seems to be contradic-
tory and perhaps cell type specific during chronic fibrotic
conditions. For example, PGE2 inhibits hepatic fibrosis (23) as
well as pulmonary fibrosis where it has been shown to limit
fibroblast proliferation and myofibroblast differentiation (37,
187). Also, although COX-2 is expressed briefly in response to
tissue injury (131), the use of COX-2 and prostaglandin inhib-
itors appears only to impart a modest effect over wound
healing (131, 244). Even though these types of inhibitors block
inflammation, they exacerbate injury since they prevent wound
healing especially in the intestine (354). Conversely, COX-2
inhibition reduces renal fibrosis (129, 302), suggesting that
PGE2 may contribute to fibrosis in the kidney. Anti-inflamma-
tory COX-2 inhibitory therapy in combination with chemopre-
vention and as adjuvant to chemotherapy shows some thera-
peutic promise (178). The role of COX-2 has been particularly
well studied in colon cancer. However, COX-2 inhibition as a
therapy may require more investigation, as prolonged COX-2
inhibition promotes drug resistance, resulting in increased
intestinal fibrosis and tumor recurrence in mice (44, 69).
Intriguingly, the induced drug resistance is believed be medi-
ated by intestinal myofibroblasts, as chronic COX-2 inhibition
promotes TGF-␤-induced myofibroblastic differentiation and
augmented stromal PGE2 synthesis (44, 69). Moreover, TAFs
from colon adenocarcinomas express a variety of factors that
also drive tumor progression (188, 231). Hence, it is possible
that the persistent myofibroblastic population maintained by
chronic COX-2 inhibition is responsible for tumor recurrence
as well as its correlation with tumor progression (178).
Peroxisome Proliferator Activated Receptor Gamma
While the previously discussed proinflammatory molecules
seem to promote the WHFC triad, the role of the peroxisome
proliferator activated receptor gamma (PPAR-␥), a transcrip-
tion factor involved in immunomodulation, is notable for its
inhibitory effects over fibrosis and cancer. During the late
stages of wound healing, PPAR-␥ activation stalls fibroblast
proliferation and overthrows the myofibroblast phenotype
(248), suggesting a mechanism for the termination of the
healing response. PPAR-␥ agonists are recognized for their
inhibitory effects on TGF-␤-induced myofibroblast differenti-
ation (31, 41, 202, 239, 241, 252, 380). This antifibrotic effect
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228 THE WHFC TRIAD
has been proposed as a strategy to attenuate pulmonary and
renal interstitial fibrosis (174, 194, 332). Then again, in cancer,
some investigators have proposed an oncogenic, while others
have stated a tumor-suppressive, role for PPAR-␥ (124). For
example, PPAR-␥ agonists have been shown to impart anti-
cancer effects (22), while a tumor-promoting effect is observed
when PPAR-␥ is inhibited (236) (see Supplemental Table S2).
Nevertheless, PPAR-␥ signaling has also been shown to exert
an inhibitory effect on TGF-␤-induced EMT in lung cancer
cells and subsequent metastasis (297). Even more, PPAR-␥
ligands can also induce EMT upon intestinal epithelial cells
through a Rho-dependent activation of ERK1/2 (51), suggesting
a tight regulation of the PPAR-␥ signaling effects that could be
associated with a particular cell type in a particular TGF-␤
signaling context. Interestingly, there is evidence to suggest an
intricate regulation of the tumor stroma in colon adenocarci-
nomas, where COX-2 and PPAR-␥ have been found coex-
pressed only in myofibroblasts at the tumor-associated but not
the normal stroma (372). These findings suggest a PPAR-␥
negative regulation of both fibrosis and cancer where its
presence at late stages of nonpathological wound healing
possibly contributes to prevent the WHFC triad occurrences.
CELL PROLIFERATION: A COMMON AVENUE USED BY THE
WHFC TRIAD
A hallmark of developmental growth but also of wound
healing is a transient hyperproliferative wave affecting both
epithelial and stromal cells (183). This feature results from a
temporary burst of diverse mitogenic signals triggered by a
disturbance in the homeostasis of a given tissue (i.e., during
wound healing). Expectedly, a similar spectrum of mitogens
can also be constitutively detected in fibrotic and tumor tissues
(Fig. 1), promoting epithelial and mesenchymal cell prolifera-
tion. Growth factors have a preponderate role among the large
variety of mitogenic signals at the WHFC triad (Supplemental
Table S1). Here we emphasize some of them.
Platelet-derived Growth Factor
One of the most abundant molecules released in response to
tissue injury is the platelet-derived growth factor (PDGF)
(227). PDGF is a key player in the persistence of chronic
fibrosis, exerting a strong mitogenic signal upon fibroblasts and
myofibroblasts (32). Also, PDGF can stimulate the prolifera-
tion of epithelial cancer cells in different types of tumors,
exerting its influence through both paracrine and autocrine
mechanisms (133, 287). Hence, PDGF-induced cell prolifera-
tion could very well sustain a desmoplastic reaction while
supporting tumor progression, thus fueling a protumorigenic
vicious cycle (20). Some studies suggest that PDGF could
sustain or even initiate desmoplasia in breast cancer (148, 326),
while others point to the fact that PDGF is a promigratory
factor (67) as well as an EMT regulator (388). Furthermore,
PDGF expression can also affect other growth factors, as
inhibition of stromal PDGF receptors in a murine model of
cervical cancer was shown to alter the levels of expression of
the fibroblast growth factors (FGF)-2 and -7 (287). Moreover,
the inhibition of FGF-2 and FGF-7 in cervical cancer restricts
their respective mitogenic and angiogenic effects, suggesting
PDGFR as an attractive therapeutic target (287).
