PERSpECTIVES

and underlying cellular processes that

Heart failure as interstitial cancer: drive HFpEF are not caused by a loss of
cardiomyocytes or focal myocardial injury,
but instead a global process of progressive
emergence of a malignant fibroblast myocardial hypertrophy and, as detailed
further below, pervasive, global fibroblast
phenotype proliferation and development of fibrosis.
In support of the distinct differences
between the HF phenotypes, some therapies
Kelsie E. Oatmen, Elizabeth Cull and Francis G. Spinale have been shown to be effective in patients
Abstract | A prolonged state of left ventricular pressure overload, commonly with HFrEF but not those with HFpEF .
8

Given that HFpEF comprises approximately

caused by hypertension and aortic valve disease, promotes remodelling of the half of all HF diagnoses1, the development
myocardium that can progress to heart failure with preserved ejection fraction of novel strategies to target the underlying
(HFpEF). In animal models, a major factor driving progression from pressure-​ pathophysiology of HFpEF is needed.
overload hypertrophy (POH) to HFpEF is the activation and proliferation of an Although the emergence of an
abnormal fibroblast phenotype that is resistant to apoptosis, degrades normal activated fibroblast population within
the myocardium can be observed in both
stromal matrix and is replaced with a fibrotic matrix structure. A similar fibroblast HFrEF and HFpEF, the stimuli triggering
phenotype has been identified in the stroma of solid cancers. This cancer-​ the two HF phenotypes, biological processes
associated fibroblast drives tumour growth and invasion. The proliferation driving their progression, and subsequent
and expansion of these abnormal fibroblast populations in both HFpEF and effects on cardiac structure and function are
cancer contribute to progression of disease. In early-​phase clinical trials, largely distinct. Specifically, the activated
chemotherapeutic agents targeting cancer-​associated fibroblasts had antitumour fibroblasts observed in HFrEF are part of
the inflammatory reparative process, similar
properties. In this Perspectives article, we postulate that, because the abnormal to that involved in scar formation5,9,10.
fibroblast populations in POH and cancer have identical characteristics, Conversely, preclinical and clinical studies
chemotherapeutic agents targeting the POH-​related fibroblast might attenuate have reported the emergence of a different
the development of myocardial fibrosis, a pathophysiological hallmark of HFpEF. fibroblast phenotype that is involved in
These agents must be designed to target the abnormal fibroblasts with high the development of POH . Specifically, the
11,12

proliferation of these abnormal fibroblasts

specificity because many classes of chemotherapeutic drugs can themselves cause occurs in the absence of myocardial injury
myocardial dysfunction and heart failure.
Heart failure (HF) is a common clinical
syndrome characterized by symptoms
such as shortness of breath, oedema and
fatigue and continues to afflict patients
at near-​epidemic levels . HF is a leading
1
cause of hospitalization and carries a
worse prognosis than most cancers1.
In most forms of cancer, a specific biological the development and progression of these
phenotype drives the therapeutic strategy,
an approach that has yielded substantial
improvements in outcomes2–4. By contrast,
HF has canonically been considered a
generalized disease process in which
therapeutics primarily target pathways that
trigger symptoms rather than targeting the
underlying pathophysiology that drives
the disease. However, the clinical value in
categorizing HF according to phenotype
was eventually recognized, leading to the
emergence of two classifications for HF1.
HF with reduced ejection fraction (HFrEF)
or reparative stimuli and is associated
with progressive and insidious myocardial
is typically caused by ischaemic heart fibrosis (excessive and abnormal matrix
disease, whereas HF with preserved ejection accumulation), increased myocardial
fraction (HFpEF) is typically caused by stiffness and, eventually, progressive diastolic
pressure-​overload hypertrophy (POH) dysfunction — the hallmark of HFpEF13–15.
owing to, for example, hypertension or Importantly, the emergence and expansion
aortic valve disease1. The pathophysiology of an abnormal fibroblast population are
and underlying cellular processes that drive not unique to POH and HFpEF. Abnormal
fibroblasts have also been observed in the
HF phenotypes are distinct. In HFrEF, the stroma of various solid tumours and are
initial stimulus is often an ischaemic event therefore named cancer-​associated fibroblasts
that causes myocardial injury5–7. This injury (CAFs)16–18. Fibroblast transdifferentiation
triggers a robust inflammatory response, has been reported in both HFpEF and
which results in a loss of contractile units cancer, characterized by the conversion of
and mediates a reparative process within relatively quiescent fibroblasts in normal
the injured myocardium. Therefore, the tissue to highly proliferative fibroblasts that
development and progression of HFrEF are resistant to apoptosis and degradation
are attributable to impaired ejection and rapidly replace normal stroma with a
performance that is secondary to a loss pathological matrix structure16,17. For the
of cardiomyocyte mass and changes in purpose of distinguishing between the two
myocardial structure and geometry. fibroblast types, the abnormal fibroblast
In marked contrast, the pathophysiology phenotypes in POH and in cancer will be

Nature Reviews | Cardiology

Perspectives

referred to as the POH fibroblast and
CAF, respectively. POH fibroblasts
and CAFs drive progression of the disease
process by degrading the normal matrix
structure and replacing the matrix with
abnormal components11–18. Modulation
of CAF activity is likely to contribute to
the antitumour effects of many currently
approved chemotherapeutic agents17 and
novel therapeutics developed to target CAFs
that have shown promising outcomes in
clinical trials18. Given the similarities in the
phenotypes of CAFs and POH fibroblasts,
chemotherapeutic agents that target
CAFs might also target POH fibroblasts.
Accordingly, in this Perspectives article, we
provide evidence to support the postulate
that POH fibroblasts and CAFs have the
same molecular signature and biological
function and, therefore, propose the concept
that chemotherapeutic agents might also
therapeutically target POH fibroblasts and
could slow or inhibit disease progression
to HFpEF.
Pathophysiology of POH and HFpEF
The natural history of POH is likely to begin
with a trigger that increases left ventricular
(LV) load, such as hypertension, advanced
age, valvular disease or a combination
of these factors13. Severe or prolonged
LV overload can induce mechanical and
neurohormonal signals to promote adaptive
changes within the myocardium, such as
cardiomyocyte hypertrophy13. This adaptive
response is considered to be initially
beneficial for maintaining cardiac output but
can become detrimental over time, resulting
in increased LV wall thickness and mass.
Cardiomyocytes increase the production
of structural proteins, causing hypertrophic
growth and altered Ca2+ handling and
energy metabolism13. Moreover, POH
fibroblasts expand and proliferate, which
in turn mediates the turnover of normal
matrix proteins and increased accumulation
of collagen and other matrix proteins,
resulting in myocardial stiffness and
impaired relaxation13–15. Together, increased
myocardial stiffness and prolonged active
relaxation ultimately lead to inadequate
LV filling, the hallmark of diastolic
dysfunction13–15. Subsequently, higher LV
filling pressures are required to maintain
cardiac output, which increases the risk
of pulmonary oedema despite a relatively
normal ejection fraction, the defining
presentation of HFpEF13–15.
Abnormal fibroblasts in POH and cancer
Whereas the origin and type of cell
markers that are involved in early
fibroblast transdifferentiation remain
under investigation, POH fibroblasts11,12
and CAFs16–18 are thought to be derived
from changes in the biological phenotype
of resident fibroblasts. Endothelial–
mesenchymal transition and epithelial–
mesenchymal transition might also
contribute to these abnormal fibroblast
populations and constitute an area of active
investigation11–18. Regardless of origin, the
emergence and proliferation of an abnormal
fibroblast phenotype in both POH and
cancer are critical determinants of disease
progression. Of note, the POH fibroblast
and the CAF are not the classical ‘reactive’
fibroblast that emerges as a function of
wound healing and the canonical fibrotic
response. Instead, in POH, quiescent
fibroblasts are replaced by an expanding
and proliferative fibroblast population,
which transforms the myocardial matrix
to an abnormal fibrotic structure. Studies
describing this process are highlighted
in Table 1. Emergence of CAFs is also a
milestone in the progression of various
solid tumours, including those in the breast
and skin16–18. As described above, the POH
fibroblast causes structural changes to the
myocardial matrix that results in stiffening
of the myocardium and progression to
HFpEF13–15. Similarly, solid cancers induce
desmoplastic changes in the surrounding
stroma, which are associated with the
emergence of CAFs16. Given that the altered
fibrotic stroma supports tumour growth and
metastasis, various parallels can be made
between POH fibroblasts and CAFs (Fig. 1).
Molecular signature
One molecular hallmark shared by both
POH fibroblasts and CAFs is the expression
of α-​smooth muscle actin (αSMA). However,
expression of αSMA is not unique to

Table 1 | Preclinical models of PoH indicating the emergence of an abnormal fibroblast phenotype
animal model Parameters measured Major findings refs
Spontaneously Fibroblast gene expression and function Increased fibroblast proliferation rate; increased matrix turnover, 39,45,111,112

hypertensive rat gene expression, and production of ED-​A fibronectin, and

collagen I and collagen III; excessive fibroblast contraction
and increased expression of αSMA
DOCA-​induced Fibroblast gene expression Increased expression of PDGFR, FSP1, αSMA, procollagen I 20

salt-​sensitive and procollagen III

hypertensive rat
Dahl salt-​sensitive Fibroblast gene expression Increased expression of αSMA, periostin, and collagen I 35

hypertensive rat and collagen III

Hypertension in rat Fibroblast gene expression and function, Expression of αSMA, integrin proteins, profibrotic growth 36,40,44

via transverse aortic matrix protein expression and signalling factors and cytokines; increased fibroblast proliferation,
constriction involved in fibroblast transdifferentiation contraction and migration; increased secretion of collagen I,
collagen III and fibronectin; inhibition of TGFβ function led to
reduced fibroblast transdifferentiation and diastolic dysfunction
Hypertension in mice Fibroblast gene expression and function, Increased expression of αSMA and periostin; increased fibroblast 113,114

via transverse aortic matrix protein expression and signalling proliferation and adhesion properties; increased expression of
constriction involved in fibroblast transdifferentiation collagen I
Pulmonary artery Morphological changes in connective Displacement of myocytes by fibroblasts and emergence 115

banding in male New tissue and characterization of fibroblast of αSMA expression

Zealand white rabbits phenotype in POH
Pulmonary artery Matrix protein expression Increased deposition of fibrillary collagens 116

banding in cats
αSMA , α-​smooth muscle actin; DOCA , deoxycorticosterone acetate; ED-​A , extra domain A ; FSP1, fibroblast-​specific protein 1; PDGFR , platelet-​derived growth
factor receptor ; POH, pressure-​overload hypertrophy ; TGFβ, transforming growth factor-​β.

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 Perspectives

these fibroblast phenotypes; αSMA is also Tumour cell CAFs

expressed in contractile-​type fibroblasts a
(myofibroblasts) associated with wound
healing and wound contracture11,12,16,17,19.
Therefore, although the term ‘myofibroblast’
has been used to describe fibroblasts
related to POH and cancer, and despite
POH fibroblasts and CAFs expressing
myofibroblast-​like features, the
colocalization of additional protein markers Liver
and associated biological functions result in
the divergence of these abnormal fibroblasts
from typical fibroblast biology11,12,16,17.
Consequently, a number of protein
markers, including αSMA, should be used
for the purposes of improving specificity
when describing molecular features of the b
fibroblast population (Table 2). Although
the use of any cluster of protein markers
to characterize the biological signature of
different cell types has inherent limitations,
the colocalization of certain protein markers
in POH fibroblasts and CAFs allows
for their identification with reasonable Heart
sensitivity and specificity for the purposes
of this Perspectives article.
In addition to αSMA, POH fibroblasts
and CAFs are associated with increased
expression of the cellular protein markers
fibroblast-​specific protein 1 (FSP1)12,20–23,
POH fibroblasts Fibrillar collagen
platelet-​derived growth factor receptor
(PDGFR)20–22,24 and fibroblast activation Fig. 1 | Parallels in the phenotypes of abnormal fibroblasts in cancer and PoH. a | An important
protein (FAP)12,18,21 as well as the cellular event in the progression of cancer, particularly in the local invasion of solid tumours (such as
matrix proteins periostin, tenascin C23,25 those in the liver), is the destruction of the stroma and extracellular matrix by a population of prolifer-
and the extra domain A variant present ating and activated fibroblasts, defined as the cancer-​associated fibroblast (CAF). b | In the setting of
in fibronectin12,26. The unique molecular chronic pressure-​overload hypertrophy (POH) in the left ventricle, a similar fibroblast phenotype
signature of POH fibroblasts and CAFs emerges, in which proliferation of active fibroblasts causes destruction of normal left ventricular (LV)
myocardial matrix and replacement with excessive and abnormal fibrillar collagen. The increased
directly contributes to malignant fibroblast
collagen content together with other matrix proteins leads to increased stiffness of the LV myocar-
growth and function. dium and thus impaired passive filling. With prolonged POH and the ensuing changes in the LV myo-
cardial matrix, a specific form of heart failure emerges known as heart failure with preserved ejection
Fibroblast function fraction, which is characterized by diastolic dysfunction.
Matrix turnover. Fibroblast proliferation
drives matrix remodelling in both the local
tumour environment and the myocardium gelatinase activity and is therefore likely resistance in some cancers41. Additionally,
in the setting of POH. POH fibroblasts and to degrade matrix products33. FAP is also fibroblast secretion of periostin and tenascin C
CAFs can both degrade the local matrix associated with CAFs and is a marker is associated with increased fibrosis in
structure and replace it with an entirely of increased invasion and metastasis in POH25,35 and with inflammation, fibrosis and
different structure. Matrix degradation is particular cancers34. tumour progression in cancer23,42. Periostin
achieved by fibroblast production of matrix POH fibroblasts and CAFs replace secreted by CAFs also facilitates adhesion and
metalloproteinases (MMPs). Specifically, the degraded matrix with various migration of isolated tumour cells43. Together,
MMP2, MMP3 and MMP9 degrade the abnormal matrix products, including these findings demonstrate that both POH
basement membrane to initiate cancer fibrillary collagens20,35–38. Deposition fibroblasts and CAFs drive pathological
cell invasion and metastasis27. Higher of fibrillar collagens I and III increase matrix remodelling that contributes to the
levels of MMP2 and MMP9 are associated myocardial stiffness in POH13–15. Fibrillar progression of HFpEF and the malignancy
with increased tumour aggressiveness28, collagens also stiffen the matrix in cancer of particular cancers, respectively.
and higher levels of MMP9, MMP11 and stroma and provide a scaffold for tumour cell
MMP13 correlate with a shorter relapse-​free migration, invasion and metastasis37,38. Contraction and migration. The contractile
period29. In both preclinical and clinical POH fibroblasts and CAFs also secrete extra properties of fibroblasts in the setting of
studies of POH, MMP2 (ref.30), MMP9 domain A fibronectin, which triggers the POH and cancer are dependent on the
(ref.31) and MMP14 (ref.32) are associated activation of transforming growth factor-​β expression of αSMA11,12,16,17. Furthermore,
with reduced indices of LV function. (TGFβ)39,40, a potent stimulus of cardiac integrin expression promotes cell adhesion
Moreover, the serine protease FAP has hypertrophy, and promotes tamoxifen and facilitates fibroblast migration11,37,44.