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FGF-2
FGF-2, also known as basic fibroblast growth factor, encom-
passes a pivotal role during wound healing (220). FGF-2 exerts
a robust mitogenic effect upon fibroblasts, and its participation
has been linked to multiple fibrotic disorders (26, 152, 162,
177, 344 –346). In addition, FGF-2 can be induced by TGF-␤
(see above), suggesting an important correlation between the
two molecules (177, 345). Nonetheless, FGF-2 has also been
reported to inhibit TGF-␤-induced myofibroblast differentia-
tion (92, 150, 154, 234, 339). Interestingly, during nonpatho-
logical wound healing, FGF-2 inhibits excessive scarring by
triggering myofibroblastic apoptosis, yet quiescent (i.e., non-
activated) fibroblasts appear to be refractory to this molecule
(1, 339). These observations suggest that, under physiological
conditions, FGF-2 may play a key regulatory role during
wound resolution, encouraging fibroblast proliferation to repair
damaged tissue but restricting the myofibroblastic population
to limit excessive scarring.
Nevertheless, FGF-2 effects have been implicated in the
development of several tumors by promoting proliferation
and survival of cancer cells and even supporting tumor
angiogenesis (368). It is not surprising that the effect of
FGF-2 and the FGF receptor family (FGFR) in cancer is
considered “complex” as the pathway has been shown to
have both protumorigenic and tumor-suppressive roles
(368). What is more, FGFR-induced activities can be ligand-
independent (via genomic mutations of signaling molecules)
or ligand dependent (368). Although the role of FGF-2 in
desmoplasia remains rather obscure, its detection and im-
plication at the stroma of prostate and mammary cancers as
well as other malignancies (223, 367, 403) suggests a fairly
broad participation (267).
Epidermal Growth Factor Receptor
The epidermal growth factor receptor (EGFR) family, also
known as the ErbB family, consists of pleiotropic membrane-
spanning cell surface receptors with intracellular tyrosine ki-
nase activities that are triggered by homo- or hetero-dimeriza-
tion when engaged by growth factors. Some of the family
growth factor ligands are known to participate in wound
healing [i.e., epidermal growth factor (EGF), heparin-binding
epidermal growth factor (HB-EGF), and TGF-␣] (281, 409).
Under physiological conditions, EGFR signaling drives wound
healing, and controlled activity of EGFR by HB-EGF has been
proposed as a therapeutic approach to prompt and accelerate
cutaneous wounds healing (161, 363). Of note, aberrant EGFR
activation is known to promote fibrosis in tissues such as lung,
heart, and pancreas (128, 214, 229, 245). EGFR activity has
been implicated in the progression of malignancies such as
colon and lung cancer (94, 134, 314). Nevertheless, EGFR
activity has also been implicated in tissue regeneration during
acute and chronic colitis where EGFR activity seems to limit
fibrosis induced tumorigenesis (80). Then again, EGFR signal-
ing activates EMT in malignant cells (130, 312). Doubly,
EGFR activity affects the tumor stroma by inducing HB-EGF
overexpression in TAFs, thus supporting tumor progression by
direct and indirect effects (259).

THE WHFC TRIAD
Additional Deregulated Developmental Signals Promoting
WHFC
The healing of a wounded tissue is known to be influenced
by signaling molecules involved in embryonic development
(183). Some of these signaling molecules are highly relevant
during wound resolution and, when deregulated, are major
players in the WHFC triad. To this end, Notch and Hedgehog
(Hh) signaling cascades constitute two well-known examples
of developmental signaling implicated in these processes (see
Supplemental Table S1).
Notch signaling is an evolutionary well-conserved pathway
known for regulating embryonic morphogenesis, tissue homeo-
stasis, angiogenesis, and maintenance of the vascular system
(25). The role of Notch during wound healing has been dem-
onstrated in vitro as well as by genetic manipulation of murine
models where Notch-deficient animals present delayed wound
healing (54, 77, 228). Regarding its mechanisms of action, it is
known that Notch signaling drives EMT, providing a vast
source of fibroblastic cells necessary for wound repair (171). In
addition, Notch activity has also been associated with fibrosis
promotion in a variety of tissues (such as skin, kidney, lung,
and cardiac tissue), influencing cell proliferation, extensive
fibrilogenesis, TGF-␤ production, and ␣-SMA expression
(171). In cancer (but not in regenerating epithelium during
wound healing), Notch has also been shown to have an onco-
genic role, promoting protein biosynthesis, cell growth, apo-
ptosis resistance, and angiogenesis (305). Moreover, it has also
been implicated in triggering EMT (224), fueling cancer inva-
sion and enriching the desmoplastic TAF population. Never-
theless, there is evidence to suggest that Notch, depending on
the cellular context, can exert a tumor suppressive role (224).
Another important signaling pathway in the WHFC triad is
the Hh cascade. The Hh signaling pathway is triggered by
several types of Hh ligands (i.e., Sonic, Desert, and Indian).
The ligands bind to the receptor Patched, which in turn releases
Smoothened to promote Gli transcription factors (Gli-1, Gli-2,
and Gli-3) (58). Gli-1 appears to be the most abundant Hh-
activated transcription factor, while Sonic Hh (SHh) is the
better characterized ligand in the signaling pathway (58). SHh
signaling is essential for wound healing as demonstrated by the
inhibitory effect imparted by the topical application of a
cyclopamine, a well-characterized inhibitor of smoothened, at
all stages of the wound healing process (200). However, SHh
signaling has also been shown to promote fibrosis in several
organs such as lung, liver, and skin (157). Likewise, Hh has
been shown to participate in tumor progression (58) by pro-
moting stromal activation/desmoplasia (149, 359). For exam-
ple, in pancreatic as well as in prostate cancer, it has been
found that SHh is released by cancer cells, affecting stromal
cells, causing differentiation and proliferation of ␣-SMA-pos-
itive myofibroblastic TAFs (15, 149, 199, 328, 376). Besides
its ability to activate the tumor stroma, SHh ligands also
promote EMT in cancer cells (396). Interestingly, while SHh
signaling facilitates tumor progression through multiple mech-
anisms, it is possible that SHh ligands are not the only possible
triggers of SHh signaling, as it has been found that TGF-␤ can
also induce the activity of Gli-1 (157). This signaling pathway
overlap strongly suggests a common participation in the
WHFC triad. Although the relationship between SHh signaling
and TGF-␤ activation merits additional investigation, the syn-
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229
ergistic interaction could constitute an interesting therapeutic
approach.