Nature Reviews | Cardiology

Perspectives

Table 2 | Markers of PoH fibroblasts and CaFs and growth factors. In models of POH,
fibroblast secretion of IL-1 (ref.49), IL-6
Protein location Marker refs for PoH refs for CaFs (ref.44), TGFβ44 and basic fibroblast
fibroblasts
growth factor (bFGF)50 directly promotes
Cell-​surface marker FAP 7 13,16,29
hypertrophy and impairs cardiomyocyte
FSP1 7 16–18
Ca2+ handling. Similarly, CAFs secrete
PDGFR 19 16,18 growth factors such as TGFβ and vascular
endothelial growth factor (VEGF), which
DDR2 7,19 117
directly promote survival, proliferation and
Intracellular proteins αSMA 19,105 13,17,18
cell cycle progression of cancer cells as well
Vimentin 7,19 18,21
as angiogenesis51,52.
Matrix components ED-​A fibronectin 7 21 Growth factors and inflammatory
Periostin 37,106 38 cytokines promote the development
and proliferation of POH and cancer
Tenascin C 20,a 18
fibroblasts in an autocrine-​mediated
αSMA , α-​smooth muscle actin; CAF, cancer-​associated fibroblast; ED-​A , extra domain A ; DDR2, discoidin fashion. For example, TGFβ stimulation
domain receptor 2; FAP, fibroblast activation protein; FSP1, fibroblast-​specific protein 1; PDGFR , platelet-​
derived growth factor receptor ; POH, pressure-​overload hypertrophy. aModels of POH induced by further upregulates TGFβ production and
mechanical strain or neurohormonal hypertrophic stress. secretion in both POH fibroblasts and
CAFs53–55. Similarly, inflammatory cytokines
In POH, the localized mechanical forces associated with invasion by cancer cells and such as IL-6 and IL-1 further upregulate
generated by fibroblast contraction metastasis, but the underlying mechanisms POH fibroblast and CAF expression of
can contribute to impaired diastolic involved are unclear. However, fibroblast inflammatory cytokines56–58. Taken together,
performance45 and activate latent TGFβ acquisition of contractile properties is well autocrine and paracrine signalling directly
expression46. In cancer, CAFs can contract to known to drive disease progression in both promotes the emergence of POH and cancer
create tunnels through the matrix, forming POH and cancer. fibroblasts, which alters the local tissue
pathways for tumour cells to invade and environment and contributes to disease
metastasize47. Invasion by tumour cells is Upregulation of growth factors and progression.
further promoted by mechanical pressure inflammatory cytokines. POH fibroblasts
from CAFs48. Expression of tenascin C23, and CAFs upregulate the production and Fibroblast regulation
FSP1 (ref.22) and PDGFR22 has also been secretion of inflammatory cytokines Numerous pathways are involved in
the development and regulation of POH
Inflammatory cytokines Vasoactive peptides fibroblasts and CAFs. The signalling
Growth factors Mechanical stimuli pathways that are particularly relevant
to current or emerging investigational
• Pirfenidone chemotherapeutics are described below.
• TGFβ monoclonal
antibody
↑ TGFβ
• TGFβ receptor inhibitor TGFβ signalling. TGFβ signalling is
• TGFβ vaccine
• Trihydroxyphenolics potentiated by various signalling pathways
• Fasudil common to both POH and cancer.
• Lipid lipoxin A4 Canonical Non-canonical • Itraconazole The vasoactive peptides endothelin 1 and
• JQ1
• Tranilast (SMADs) (kinases)
• Retinoic acid angiotensin II are likely to promote the
• SOM230 fibroblast phenotype in POH and cancer
by activating growth factor pathways, most
• 5-Fluorouracil Activation and • 5-Fluorouracil notably TGFβ pathways59–62. The mechanical
• FAK inhibitors proliferation • Adenosine receptor environment also influences TGFβ levels
• FGFR inhibitors antagonists
• Heat shock protein • Bortezomib as compression from cancerous tumours63
inhibitors • Carflizomib and tissue rigidity in POH64 activate
• Nab-paclitaxel • Cisplatin latent TGFβ in the local matrix. Similar
• NT157 • FAP inhibitors
• PG-S3-001 • FGFR inhibitors positive-feedback loops between fibroblasts
• Sonic hedgehog • Gemcitabine and surrounding cells potentiate TGFβ and
inhibitors • Nab-paclitaxel
• Navitoclax thereby promote the persistence of the
• PG-S3-001 abnormal fibroblast phenotype. TGFβ
Quiescent CAF maintenance secreted by the POH fibroblasts and CAFs
fibroblast and survival stimulates cardiomyocytes53 and tumour
cells54,55, respectively, to upregulate TGFβ
Fig. 2 | regulation of the abnormal fibroblast by TgFβ. Transforming growth factor-​β (TGFβ) path- expression. Additional growth factors65,66
ways are central to the expansion and proliferation of an abnormal fibroblast population in cancer.
and inflammatory cytokines56 released
Numerous cytokines, growth factors, vasoactive peptides and mechanical stimuli are involved in
TGFβ-​mediated activation and proliferation of cancer-​associated fibroblasts (CAFs). Furthermore, into the myocardial interstitium and
numerous mechanisms can be targeted by chemotherapeutic agents in cancer, including TGFβ sig- cancer microenvironment also potentiate
nalling, canonical and non-​canonical signalling pathways, and fibroblast function, proliferation and TGFβ signalling and thereby promote the
survival. FAK, focal adhesion kinase; FAP, fibroblast activation protein; FGFR, fibroblast growth factor continued proliferation and activation of
receptor; SMAD, mothers against decapentaplegic homologue. POH and cancer fibroblasts.

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 Perspectives

Table 3 | Clinical status and preliminary outcomes of chemotherapeutic drugs targeting CaFs
agent or CaF Target or mechanism Clinical status Preliminary outcomes refs
target pathway of intervention
Currently approved chemotherapies that potentially target CAFs
Nab-​paclitaxel Microtubule inhibitor Treatment of breast cancer, lung cancer Antitumour effects, reduced CAF density 82

and pancreatic cancer and deposition of fibrillary collagen in

breast cancer stroma
5-Fluorouracil Antimetabolite Treatment of gastric cancers, breast cancer Reduced drug resistance in tumour cells 84

and skin cancer by eliminating and reprogramming CAFs

Cisplatin Alkylating agent Treatment of NSCLC, bladder cancer, Induced CAF apoptosis but correlation 79,93,118

gynaecological cancers, testicular cancer, with tumour regression was variable

and head and neck cancers
Gemcitabine Antimetabolite Treatment of breast cancer, lung cancer, Induced CAF apoptosis 80

ovarian cancer and pancreatic cancer

Bortezomib and Proteasome inhibitors Treatment of haematological malignancies Induced CAF apoptosis 81

carfilzomib
Investigational agents developed to target CAFs
TGFβ TGFβ receptor inhibitor Phase I and II trials in glioblastoma, NSCLC, Trend towards increased survival 85

hepatocellular carcinoma and pancreatic

adenocarcinoma
Monoclonal antibody Phase I and II trials in NSCLC, metastatic Evidence of antitumour activity 85,119

breast cancer and renal cell carcinoma

Vaccination Phase I, II and III trials for NSCLC, Ewing Trend towards increased survival 85,120,121

sarcoma, melanoma, colorectal carcinoma, and increased relapse-​free survival

ovarian cancer, glioblastoma and astrocytoma
FAP Monoclonal antibody Phase I and II trials in metastatic colon cancer Well tolerated; no improvement in 90,122,123

and other FAP cancers objective tumour measurements

Enzymatic inhibition Phase II trials in metastatic colon cancer Minimal antitumour activity and no 90

and NSCLC evidence of increased activity when

administered with docetaxel in NSCLC
FGFR Tyrosine kinase inhibitors Phase II trials in biliary carcinomas and other Evidence of antitumour activity 87,88

(ponatinib and BGJ398) solid and haematological malignancies

CAF, cancer-​associated fibroblast; FAP, fibroblast activation protein; FGFR , fibroblast growth factor receptor ; NSCLC, non-​small cell lung cancer ; TGFβ, transforming
growth factor-​β.