PATHOLOGICALLY ALTERED ECMS CONSTITUTE BOTH
CAUSE AND CONSEQUENCE OF CHRONIC FIBROSIS AND
TUMOR PROGRESSION
Below we discuss the participation of physical ECM (i.e.,
architecture or stiffness) properties, as well as noteworthy
components of pathological ECM common to the WHFC triad.
Topographical/architectural Changes in ECM
A pathological mesenchymal ECM differs from its normal
counterpart and is recognized by an altered and constitutive
expression of its building molecules, as well as for their
characteristic architectural organization (294, 295), which to-
gether are believed to impart distinct physical and biochemical
properties to the ECM (97, 410). Moreover, the altered archi-
tectural composition of a pathological ECM has been associ-
ated with clinical outcomes in breast cancer (59). Functionally,
it has been suggested that topographical ECM alterations can
impact normal stromal cells’ behaviors, thereby supporting a
phenotypic switch (i.e., myofibroblastic activation) (4, 139).
Concurrently, these newly activated cells continue synthesiz-
ing the above-mentioned altered ECM, feeding a vicious cycle
affecting additional adjacent stromal (4, 16, 115, 137), as well
as epithelial cells (16, 45, 97, 116, 197, 201), in a continuously
expanding “field effect.”
ECM Stiffness
Both fibrotic and tumor-associated (i.e., desmoplastic)
ECMs are characterized by an increase in stiffness compared
with their normal stromal equivalent, which is known to be
more flexible or compliant (116, 208, 277, 364). A less flexible
environment exerts a greater physical tension to the cell body,
which is transduced into multiple intracellular signals, modi-
fying cell behavior. For example, relatively stiff ECMs alter
cell growth, modify gene expression, and alter the differenti-
ated status of cells (292, 338, 378). Moreover, ECMs subjected
to a higher physical tension induce structural modifications to
ECM-associated molecules, modulating their bioactivity (i.e.,
releasing active molecules of TGF-␤), which in turn, for
instance, can trigger myofibroblastic differentiation (139) and
also further fuel the production of the altered (166) and stiffer
ECM. Hence, in chronic fibrosis, tissue stiffness fuels a posi-
tive feedback enhancing the chronicity of fibrotic disease
(218). Meanwhile in cancer, a rigid ECM induces tumor
progression (42, 208, 282, 410) but also an enrichment of
activated/myofibroblastic cells (i.e., TAFs), which in turn sus-
tain a desmoplastic reaction and further promote tumorigenesis
(16, 20, 64, 116, 399). ECM rigidity regulates the effects of
TGF-␤ upon tumor cells, as compliant matrices facilitate
TGF-␤-induced apoptosis, while stiffer matrices promote
TGF-␤-induced EMT (206). Various ECM-related modifiers
and a plethora of molecular components participate in the
WHFC triad, and a few are listed below as well as in Supple-
mental Table S1.
Fibronectin
A native well-conserved constituent of the mesenchymal
ECM that plays a determinant role in the WHFC triad is
Review
230 THE WHFC TRIAD
fibronectin (FN). Plasma FN (307) is commonly found in the
circulation, while cellular FN (400) is the glycoprotein that is
expressed by fibroblastic cells and is incorporated into the
fibrillar ECM mesh. From a single human gene and as product
of alternative mRNA splicing, several cellular FN variants can
be expressed (384). Two spliced exons called “extra domains
A” and “B” (EDA and EDB) are particularly and abundantly
expressed during embryonic developmental stages, while an
important (i.e., normal) reduction is observed in adult tissues
(384). Nevertheless, during the physiological ECM restructur-
ing of wounded tissue, EDA-FN is upregulated by myofibro-
blastic cells (118). Moreover, in a positive feedback regulation,
EDA-FN has been shown to exert a permissive action during
myofibroblastic activation (82). EDA-FN overexpression has
been found to occur in response to increased ECM tension
(364), and it is influenced by high levels of TGF-␤ at the
specific microenvironment of acute injuries (324). The rela-
tionship of EDA-FN with TGF-␤ appears to be a determinant
for the progression of several fibrotic diseases (i.e., atheroscle-
rosis and lung and liver fibrosis) as demonstrated in various in
vivo FN mutant animal models (384). Researchers believe that
the sustained TGF-␤-promoted myofibroblastic differentiation
occurs via production and signaling of EDA-FN, supporting a
chronic fibrotic niche (384). EDA-FN also influences the tumor
microenvironment, affecting both stromal and tumor cells. At
the stromal compartment, EDA-FN seems to be intimately
related to the bioavailability of active TGF-␤ for the subse-
quent sustainability of the reactive stroma (384). EDA-FN is
known for promoting tumor growth, EMT, and tumor-induced
lymphangiogenesis (349, 391). EDB-FN has also been associ-
ated with tumor progression, in particular with tumor angio-
genesis and is being tested as a potential tumor target in the
clinic (320). Hence, alternative spliced forms of FN seem to
play important roles in the WHFC triad.
Collagen
As the major ECM component in the connective tissue and
the most abundant protein in mammals, collagen has been
described as a heterotrimeric triple helix glycoprotein that can
be assembled into de novo fibrous matrices during healing,
playing a crucial role during the repair of tissue defects.
Collagen deposition increments the ECM tension during the
restoration of the vessels network and the recovery of tissue
architecture during wound healing (118). Among the collagen
family, Col-I is the most abundant interstitial protein of the
ECM (107) often seen in fibrotic tissue and desmoplasia. Then
again, Col-IV is the main component of epithelial and endo-
thelial basal membrane (167). The activated/myofibroblastic
phenotype seen in the WHFC triad is commonly described as
containing abundant Col-I and -III, although reports showing
changes in Col-IV and -V are also evident (136). In addition,
Col-VI spiked some attention due to its selective expression in
some fibrotic conditions (i.e., kidney and myocardial fibrosis)
as well as in hepatocellular carcinoma (136). In fact, its level
of expression has been recently proposed to serve as a clinical
prognostic marker (204, 205). Carcinomas that typically pres-
ent an aggressive progression (i.e., liver and pancreas) are
characterized by a large deposition of interstitial FN and
collagen. These occurrences are blamed for augmented tumor
cell proliferation that is accompanied by an intense desmoplas-
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tic reaction (12). For example, it was reported that pancreatic
cancer cells can trigger fibroblastic activation while promoting
increased deposition of Col-I and -III in a nude murine model
(12). In breast cancer, Col-I cross-linking is increased, showing
a reduction on its degradation rate, resulting in excessive
deposition (168). In sum, Col-I and -III changes are typically
described in diseases associated with the WHFC triad.
Lysyl Oxidase
An important regulator of ECM rigidity is the activity of the
enzyme lysyl oxidase (LOX), which catalyzes the cross-linking
of collagen (see above) and elastin bundles, modifying the
tensile strength of the ECM (165). LOX is essential for main-
taining ECM strength during normal development (233) and
becomes highly expressed during the course of several fibrotic
diseases (164, 392). Throughout cancer progression, LOX
facilitates Col-I cross-linking, promoting ECM stiffening and
therefore altering known integrin-regulated signaling pathways
(208). In fact, increased LOX activity has been associated with
a poor prognosis in several carcinomas (392). LOX and LOX-
like enzyme 2 (LOXL2) are downstream targets of HIF-1␣
and, under hypoxic conditions, promote EMT by repressing
E-cadherin (319). In a xenograft tumor model, the inhibition of
LOX2 decreased the number of ␣-SMA-positive TAFs (17).
Furthermore, LOXL2 has been proposed as a prognostic bio-
marker for squamous cell carcinomas (283). Together these
data support the correlation between increased cross-linked
Col, stiffer ECM, an enriched TAF population, and the exac-
erbation of tumor desmoplastic reaction. Interestingly, the
same LOX inhibitory antibody hinders murine liver and pul-
monary fibrosis (17), suggesting a compelling similarity as
proposed in the WHFC triad (Supplemental Table S2).
MMPs
Even though, intuitively, MMPs, are ECM-cleaving protein-
ases, they do not antagonize fibrosis, cancer, or fibrosis-
induced cancer. Hence, these enzymes are regarded as ECM
remodeling proteins as opposed to ECM-degrading proteins
(278). MMPs play a crucial role during inflammation, re-
epithelialization, and ECM remodeling associated with regen-
erative wound healing (113). Specifically, MMPs mediate
ECM remodeling during scar resolution, cleave and activate
ECM-associated growth factors, regulate chemokine activity,
and also facilitate keratinocyte migration into the wound (113,
176, 278). MMPs can be expressed by inflammatory cells,
epithelial cells, fibroblasts, and myofibroblasts. The sources
and functions of MMPs implicated in the context of cancer
(176) and fibrosis (278) are very diverse and beyond the scope
of this review. Nonetheless, we highlight two gelatinases,
MMP-2 and MMP-9 (19, 176), as these enzymes seem to
convey a recurrent presence in the WHFC triad.
The participation of MMP-2 and MMP-9 in chronic fibrosis
appears to be contentious. For example, a clear upregulation of
these MMPs expressed by myofibroblasts is evident during the
development of idiopathic pulmonary fibrosis (322). Also,
MMP-2 has been found to be highly expressed in fibrotic liver
myofibroblasts (293), which incidentally has been proven to
constitute a noteworthy predisposition to developing hepatic
cell carcinoma (86). Nonetheless, a downregulation of MMP-2
has been reported during in vitro myofibroblastic differentia-

THE WHFC TRIAD
tion of rat embryonic fibroblasts (141), while its inhibition has
been shown to accelerate murine renal fibrosis (268).
In cancer, MMP-2 and MMP-9 are known to promote tumor
progression by facilitating the release of stored latent growth
and other factors (i.e., TGF-␤) from the ECM, thus enhancing
respectively cell proliferation and migration (36). MMPs can
also facilitate cancer cell migration (385) by interaction with
cell-matrix adhesion molecules, such as integrins, promoting
degradation of cancer cells from cell-cell and cell-matrix ad-
hesions (36). To further fuel the recurring cycle, EMT en-
hances the expression of MMP-2 and MMP-9 (36). Interest-
ingly, MMP cleaved ECM peptides (i.e., soluble ECMs) are
known to induce an integrin-dependent TGF-␤-like signaling
response (106). Also, CD147, a cell-surface glycoprotein up-
regulated in tumor cells, can stimulate both stromal MMP
production and myofibroblast differentiation (147). In sum,
MMPs produced by cancer cells promote tumoral invasion as
well as myofibroblast differentiation, reinforcing a tumor-
supportive stroma, which in turn further secretes and activates
additional MMPs to further fuel this vicious cycle.
Hyaluronan
A particular component of the ECM, with no inflammatory
activity but related to inflammation, is the glycosaminoglycan
hyaluronan (HA). This macropolysaccharide molecule con-
tains multiple unit repetitions of N-acetyl-glucosamine as well
as of glucuronic acid, and it binds and stores large amounts of
water molecules conforming a viscous gel (355). HA has been
suggested to function as a pliable substrate for tissue remod-
eling necessary for wound healing (355). It also binds fibrin-
ogen, supporting clotting, and acts as a mesh that traps inflam-
matory cells (342). Large HA molecules of ⬃25,000 disaccha-
ride units (355) encourage cellular quiescence, while small HA
fragments ranging from 4 to 25 units encourage proliferation
and angiogenesis (342). It has been proposed that HA break-
down at the injury site renders fragments that participate in the
initiation of the healing response (342).
HA accumulation is associated with exacerbation of fibrosis
(27, 159). The expression of HA synthesizing enzymes “hya-
luronan synthase (HAS) 1–3” during chronic fibrosis has been
associated with an increased inflammatory reaction (52, 213).
Knockdown of HAS2 reduces the effectiveness of TGF-␤-
stimulated EMT (291), and elevated HAS2 expression is suf-
ficient to induce EMT in normal epithelial cells (418). More-
over, inhibition of HA synthesis antagonizes TGF-␤-induced
myofibroblastic differentiation (381), and inhibition of HAS2
impairs myofibroblast accumulation in mouse models of pul-
monary fibrosis (213). Since elevated HA has been observed in
a variety of fibrotic diseases (210, 213, 357) and HAS2
regulates TGF-␤-dependent functions (291), their accumula-
tion and increase in expression are respectively suggestive (i.e.,
markers) of fibrotic myofibroblast differentiation and EMT.