In both POH and cancer, TGFβ regulates
fibroblast gene expression through both
canonical and non-​canonical pathways,
thereby contributing to the protein
expression profiles of the fibroblasts
outlined in Table 2. TGFβ receptor type l
(TGFβR1) interacts with mothers against
decapentaplegic homologue (SMAD)
pathways, whereas the non-​canonical
pathway involves TGFβR2 activation of
various kinases to regulate fibroblast gene
transcription67 (Fig. 2). Using in vitro models
of POH, fibroblasts exposed to TGFβ show
increased αSMA expression and collagen
production68. Additionally, inhibition of the
TGFβ pathways in a preclinical model of
POH reduced POH fibroblast proliferation,
collagen deposition and fibrosis, which
subsequently resulted in improved cardiac
performance36. Similarly, TGFβ induced
the expression of αSMA in cultured
fibroblasts in various models of cancer54,55,
whereas inhibition of TGFβ prevented
fibroblast expression of αSMA and FAP69.
CAFs exposed to TGFβ also showed
increased matrix remodelling and collagen
deposition38.
Growth factors and inflammatory cytokines.
As mentioned above, TGFβ has a central
role in the emergence and proliferation
of the POH and cancer fibroblasts, but
additional growth factors might also be
involved in this process. For example,
PDGF can improve CAF survival by
promoting proliferation and angiogenesis
of the tumour stroma70. Additionally, bFGF
induced αSMA expression and collagen
deposition of stromal cells in a model of
breast cancer71 and can also maintain the
CAF phenotype by promoting fibroblast
proliferation and migration as well as
prevent CAF apoptosis71. Similarly, bFGF
is upregulated in clinical models of POH
and is associated with severe fibrosis and
deposition of fibrillary collagens50. Findings
from an in vitro study suggest that bFGF
can stimulate POH fibroblast proliferation72
and expression of αSMA73. Furthermore,
hepatic growth factor74 and VEGF75 can also
promote the CAF phenotype.
Maintenance of the inflammatory
environment by these growth factors
might contribute to the persistence of the
abnormal fibroblast phenotype. Studies
using various cancer cell lines have
shown that IL-6 can upregulate fibroblast
expression of αSMA76 and FAP56. IL-6
further promotes the CAF phenotype by
upregulating fibroblast secretion of IL-6
and TGFβ56,76. Similarly, IL-1α perpetuates
the inflammatory environment in both
cancer58 and POH57 by promoting fibroblast
proliferation and secretion of inflammatory
cytokines. Studies using mouse models
have also demonstrated that IL-4 promotes
the survival of POH fibroblasts77 and that
IL-18 promotes the deposition of fibrillary
collagens78. Taken together, both growth
factors and inflammatory cytokines are
likely to contribute to the emergence and
maintenance of POH and cancer fibroblasts.
Chemotherapeutic agents
Targeting CAFs
Chemotherapeutic agents that have shown
clinical antitumour activity by influencing
CAF protein expression or viability are
outlined in Table 3. Figure 2 shows the
potential mechanisms by which various
clinical and investigatory therapies can
target CAFs. Several well-​established

Nature Reviews | Cardiology

Perspectives

chemotherapeutic agents might exert
antitumour effects by modifying CAFs.
Cisplatin (an alkylating agent)79, gemcitabine
(an antimetabolite)80, and bortezomib
and carfilzomib (proteasome inhibitors)81
have been shown to induce apoptosis of
CAFs in both disease models and patients
with cancer. Nab-​paclitaxel, a microtubule
inhibitor, exerts antitumour effects in
patients with pancreatic cancer that were
associated with reduced CAFs and fibrillary
collagens82. Furthermore, nab-​paclitaxel
blocked CAF secretion of IL-6 in vitro,
which reduced cancer cell migration
and invasion83. The antimetabolite
5-flurouracil similarly reduced CAF density
in preclinical trials84.
Therapies designed specifically to target
CAFs are currently under investigation
in both preclinical models and clinical
trials, including agents that target
TGFβR pathways. The TGFβR1 inhibitor
galunisertib prevented the expression αSMA
and FAP in fibroblasts exposed to TGFβ
in vitro69. Subsequently, a phase II study has
shown that TGFβR1 inhibitors increased
survival in patients with pancreatic or
hepatocellular cancer85. Anti-​TGFβ
antibodies have also shown antitumour
effects and are associated with reduced
αSMA expression in cultured CAFs86.
Ponatinib and BGJ398, both bFGF receptor
inhibitors, induced CAF senescence in vitro
and have shown promising antitumour
activity in phase II clinical trials87,88.
A multitude of agents targeting FAP are
also under investigation. Anti-​FAP
antibodies prevented CAF migration and
invasion in vitro89, but clinical studies with
FAP monoclonal antibodies have yet to show
antitumour properties90. However, agents
inhibiting FAP enzymatic activity have
shown antitumour activity in clinical trials90,
probably by reducing CAF expression, as
demonstrated in preclinical studies91.
The complex pathways regulating CAFs
represent numerous potential therapeutic
targets, many of which are now being
explored in vitro. A comprehensive list
of in vitro studies that aim to repurpose
currently approved agents or identify new
strategies to target CAFs are presented in
Table 4. Of note, many of these agents alter
TGFβ signalling pathways, which in turn
will affect the emergence and persistence
of CAFs. Although trihydroxyphenolic
compounds92 and pirfenidone, approved for
idiopathic pulmonary fibrosis93, probably
act at the level of TGFβ, others regulate
canonical or non-​canonical signalling

Table 4 | Pharmacological agents and investigatory molecules targeting CAFs in in vitro studies
Pharmacological agent or molecule Target CaF outcomes refs
Drugs that disrupt TGFβ signalling
Fasudil ROCK1 kinase Reduced fibroblast αSMA expression 97

Itraconazole S6 and MAPK inhibition Inhibited CAF growth and secretion 96

JQ1 MAPK/ERK signalling Reduced fibroblast αSMA expression, suppressed 124

matrix deposition, and decreased cytokine and growth

factor secretion
Lipid lipoxin A4 SMAD signalling Prevented fibroblast expression of αSMA in the 95

presence of TGFβ and reduced collagen content

Pirfenidone TGFβ antagonist Induced CAF apoptosis and reduced collagen content 93

Retinoic acid MAPK inhibition Reduced fibroblast expression of αSMA, FAP and IL-6 125