With regards to cancer, increased HA is linked to poor
cancer outcomes (355), while upregulation of HAS2 is a
common occurrence in highly metastatic breast cancer cells
(273). Nevertheless, the role of HA in cancer seems to be tissue
specific. In general, accumulation of HA in tissues where it is
normally absent facilitates tumor growth (i.e., gastric cancers),
while reduced HA is associated with cancer in normally HA-
rich stratified epithelia containing tissues such as skin, mouth,
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231
and larynx (355). Interestingly, epithelial HA accumulation in
colon cancer constitutes a bad prognostic occurrence (304),
while stromal HA buildups have been associated with an
unfavorable prognosis in ovarian, prostate, breast, and nons-
mall cell lung cancers (11, 217, 289, 382). In the case of liver,
the main organ in charge of processing HA (98), a large
synthesis of the glycosaminoglycan and increasing circulating
levels of HA have been found to correlate with liver fibrosis
(cirrhosis) (280). In addition, hepatic cirrhosis is known to
predispose for hepatocarcinoma, and HA deposition has also
been associated with cancer progression (285, 341). Most of
the mechanisms of HA’s driven tumor progression deal with
the promotion of cell proliferation, NF-␬B activity, and angio-
genesis (333). HA also binds to the cellular receptor CD44,
which encourages motility and invasion (333). Intriguingly,
HA expression is increased via growth factors such as EGF,
keratinocyte growth factor, and PDGF (355), suggesting a
more complicated role for certain growth factors, which could
promote both cancer cell proliferation and HA accumulation.
Interestingly, the antiproliferative and proapoptotic effect of
HA inhibition, affecting both the tumor and surrounding
stroma (285), highlights the importance of designing antican-
cer strategies focused on attacking both the tumor and its
associated fibrotic stroma.
Periostin
Periostin is a matricellular protein that increases ECM stiff-
ness by direct binding to fibrillar ECM proteins such as Col-I
(270) and by interacting with the TGF-␤-related protein
BMP-1, which is needed to activate LOX (240). In addition,
periostin functions as a ligand for integrins ␣v␤3, ␣v␤5, and
␣6␤4 (102, 306). In general, periostin expression seems to play
a main role during wound healing and tissue regeneration
(reviewed in Ref. 192). For example, periostin-deficient mice
present a reduction in the number of cutaneous wound healing/
repair myofibroblasts (88). Periostin has been associated with
myofibroblastic differentiation in vivo and in vitro via an
integrin-dependent mechanism as well as with ECM remodel-
ing (60, 87). As a consequence, periostin increases are also
associated with pathologies marked by a fibrotic condition such
as idiopathic pulmonary fibrosis, renal fibrosis, asthma, and
skin sclerosis in scleroderma (261, 323, 331, 401).
Regarding cancer, periostin has been found to be expressed
by cancer epithelial cells (255, 306), and recently it has been
associated with increased esophageal cancer invasion of p53
mutants via STAT1 induction (386). Moreover, periostin can
also be expressed by stromal cells and, as such, has been
identified in desmoplastic pancreatic cancer (102), colon can-
cer, cholangiocarcinoma (179, 369), and other types of cancer
(193, 222, 249, 255, 306). Consequently, periostin seems to
facilitate both tumoral and stromal progressions. Periostin
integrin-dependent signaling activates focal adhesion kinase
(FAK), as well as the PI3K/AKT pathway, thus generally
promoting malignant cell survival, proliferation, and angiogen-
esis (255, 306). Moreover, activation of integrins by periostin
promotes EMT in cancer cells (255). Intriguingly, in bladder
cancer, periostin seems to function as a tumor suppressor by in
vitro inhibition of invasion and reduction of in vivo metastasis
(180). Moreover, in many cancer cell lines in vitro periostin
seems to suppress anchorage-independent growth, while low
Review
232 THE WHFC TRIAD
periostin mRNA levels are observed in lung cancer in vivo
(408).
Tenascin C
Tenascin C is another ECM-related glycoprotein expressed
in response to tissue injury known to modulate the wound
healing response (251). Tenascin C levels decrease subse-
quently to wound healing resolution (251). This decrease in
tenascin C is also associated with a natural reduction in
myofibroblasts (251). Hence, it is not surprising that a mis-
regulated and continuous expression of tenascin C is a common
occurrence, which is believed to drive fibrosis and cancer via
increased angiogenesis, ECM alterations, and immunomodula-
tion (250). For example, tenascin C-deficient mice are pro-
tected from pulmonary and liver fibrosis (43, 85). In addition,
tenascin C has been shown to promote tumorigenic progression
by supporting cell motility, metastasis, and more (101, 127,
207, 274, 279). Tenascin C is synthesized by both tumoral and
stromal cells (71, 276). Then again, tenascin C could also
indirectly promote the WHFC triad by its effect on the down-
regulation of tPA, which facilitates fibrin accumulation, thus
triggering a mitogenic response (40).
Osteonectin/SPARC
The secreted protein and rich in cysteine (SPARC), also
known as osteonectin, is a matricellular protein that is known
to affect ECM remodeling/dynamics. SPARC is often highly
expressed during wound healing, cancer, and fibrosis (18, 55,
365). For example, the upregulated expression of SPARC
seems to be a common event during several chronic fibrotic
conditions such as in the cases of heart, lungs, kidneys, liver,
dermis, intestine, and eyes (365). SPARC is produced by
fibroblasts in response to TGF-␤, but it can also promote Col-I
and TGF-␤ synthesis (365). In a SPARC null murine model, a
decreased deposition of dermal collagen constitutes a predom-
inant trait accompanied by an enhanced contractile behavior of
dermal fibroblasts (39). By affecting collagen deposition and
reducing the number of myofibroblasts, decreased SPARC
expression reduces liver fibrosis (10). Nonetheless, despite the
implication of SPARC in the control of wound healing, its
precise role remains rather unclear. For instance, it has been
reported that SPARC can both induce and inhibit the wound
healing process (18, 39).