Somatostatin analogue SOM230 Inhibition of mTOR pathways Inhibited CAF protein synthesis 126

Tranilast SMAD signalling Prevented fibroblast expression of αSMA in the 94

presence of TGFβ
Trihydroxyphenolic compounds TGFβR1 kinase Prevented fibroblast expression of αSMA in the 92

presence of TGFβ and reduced collagen content

Drugs that disrupt growth factor signalling
Imatinib PDGFR kinase inhibitor Reduced CAF proliferation 99

MEDI-575 PDGFR monoclonal antibody Reduced CAF proliferation and deposition of collagen 100

NT157 Inhibit IGF1R and STAT3 Reduced fibroblast expression of αSMA, fibrillary 127

collagen and inflammatory cytokines

Nintedanib Inhibit kinase activity of VEGFR, Reduced fibroblast expression of αSMA and fibrillary 98

PDGFR and FGFR collagen

PD173074 FGFR inhibitor Reduced CAF proliferation 128

PG-​S3-001 Activate STAT3 inhibitor Reduced CAF survival and proliferation 129

Drugs that target other pathways

Dipalmitoyl-​radicicol and 17-DMAG Inhibit heat shock protein 90 Reduced CAF migration and contractility 130

GDC-0449, cyclopamine and vismodegib Inhibit sonic hedgehog signalling Reduced fibroblast αSMA and collagen expression 101,131,132

LOXL2 and PF-562,271 Inhibit FAK signalling Reduced fibroblast αSMA expression and migration 102,133

Navitoclax BCL-2 inhibitor Induced CAF apoptosis 102

SCH58261 and ZM241385 Adenosine receptor antagonist Induced CAF apoptosis 93

αSMA , α smooth muscle actin; BCL-2, B cell lymphoma 2; CAF, cancer-​associated fibroblast; ERK , extracellular signal-​regulated kinase; FAK , focal adhesion kinase;
FAP, fibroblast activation protein; FGFR , fibroblast growth factor receptor ; IGF1R , insulin-​like growth factor 1 receptor; MAPK , mitogen-​activated protein kinase;
mTOR , mechanistic target of rapamycin; PDGFR , platelet-​derived growth factor receptor ; ROCK1, Rho kinase 1; SMAD, mothers against decapentaplegic
homologue; STAT3, signal transducer and activator of transcription 3; TGFβ, transforming growth factor-​β; TGFβR1, transforming growth factor-​β receptor 1;
VEGFR , vascular endothelial growth factor receptor.