Similarly, SPARC has also been implicated in tumor pro-
gression where it is believed to sometimes promote, and at
other times prevent, this process apparently in a tissue- and
cell-specific manner (55). Among other functions, SPARC
participates both in carcinoma EMT and in TAFs’ myofibro-
blastic differentiation, thus promoting both tumorigenesis and
desmoplasia (55). In prostate cancer, for example, the expres-
sion of SPARC by malignant cells can be predictive of metas-
tasis, while in pancreatic and nonsmall cell lung cancers,
elevated expression of SPARC at the tumor stroma indicates
poor prognostics (29, 74, 189). Regarding SPARC’s tumor-
suppressing effects in breast, ovarian, colon, and bladder car-
cinomas, SPARC has been associated with inhibition of pro-
liferation and induction of apoptosis (55, 309). Intriguingly, a
positive feedback between SPARC and TGF-␤ has been ob-
served, as both can induce the expression of each other (365).
Nevertheless, a comprehensive comparative proteomic analy-
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sis has demonstrated that not all the cellular responses to
SPARC signaling depend on TGF-␤ (114), and, although there
is a certain parallelism between them promoting neoplasia
(242), a balance of both SPARC and TGF-␤ activity could be
responsible for tumor progression (114). These facts suggest
that an intricate regulation of the SPARC/TGF-␤ signaling axis
also constitutes a common occurrence of the WHFC triad
(Supplemental Table S1 and Fig. 1).
Proteoglycans
Comprising a diverse group of members, the proteoglycan
family includes both cell surface proteins, such as heparan
sulfate proteoglycans, and ECM components, such as small
leucine-rich proteoglycans (SLRPs), and large chondroitin sul-
fate proteoglycans (153). Proteoglycans participate in immu-
nity regulation (57, 99), ECM assembly (53), and cancer
modulation (153). However, as a complete description of
proteoglycans is beyond the scope of this review, we highlight
a selection of ECM proteoglycans most relevant to the WHFC
triad.
Versican, a large chondroitin sulfate proteoglycan, is up-
regulated during both wound repair and cancer progression
(63, 112, 301, 353). During normal conditions, myofibroblasts
from human granulation tissue express elevated levels of ver-
sican (126). There is a lack of studies investigating the role of
versican in the context of chronic fibrosis. However, the
expression of versican mRNA has been detected as increased
in rat lungs after bleomycin-induced injury, and TGF-␤ sig-
naling increases versican synthesis in fibrotic lung in vivo
(373). On the other hand, versican expression correlates with a
poor prognosis in many cancer types (301, 325). This pro-
teoglycan interacts with multiple ECM and cell surface com-
ponents, promoting cell proliferation, cell motility, and metas-
tasis (301, 310, 382). Intriguingly, in breast cancer, versican
has been associated with chemotherapy resistance related to
EGFR hypersignaling and enhanced cancer cell self-renewal
(78, 79). Moreover, versican synthesis appears to be upregu-
lated by TAFs in the ovarian cancer stroma (407) where TGF-␤
signaling triggers versican expression, and together they con-
tribute to promote ovarian cancer aggressiveness (407).
The SLRP biglycan expression is enhanced in myofibro-
blasts from human granulation tissue (126). The role of bigly-
can in fibrosis may be tissue specific since biglycan does not
affect TGF-␤-induced pulmonary fibrosis (186), and biglycan
mRNA appears not to be increased in mercuric chloride-
induced renal tubulointerstitial fibrosis (350). However, bigly-
can expression and serological levels of its processed byprod-
ucts correlate with the extent of liver fibrosis in murine models
(108, 204). Biglycan is also involved with progression and
poor prognosis in a variety of malignancies such as gastroin-
testinal and endometrial cancers (7, 122, 221, 377, 415). In
contrast, biglycan expression correlates with a favorable prog-
nosis in bladder cancer where it seems to have an inhibitory
effect on tumor cell proliferation (266).
In addition to biglycan, the SLRP decorin also plays an
active role in the WHFC triad, although its participation in
chronic fibrosis and tumor progression seems to have an
inhibitory effect. Animal models have shown that absence of
decorin exacerbates fibrosis (13, 247, 316). Moreover, inter-
esting data suggest that decorin itself could be a beneficial

THE WHFC TRIAD
antifibrotic therapeutic alternative (156, 186, 402). A suggested
antifibrotic mechanism of decorin deals, at least partially, with
the inactivation of TGF-␤ signaling (14), impairing myofibro-
blastic differentiation in liver fibrosis models (14). Another
mechanism described is the direct interaction with the cytokine
known as connective tissue growth factor or CTGF, inhibiting
its fibroblastic activation role (374). In cancer, decorin gene
therapy or delivery of decorin protein inhibits tumor growth,
tumor progression, and metastasis (153). Besides the attenua-
tion of TGF-␤ signaling by decorin described in fibrosis
models (14, 402), another mechanism of action has been found
in the tumor microenvironment where it could also be inhib-
iting EGFR signaling (153). Decorin binds to EGFR overlap-
ping with the EGF binding domain and inducing internalization
of EGFR via caveolar endocytosis, resulting in decreasing
EGFR accessibility on the cell surface (153). Together, these
effects evoke a downregulation of EGFR signaling in tumor
xenografts and apoptosis induction (153). Decorin has also
shown additional antitumor effects including the inhibition of
angiogenesis and induction of p21 (153, 264). Although re-
duced decorin expression in the tumor stroma indicates poor
prognosis in models of breast cancer (264), decorin can be
found in both the tumor stroma and fibrotic tissue (14, 153).
This could be explained as a protective response (153), al-
though it has also been observed that collagen-bound decorin
found in the ECM could not be effectively protective (14).
Future work may seek to clarify the influence of decorin on the
myofibroblastic cells during chronic fibrosis and tumor desmo-
plasia.