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pathways further downstream of TGFβ.
For example, tranilast, an antiallergy
drug94, and lipoxin A4, an endogenous
bioactivity lipid95, prevented fibroblast
expression of αSMA by inhibiting SMAD
pathways, whereas the antifungal drug
itraconazole96 and the vasodilatating
agent fasudil97 inhibited fibroblast
expression by regulating kinase signalling.
Inhibitors of PDGF kinase activity, such
as nintedanib and imatinib, reduced
αSMA expression, CAF proliferation and
fibrillar collagens in vitro98,99. Similarly, a
PDGFR monoclonal antibody, MEDI-575,
reduced CAF proliferation and collagen
deposition100. Several in vitro studies
have also demonstrated the potential of
targeting CAFs via alternative signalling
pathways, including sonic hedgehog101 and
focal adhesion kinase pathways102. Target
specificity for the emerging fibroblast is of
critical importance given that other classes
of chemotherapeutic agents can themselves
cause myocardial dysfunction and HF103–105.
For example, a strong causal link has been
described between anthracycline therapy
and the development of a cardiomyopathy
that can result in systolic failure and
HFrEF103,105. Chemotherapeutic drugs
targeting growth factor receptors, such as
human epidermal growth factor receptor 2,
can also induce cardiotoxic effects104,105.
Finally, other chemotherapeutic agents,
such as nintedanib, might also have adverse
effects in patients with cardiovascular
disease106. Future research efforts are needed
to improve the specificity of drugs targeting
POH fibroblasts to minimize adverse effects.
Potential targets for POH and HFpEF
Given that a number of approved and
investigational chemotherapeutic drugs
have shown antitumour activity by
targeting CAFs, we predict that targeting
the development and viability of POH
fibroblasts could halt disease progression
to HFpEF. The transition of a normal
fibroblast to the aberrant, proliferating
POH fibroblast is unlikely to be a binary
process but instead a continuum whereby
the fibroblast progressively becomes more
abnormal in POH through to HFpEF
(Fig. 3). Accordingly, imaging and biomarker
diagnostic tools will need to be developed
to identify relevant transition points for
the emergence and proliferation of POH
fibroblasts and to determine the appropriate
time point for the administration of possible
chemotherapeutic agents. A valuable
next step in exploring the potential of
chemotherapeutic agents to treat POH and
HFpEF will be to investigate the specificity
Nature Reviews | Cardiology
Perspectives
Normal fibroblast HFpEF fibroblast
Fig. 3 | abnormal growth and proliferation of fibroblasts in pressure-​overload hypertrophy.
In the normal myocardium on the left-​hand side of the figure, fibroblasts contribute to a steady-​state
turnover and maintenance of the extracellular matrix. On the right-​hand side of the figure, the devel-
opment and progression of heart failure secondary to a pressure-​overload stimulus causes prolifera-
tion of abnormal cardiac fibroblasts, which are similar in phenotype to the cancer-​associated
fibroblasts. This abnormal fibroblast, the pressure-​overload hypertrophy fibroblast, causes degradation
of the normal myocardial matrix architecture and is progressively replaced by a thickened fibrotic
weave, which in turn impairs ventricular performance. Impairment in diastolic filling is a fundamental
physiological finding in heart failure with preserved ejection fraction (HFpEF).
of the aforementioned chemotherapeutic Conclusions
agents that target CAFs. These currently HFpEF is a distinct form of HF characterized
approved chemotherapeutic agents that by abnormal growth and expansion of the
target CAFs clearly influence cells and myocardial interstitium and the emergence
tissues beyond the cancer stroma, as of an aberrant fibroblast population. HFpEF
demonstrated by the adverse effects on fibroblasts are proliferative, resistant to
multiple organ systems including the apoptosis and contribute to an abnormal
cardiovascular system107. Characterizing the overgrowth of the myocardial matrix. Given
adverse effects of these agents for various that a fundamental physiological feature
modes of delivery in disease models of of HFpEF is resistance to passive filling,
POH would also be of benefit. Moreover, HFpEF fibroblasts are thought to contribute
studies of investigational agents that to disease initiation and progression.
target specific CAF pathways need to be POH-induced HFpEF fibroblasts and
conducted using cardiac fibroblasts and CAFs share many similarities. Accordingly,
preclinical models of POH. For example, therapeutic strategies targeting CAFs might
previous studies evaluating these or similar also be relevant for HFpEF. Specifically, a
agents have predominantly used noncardiac number of chemotherapeutics that target
fibroblasts, such as dermal myofibroblasts108 CAFs might potentially be ‘repurposed’
or pulmonary fibroblasts109. Furthermore, to be used to blunt the development and
many preclinical studies targeting fibroblasts progression of HFpEF.
in POH use highly specific mechanisms, Kelsie E. Oatmen1,2,3, Elizabeth Cull4,5 and
such as inhibiting bFGF pathways by using Francis G. Spinale1,2,3*
transgenic bFGF-​deficient mice, which 1
Cardiovascular Translational Research Center,
resulted in the attenuation of cardiac University of South Carolina School of Medicine,
fibrosis after aortic banding110. However, Columbia, SC, USA.
chemotherapeutic agents targeting bFGF are 2
Department of Cell Biology and Anatomy, University of
less specific than genetic modifications, and South Carolina School of Medicine, Columbia, SC, USA.
outcomes and adverse effects are likely to be 3
Columbia VA Health Care System, Columbia, SC, USA.
different. Taken together, studies exploring Prisma Health AYA Oncology Program, Greenville
4
the specific mechanisms and outcomes Memorial Medical Campus, Greenville, SC, USA.
of the presented agents on POH fibroblasts 5
University of South Carolina School of Medicine
are necessary next steps in the development Greenville, Greenville, SC, USA.
of chemotherapeutic strategies to interrupt *e-​mail: cvctrc@uscmed.sc.edu
the development and progression of https://doi.org/10.1038/s41569-019-0286-y
POH-induced HFpEF. Published online xx xx xxxx
Perspectives
1. Mozaffarian, D. et al. Heart disease and stroke
statistics — 2016 update: a report from the American
Heart Association. Circulation 133, e38–e360
(2016).
2. Baselga, J. Clinical trials of herceptin (trastuzumab).
Eur. J. Cancer 37, S18–S24 (2001).
3. Fisher, B. et al. A randomized clinical trial evaluating
tamoxifen in the treatment of patients with node-​
negative breast cancer who have estrogen-​receptor-
positive tumors. N. Engl. J. Med. 320, 479–484
(1989).
4. Yang, Y. Cancer immunotherapy: harnessing the
immune system to battle cancer. J. Clin. Invest. 125,
3335–3337 (2015).
5. Prabhu, S. D. & Frangogiannis, N. G. The biological
basis for cardiac repair after myocardial infarction:
from inflammation to fibrosis. Circ. Res. 119, 91–112
(2016).
6. Westman, P. C. et al. Inflammation as a driver
of adverse left ventricular remodeling after acute
myocardial infarction. J. Am. Coll. Cardiol. 67,
2050–2060 (2016).
7. D’Elia, N., D’hooge, J. & Marwick, T. H. Association
between myocardial mechanics and ischemic LV
remodeling. JACC Cardiovasc. Imaging 8, 1430–1443
(2015).
8. Poppe, K. K. & Doughty, R. N. Outcomes in patients
with heart failure with preserved ejection fraction.
Heart Fail. Clin. 10, 503–510 (2014).
9. Huet, E. et al. Stroma in normal and cancer wound
healing. FEBS J. 286, 2909–2920 (2019).
10. Bainbridge, P. Wound healing and the role of
fibroblasts. J. Wound Care. 22, 410–412 (2013).
11. Joshua, G. Cardiac fibrosis: the fibroblast awakens.
Circ. Res. 118, 1021–1040 (2016).
12. Moore-​Morris, T., Guimarães-​Camboa, N., Yutzey, K. E.,
Pucéat, M. & Evans, S. M. Cardiac fibroblasts: from
development to heart failure. J. Mol. Med. 93,
823–830 (2015).
13. Frohlich, E. D. & Susic, D. Pressure overload.
Heart Fail. Clin. 8, 21–32 (2012).
14. Creemers, E. E. & Pinto, Y. M. Molecular mechanisms
that control interstitial fibrosis in the pressure-​
overloaded heart. Cardiovasc. Res. 89, 265–272
(2011).
15. Spinale, F. G. Myocardial matrix remodeling and the
matrix metalloproteinases: influence on cardiac form
and function. Physiol. Rev. 87, 1285–1342 (2007).
16. Heneberg, P. Paracrine tumor signaling induces
transdifferentiation of surrounding fibroblasts.
Crit. Rev. Oncol. Hematol. 97, 303–311 (2016).
17. LeBleu, V. S. & Kalluri, R. A peek into cancer-​
associated fibroblasts: origins, functions and
translational impact. Dis. Model. Mech. 11,
dmm029447 (2018).
18. Kakarla, S., Song, X. T. & Gottschalk, S. Cancer
associated fibroblast as targets for immunotherapy.
Immunotherapy 4, 1129–1138 (2012).
19. Ellis, S., Lin, E. J. & Tartar, D. Immunology of wound
healing. Curr. Dermatol. Rep. 7, 350–358 (2018).
20. Fan, B. et al. Role of PDGFs/PDGFRs signaling
pathway in myocardial fibrosis of DOCA/salt
hypertensive rats. Int. J. Clin. Exp. Pathol. 7, 16–27
(2013).
21. Park, C. K., Jung, W. H. & Koo, J. S. Expression of
cancer-​associated fibroblast-​related proteins differs
between invasive lobular carcinoma and invasive
ductal carcinoma. Breast Cancer Res. Treat. 159,
55–69 (2016).
22. Zhang, X. F. et al. Expression pattern of cancer-​
associated fibroblast and its clinical relevance in
intrahepatic cholangiocarcinoma. Hum. Pathol. 65,
92–100 (2017).
23. Ni, W. D. et al. Tenascin-​C is a potential cancer-​
associated fibroblasts marker and predicts poor
prognosis in prostate cancer. Biochem. Biophys.
Res. Commun. 486, 607–612 (2017).
24. Ali, S. R. et al. Developmental heterogeneity of cardiac
fibroblasts does not predict pathological proliferation
and activation. Circ. Res. 115, 625–635 (2014).
25. Shimojo, N. Tenascin-​C may accelerate cardiac fibrosis
by activating macrophages via the integrin αVβ3/
nuclear factor-​κB/interleukin-6 axis. Hypertension 66,
757–766 (2015).
26. Huang, L., Xu, A. M., Liu, S., Liu, W. & Li, T. J.
Cancer-​associated fibroblasts in digestive tumors.
World J. Gastroenterol. 20, 17804–17818 (2014).
27. Taddei, M. L., Giannoni, E., Comito, G. & Chiarugi, P.
Microenvironment and tumor cell plasticity: an easy
way out. Cancer Lett. 341, 80–96 (2013).
28. Koontongkaew, S. The tumor microenvironment
contribution to development, growth, invasion
and metastasis of head and neck squamous cell
carcinomas. J. Cancer 4, 66–83 (2013).
29. Paulsson, J. & Micke, P. Prognostic relevance
of cancer-​associated fibroblasts in human cancer.
Semin. Cancer Biol. 25, 61–68 (2014).
30. Zile, M. R. et al. Plasma biomarkers that reflect
determinants of matrix composition identify the
presence of left ventricular hypertrophy and diastolic
heart failure. Circ. Heart Fail. 4, 246–256 (2011).
31. Chen, R., Xue, J. & Xie, M. Osthole regulates TGF-​β1
and MMP-2/9 expressions via activation of PPARα/γ
in cultured mouse cardiac fibroblasts stimulated with
angiotensin II. J. Pharm. Pharm. Sci. 16, 732–741
(2013).
32. Polyakova, V., Hein, S., Kostin, S., Ziegelhoeffer, T. &
Schaper, J. Matrix metalloproteinases and their tissue
inhibitors in pressure-​overloaded human myocardium
during heart failure progression. J. Am. Coll. Cardiol.
44, 1609–1618 (2004).
33. Tillmanns, J. et al. Fibroblast activation protein
alpha expression identifies activated fibroblasts
after myocardial infarction. J. Mol. Cell Cardiol. 87,
194–203 (2015).
34. Zi, F. et al. Fibroblast activation protein α in tumor
microenvironment: recent progression and implications
(review). Mol. Med. Rep. 11, 3203–3211 (2015).
35. Wu, H. et al. Periostin expression induced by oxidative
stress contributes to myocardial fibrosis in a rat model
of high salt-​induced hypertension. Mol. Med. Rep. 14,
776–782 (2016).
36. Kuwahara, F. et al. Transforming growth factor-​beta
function blocking prevents myocardial fibrosis and
diastolic dysfunction in pressure-​overloaded rats.
Circulation 106, 130–135 (2002).
37. Levental, K. R. et al. Matrix crosslinking forces tumor
progression by enhancing integrin signaling. Kandice
R. Cell. 139, 891–906 (2009).
38. Stanisavljevic, J. et al. Snail1-expressing fibroblasts
in the tumor microenvironment display mechanical
properties that support metastasis. Cancer Res. 75,
284–295 (2015).
39. Philips, N., Bashey, R. I. & Jimenez, S. A. Collagen
and fibronectin expression in cardiac fibroblasts from
hypertensive rats. Cardiovasc. Res. 28, 1342–1347
(1994).
40. Grimm, D. et al. Extracellular matrix proteins in
cardiac fibroblasts derived from rat hearts with
chronic pressure overload: effects of beta-​receptor
blockade. J. Mol. Cell. Cardiol. 33, 487–501 (2001).
41. Pontiggia, O. et al. The tumor microenvironment
modulates tamoxifen resistance in breast cancer:
a role for soluble stromal factors and fibronectin
through β1 integrin. Breast Cancer Res. Treat. 133,
459–471 (2012).
42. Ratajczak-​Wielgomas, K. et al. Periostin expression
in cancer-​associated fibroblasts of invasive ductal
breast carcinoma. Oncol. Rep. 36, 2745–2754
(2016).
43. Underwood, T. J. et al. Cancer-​associated fibroblasts
predict poor outcome and promote periostin-​
dependent invasion in oesophageal adenocarcinoma.
J. Pathol. 235, 466–477 (2015).
44. Stewart, J. A. Jr. et al. Temporal alterations in cardiac
fibroblast function following induction of pressure
overload. Cell Tissue Res. 340, 117–126 (2010).
45. Marganski, W. A., De Biase, V. M., Burgess, M. L.
& Dembo, M. Demonstration of altered contractile
activity in hypertensive heart disease. Cardiovasc. Res.
60, 547–556 (2003).
46. Wipff, P. J., Rifkin, D. B., Meister, J. J. & Hinz, B.
Myofibroblast contraction activates latent TGF-​beta1
from the extracellular matrix. J. Cell. Biol. 179,
1311–1323 (2007).
47. Brentnall, T. A. Arousal of cancer-​associated stromal
fibroblasts: palladin-​activated fibroblasts promote
tumor invasion. Cell Adh. Migr. 6, 488–494 (2012).
48. Karagiannis, G. S. et al. Cancer-​associated fibroblasts
drive the progression of metastasis through both
paracrine and mechanical pressure on cancer tissue.
Mol. Cancer Res. 10, 1403–1418 (2012).
49. Porter, K. E. & Turner, N. A. Cardiac fibroblasts:
at the heart of myocardial remodeling. Pharmacol. Ther.
123, 255–278 (2009).
50. He, Z. Y., Feng, B., Yang, S. L. & Luo, H. L. Intracardiac
basic fibroblast growth factor and transforming growth
factor-​beta 1 mRNA and their proteins expression
level in patients with pressure or volume-​overload
right or left ventricular hypertrophy. Acta Cardiol. 60,
21–25 (2005).
51. Luo, H., Tu, G., Liu, Z. & Liu, M. Cancer-​associated
fibroblasts: a multifaceted driver of breast cancer
progression. Cancer Lett. 361, 155–163 (2015).
52. Yang, J. Vascular mimicry formation is promoted
by paracrine TGF-​β and SDF1 of cancer-​associated
fibroblasts and inhibited by miR-101 in hepatocellular
carcinoma. Cancer Lett. 383, 18–27 (2016).
53. Fujiu, K. & Nagai, R. Fibroblast-​mediated pathways in
cardiac hypertrophy. J. Mol. Cell Cardiol. 70, 64–73
(2014).
54. Grubisha, M. J., Cifuentes, M. E., Hammes, S. R.
& Defranco, D. B. A local paracrine and endocrine
network involving TGFbeta: Cox-2, ROS, and
estrogen receptor beta influences reactive stromal
cell regulation of prostate cancer cell motility.
Mol. Endocrinol. 26, 940–954 (2012).
55. Hawinkels, L. J. et al. Interaction with colon cancer
cells hyperactivates TGF-​beta signaling in cancer-​
associated fibroblasts. Oncogene 33, 97–107 (2014).
56. Hendrayani, S. F., Al-​Harbi, B., Al-​Ansari, M. M.,
Silva, G. & Aboussekhra, A. The inflammatory/cancer-​
related IL-6/STAT3/NF-​κB positive feedback loop
includes AUF1 and maintains the active state of
breast myofibroblasts. Oncotarget 7, 41974–41985
(2016).
57. Turner, N. A. et al. Interleukin-1alpha stimulates
proinflammatory cytokine expression in human
cardiac myofibroblasts. Am. J. Physiol. Heart Circ.
Physiol. 297, H1117–H1127 (2009).
58. Tjomsland, V. et al. Interleukin 1α sustains the
expression of inflammatory factors in human
pancreatic cancer microenvironment by targeting
cancer-​associated fibroblasts. Neoplasia 13,
664–675 (2011).
59. Phosri, S. et al. Stimulation of adenosine a2b receptor
inhibits endothelin-1-induced cardiac fibroblast
proliferation and α-​smooth muscle actin synthesis
through the cAMP/Epac/PI3K/Akt-​signaling pathway.
Front. Pharmacol. 8, 428 (2017).
60. Lijnen, P. J., Petrov, V. V. & Fagard, R. H. Induction of
cardiac fibrosis by angiotensin II. Methods Find Exp.
Clin. Pharmacol. 22, 709–723 (2000).
61. Hinsley, E. E., Kumar, S., Hunter, K. D., Whawell, S. A.
& Lambert, D. W. Endothelin-1 stimulates oral
fibroblasts to promote oral cancer invasion. Life Sci.
91, 557–561 (2012).
62. Fujita, M. et al. Angiotensin type 1a receptor signaling-​
dependent induction of vascular endothelial growth
factor in stroma is relevant to tumor-​associated
angiogenesis and tumor growth. Carcinogenesis. 26,
271–279 (2005).
63. Zhang, K. et al. Mechanical signals regulate and
activate SNAIL1 protein to control the fibrogenic
response of cancer-​associated fibroblasts. J. Cell Sci.
129, 1989–2002 (2016).
64. Wang, J., Chen, H., Seth, A. & McCulloch, C. A.
Mechanical force regulation of myofibroblast
differentiation in cardiac fibroblasts. Am. J. Physiol.
Heart Circ. Physiol. 285, H1871–H1881 (2003).
65. Cadamuro, M. Platelet-​derived growth factor-​D
and Rho GTPases regulate recruitment of cancer-​
associated fibroblasts in cholangiocarcinoma.
Hepatology. 58, 1042–1053 (2013).
66. Liao, C. H. Cardiac mast cells cause atrial fibrillation
through PDGF-​A-mediated fibrosis in pressure-​
overloaded mouse hearts. J. Clin. Invest. 120,
242–253 (2010).
67. Leask, A. & Abraham, D. J. TGF-​beta signaling and the
fibrotic response. FASEB J. 18, 816–827 (2004).
68. Lijnen, P. & Petrov, V. Transforming growth factor-​beta
1-induced collagen production in cultures of cardiac
fibroblasts is the result of the appearance of
myofibroblasts. Methods Find. Exp. Clin. Pharmacol.
24, 333–344 (2002).
69. Liu, F. L. et al. Autophagy is involved in TGF-​β1-induced
protective mechanisms and formation of cancer-​
associated fibroblasts phenotype in tumor
microenvironment. Oncotarget 7, 4122–4141 (2016).
70. Skobe, M. & Fusenig, N. E. Tumorigenic conversion of
immortal human keratinocytes through stromal cell
activation. Proc. Natl Acad. Sci. USA 95, 1050–1055
(1998).
71. Hao, J., Ding, X. L., Yang, X. & Wu, X. Z. Prunella
vulgaris polysaccharide inhibits growth and migration
of breast carcinoma-​associated fibroblasts by
suppressing expression of basic fibroblast growth
factor. Chin. J. Integr. Med. https://doi.org/10.1007/
s11655-016-2587-x (2016).
72. Virag, J. A. et al. Fibroblast growth factor-2
regulates myocardial infarct repair: effects on cell
proliferation, scar contraction, and ventricular
function. Am. J. Pathol. 171, 1431–1440 (2007).
73. Santiago, J. J. et al. Cardiac fibroblast to
myofibroblast differentiation in vivo and in vitro:
expression of focal adhesion components in neonatal
www.nature.com/nrcardio