CHRONIC FIBROSIS AND CANCER DIFFER FROM
TRANSIENT WOUND HEALING IN THAT THEY BOTH
ENCOMPASS A SUSTAINED MYOFIBROBLASTIC POPULATION
While regenerative healing wounds, fibrosis, and tumor-
associated desmoplasia all contain metabolically active myo-
fibroblasts and EMT cells, it is only under normal healing/
regenerative (i.e., nonpathological) conditions that the activity
of these cells eventually ceases. This may result from activated
cells’ (i.e., EMT or myofibroblasts) senescence and subsequent
elimination. This can occur through p53- and/or integrin-
regulated apoptosis or potentially by cell clearance via natural
killer (NK) cells and/or by interferon gamma secretion (146,
181, 198, 209, 360, 398). From the one side, myofibroblastic
apoptosis could promote pathologic scarring (75). Then again,
the persistence of myofibroblasts during fibrosis and cancer-
associated desmoplasia suggests that these cells escape from
their natural elimination process by alterations in the myofi-
broblastic cells-clearance mechanisms. Alternatively, persis-
tent activated cells may “sense” chronic injury or tumor-
associated microenvironment (i.e., desmoplasia) and consistently
respond “normally.” In addition, fibroblastic cells naturally prog-
ress and become senescent in response to a variety of signals.
Nevertheless, under pathological circumstances when clear-
ance mechanisms (i.e., wound resolution) are evaded, cells can
develop what is known as the “senescence associated secretory
phenotype” or SASP, thus turning them into sustained and
proinflammatory senescent cells (61). In response to SASP,
affected fibroblastic cells produce a variety of diffusible factors
that in turn can drive both fibrosis and tumorigenesis (61),
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233
further fueling the WHFC triad’s fibrosis/tumorigenesis vi-
cious cycle (see Fig. 1).
To further complicate things, although SASP seems to fuel
the WHFC triad, evidence also suggests that the sole escape of
fibroblasts from senescence can also support WHFC. For
example, during normal wound healing, the matricellular pro-
tein CCN1 (also known as cysteine-rich protein 61 or CYR61)
is expressed by myofibroblasts and tends to accumulate along
with the myofibroblastic cell population (198). High concen-
trations of CCN1 induce myofibroblast senescence (198) and
promote downregulation of collagen and TGF-␤ as well as
upregulation of MMPs (198). Together these changes induce a
senescent matrix-degrading cell state (198). During wound
healing resolution, myofibroblast senescence serves to prevent
pathological scarring (198). Hence, senescence is generally
recognized to inhibit fibrosis (163, 190), so it is not surprising
then that mice expressing defective CCN1 suffer from exacer-
bated fibrosis in response to injury (198). Furthermore, recent
findings have shown that restoring lost levels of CNN1 in a
hepatic fibrosis murine model can induce myofibroblastic se-
nescence and reduce chronic tissue-damaging fibrosis (182).
Nevertheless, the role that CCN1 plays in both tumor-associ-
ated stroma (i.e., desmoplasia) and in tumorigenesis remains
rather obscure. CCN1 has been shown to present opposing
effects on tumor progression, as some data indicates that CCN1
inhibits tumor growth by inducing apoptosis and senescence,
while other reports suggest it promotes tumor growth via the
stimulation of cancer cell proliferation and angiogenesis (198).
In addition, it is known that CCN1 induces senescence by
activating the p16(INK4A)/pRb pathway (198). Interestingly,
TAFs are hyperproliferative cells that express diminished lev-
els of p16(INK4A) (3). Also, p16(INK4A) downregulation in
normal human breast stromal fibroblasts is accompanied by an
increase in ␣-SMA expression, suggesting that absence of
p16(INK4A) could promote myofibroblastic differentiation
(3). Additionally, p16(INK4A)-deficient fibroblasts enhance
xenograft tumor growth compared with effects imparted by
wild-type cells (3). Finally, fibroblasts from oral squamous cell
carcinoma with a p53 and p16(INK4A) inactive background
have been shown to induce the upregulation of ␣-SMA expres-
sion, which correlates with poor patient prognosis (215). All
these data strongly suggest that inactive p16(INK4A) is a
hallmark of TAFs and, therefore, of cancer progression. Re-
garding p53, it has recently been shown that stromal p53
decrease in chronic liver damage promotes tumor development
by a noncell autonomous mechanism that upregulates a tumor
promoting M2 macrophage microenvironmental state (226).
Hence, there is strong possibility that at least two distinctive
populations of TAFs that drive tumorigenesis coexist at the
tumor stroma: a hyperproliferative p16 low population and a
rather quiescent SASP positive and presumably p16 high
population. This type of TAF heterogeneity reveals a high level
of complexity at the tumor-stromal interaction niche, which
requires a better understanding to improve the design of in-
creasingly effective stroma targeting therapeutics.
If one considers the fact that cell death, for example during
injury, causes fibrosis, then another important fact of the
WHFC triad is that some types of fibrotic tissues are often
characterized by regions of cellular death (219, 269, 288),
while, similarly, tumors contain noteworthy areas of necrotic
tissue (226). Cell death is well known to activate an inflam-
Review
234 THE WHFC TRIAD
matory response, which when sustained and prolonged, in turn,
would facilitate both fibrosis and tumorigenesis (35, 195, 389).
Moreover, whether fibrotic myofibroblasts and TAFs are se-
nescent or hyperproliferative, they also must evade stromal cell
clearing mechanisms, such as apoptosis, which promote wound
resolution (Fig. 1). In hypertrophic scars, the presence of
apoptosis-resistant myofibroblasts high in antiapoptotic protein
Bcl-2 has been reported (256). Although the mechanisms
remain unclear, TGF-␤ may induce myofibroblast resistance to
apoptosis (138). Intriguingly, the fact that tumors release a
variety of molecules that can interfere with the immune re-
sponse as well as with NK cell infiltration and activation (209)
suggests the prevalence of an immunosuppressive microenvi-
ronment that may protect fibrotic myofibroblasts and desmo-
plastic TAFs from active NK cell elimination. For example, it
has been shown that TGF-␤ is a potent inhibitor of NK (366).
Although there is not much information about this mechanism
in cancer and specifically on the tumor stroma, research on the
chronic fibrosis field has shown a relationship between the
persistence of myofibroblasts with an immunosuppressed mi-
croenvironment profile (i.e., myofibroblasts attract immune-
suppressive cells) (38, 181, 375). Hence, facilitating the NK
cell-mediated elimination of myofibroblastic and tumoral cells
is expected to be a feasible approach to counteract the WHFC
triad (38).
CONCLUDING REMARKS
Possible Approaches to Clinically Interfere With the WHFC
Triad
Since a convergence between wound healing, cancer, and
fibrosis is compelling, its implications for fibrosis and cancer
treatment are profound. To achieve effective drug delivery, it is
crucial to comprehend the challenge that a fibrotic microenvi-
ronment represents. For example, due to a dense and altered
ECM deposition, the free access for drugs and other molecules,
including glucose and oxygen, is severely impaired in desmo-
plastic malignancies (65). In this context, it is necessary to
develop novel drug delivery strategies to obtain better results
while targeting both fibrosis (to obtain stromal normalization)
and cancer (see Supplemental Table S2). This is true in
particular with regards to carcinomas displaying an intense
desmoplastic reaction such as in pancreatic cancer (263).
Importantly, it is troubling that current approaches aimed at
treating fibrosis and cancer also counteractively promote the
loss of homeostatic equilibrium, which in turn further promotes
the WHFC triad (Fig. 1). For example, surgical procedures and
radiation are effective in resecting and eliminating cancerous
and chronically fibrotic masses. Nevertheless, the same treat-
ments also create wounds that must be healed, hence possibly
further promoting fibrosis and hyperplastic growth (2, 49, 73).
Moreover, while surgery triggers a wound healing response,
chemotherapy also activates the same mechanisms that induce
fibrosis (49, 272). Above we stated that fibrotic disease fuels
cancer progression and vice versa (Fig. 1). Since it is possible
that radiation and chemotherapy-induced fibrosis also stimulate
relapse or latent escape of secondary tumors, a more optimistic
perspective will rely on the use of antifibrotic therapies in
cancer treatments. This approach could have a great impact on
those malignancies where fibrosis constitutes a clear predispo-
sition, such as in the cases of pancreatic or hepatic cell
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carcinomas, where studies have shown promising results tar-
geting and repressing both tumor and stroma (285). These may
offer an advantage when used against cancer, while some
chemotherapies and targeted cancer treatments could also have
great impact on resolving fibrotic chronic diseases. For this we
have put together Supplemental Table S2, which lists some of
the current common WHFC triad treatments under investiga-
tion or in clinical use today.
Reflecting Upon the WHFC Triad
This review attempts to highlight the importance of under-
standing wound healing mechanisms, as a pathway to compre-
hend two subsequent conditions, derived from the persistence
and exacerbation of the healing process. In the absence of
wound resolution, continuous alterations to tissue homeostasis
engage both stroma and epithelia for the onset of chronic
fibrosis and/or cancer. We propose the consolidation of com-
monalities from these three conditions under the concept of the
WHFC triad. In other words, similar mechanisms operate in
this triad to sustain a vicious cycle where a fibrotic stroma
could trigger a malignant behavior of epithelial cells, while the
progression of carcinomas also promotes a fibrotic/desmoplas-
tic stroma fueling the conditions for both (Fig. 1).
The WHFC triad is assembled by common biological re-
sponses from the three described conditions. Several proteins
and signaling pathways encompass a remarkable degree of
overlap amongst wound healing, pathological chronic fibrosis,
and cancer (317). The mentioned players can be clustered
based on their biological mechanisms, in a coagulation/fibri-
nolysis-like response, inflammation signaling processes, as
well as ECM remodeling mechanisms. These biological occur-
rences are responsible for triggering hyperproliferative cell
behavior and phenotypic/activating modifications such as EMT
and myofibroblastic differentiation (Fig. 1 and Supplemental
Table S1).
Specifically for cancer, the WHFC triad constitutes a rather
fertile ground facilitating genetic mutations and epigenetic
hyperplastic occurrences, which eventually constitute the ma-
lignant cell population (91). Moreover, an additional difference
between chronic fibrosis and cancer is that, although both
expand in an immediate field-like effect through the affected
tissue, only cancer is known to metastasize to tissues localized
at considerable distances from the primary lesion, while sec-
ondary neoplastic niches are actively preconditioned to facili-
tate metastatic cancer cell adaptation (120). Importantly, cru-
cial aspects of the WHFC triad that have already started to
receive attention, such as genetic and epigenetic signatures as
well as microRNA profiles (24, 404), although in need of being
fully understood, are already being proposed to serve as pre-
dictors of the outcome of some fibrosis-related malignancies.
Hence, we conclude by stating that a better recognition and a
deeper understanding of the commonalities and disparities
within the WHFC triad will surely provide insights for a more
effective therapeutic targeting of these interconnected pathol-
ogies (Supplemental Table S2).
ACKNOWLEDGMENTS
The authors thank Drs. Kerry Campbell and Sergei Grivennikov from Fox
Chase Cancer Center (FCCC) and Dr. Rebecca Wells from the University of
Pennsylvania for insightful comments during the preparation of this document.

THE WHFC TRIAD
Graphic design was by Perla Ovseiovich from Paralelo 19, Mexico City.
Proofreading was conducted with the help of Ellen Ragan.
Current address for B. Rybinski: JVA Group, Dept. 4, Tumor Microenvi-
ronment, Avondale, PA.
GRANTS
Funding used for the preparation of this manuscript included finances from
the Commonwealth of Pennsylvania, FCCC’s Keystone Program in Personal-
ized Kidney Cancer Therapy, a Nodal Temple-FCCC Award, The Bucks
County Board of Associates, as well as National Cancer Institute Grants
CA-113451 and CA-06927.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
Author contributions: B.R., J.F.-B., and E.C. drafted manuscript; J.F.-B.
and E.C. conception and design of research; J.F.-B. and E.C. prepared figures;
J.F.-B. and E.C. edited and revised manuscript; E.C. approved final version of
manuscript.
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