and adult rat ventricular myofibroblasts. Dev. Dyn.
239, 1573–1584 (2010).
74. Wu, X. Hepatocyte growth factor activates tumor
stromal fibroblasts to promote tumorigenesis in
gastric cancer. Cancer Lett. 335, 128–135 (2013).
75. Shen, H. Reprogramming of normal fibroblasts into
cancer-​associated fibroblasts by miRNAs-​mediated
CCL2/VEGFA signaling. PLOS Genet. 12, e1006244
(2016).
76. Giannoni, E. et al. Reciprocal activation of prostate
cancer cells and cancer-​associated fibroblasts
stimulates epithelial–mesenchymal transition and
cancer stemness. Cancer Res. 70, 6945–6956
(2010).
77. Kanellakis, P., Ditiatkovski, M., Kostolias, G. & Bobik, A.
A pro-​fibrotic role for interleukin-4 in cardiac pressure
overload. Cardiovasc. Res. 95, 77–85 (2012).
78. Yu, Q. et al. IL-18 induction of osteopontin mediates
cardiac fibrosis and diastolic dysfunction in mice.
Am. J. Physiol. Heart Circ. Physiol. 297, H76–H85
(2009).
79. Schmid, J. O. et al. Cancer cells cue the p53 response
of cancer-​associated fibroblasts to cisplatin. Cancer Res.
72, 5824–5832 (2012).
80. Cham, K. K. et al. Metronomic gemcitabine
suppresses tumour growth, improves perfusion,
and reduces hypoxia in human pancreatic ductal
adenocarcinoma. Br. J. Cancer 103, 52–60 (2010).
81. Lee, H. M. et al. Drug repurposing screening identifies
bortezomib and panobinostat as drugs targeting
cancer associated fibroblasts (CAFs) by synergistic
induction of apoptosis. Invest. New Drugs 36,
545–560 (2018).
82. Alvarez, R. et al. Stromal disrupting effects of nab-​
paclitaxel in pancreatic cancer. Br. J. Cancer 109,
926–933 (2013).
83. Feng, R. et al. Nab-​paclitaxel interrupts cancer-​
stromal interaction through c-​x-c motif chemokine
10-mediated interleukin-6 downregulation in vitro.
Cancer Sci. 109, 2509–2519 (2018).
84. Ma, Y. et al. Extreme low dose of 5-fluorouracil
reverses MDR in cancer by sensitizing cancer
associated fibroblasts and down-​regulating P-​gp.
PLOS ONE 12, e0180023 (2017).
85. de Gramont, A., Faivre, S. & Raymond, E. Novel TGF-​β
inhibitors ready for prime time in onco-​immunology.
Oncoimmunology 6, e1257453 (2016).
86. Fuyuhiro, Y. et al. Upregulation of cancer-​associated
myofibroblasts by TGF-​β from scirrhous gastric
carcinoma cells. Br. J. Cancer 105, 996–1001 (2011).
87. Katoh, M. FGFR inhibitors: effects on cancer cells,
tumor microenvironment and whole-​body homeostasis
(review). Int. J. Mol. Med. 38, 3–15 (2016).
88. Procopio, M. G. et al. Combined CSL and p53
downregulation promotes cancer-​associated fibroblast
activation. Nat. Cell Biol. 17, 1193–1204 (2015).
89. Teichgräber, V. et al. Specific inhibition of fibroblast
activation protein (FAP)-alpha prevents tumor
progression in vitro. Adv. Med. Sci. 60, 264–272
(2015).
90. Liu, R., Li, H., Liu, L., Yu, J. & Ren, X. Fibroblast
activation protein: a potential therapeutic target
in cancer. Cancer Biol. Ther. 13, 123–129 (2012).
91. Li, M. et al. Targeting of cancer-​associated fibroblasts
enhances the efficacy of cancer chemotherapy by
regulating the tumor microenvironment. Mol. Med. Rep.
13, 2476–2484 (2016).
92. Wei, Y. et al. Fibroblast-​specific inhibition of TGF-​β1
signaling attenuates lung and tumor fibrosis. J. Clin.
Invest. 127, 3675–3688 (2017).
93. Mediavilla-​Varela, M., Boateng, K., Noyes, D. &
Antonia, S. J. The anti-​fibrotic agent pirfenidone
synergizes with cisplatin in killing tumor cells and cancer-​
associated fibroblasts. BMC Cancer 16, 176 (2016).
94. Saito, H. et al. Importance of human peritoneal
mesothelial cells in the progression, fibrosis, and
control of gastric cancer: inhibition of growth
and fibrosis by tranilast. Cancer 21, 55–67 (2018).
95. Schnittert, J., Heinrich, M. A., Kuninty, P. R., Storm, G.
& Prakash, J. Reprogramming tumor stroma using an
endogenous lipid lipoxin A4 to treat pancreatic cancer.
Cancer Lett. 420, 247–258 (2018).
96. Hara, M., Nagasaki, T., Shiga, K. & Takeyama, H.
Suppression of cancer-​associated fibroblasts and
endothelial cells by itraconazole in bevacizumab-​
resistant gastrointestinal cancer. Anticancer Res. 36,
169–177 (2016).
97. Whatcott, C. J. et al. Inhibition of ROCK1 kinase
modulates both tumor cells and stromal fibroblasts
in pancreatic cancer. PLoS One 12, e0183871 (2017).
Nature Reviews | Cardiology
98. Gabasa, M., Ikemori, R., Hilberg, F., Reguart, N.
& Alcaraz, J. Nintedanib selectively inhibits the
activation and tumour-​promoting effects of fibroblasts
from lung adenocarcinoma patients. Br. J. Cancer
117, 1128–1138 (2017).
99. Kinoshita, K. et al. Imatinib mesylate inhibits the
proliferation-​stimulating effect of human lung cancer-​
associated stromal fibroblasts on lung cancer cells.
Int. J. Oncol. 37, 869–877 (2010).
100. Laing, N. et al. Inhibition of platelet-​derived growth
factor receptor α by MEDI-575 reduces tumor growth
and stromal fibroblast content in a model of non-​small
cell lung cancer. Mol. Pharmacol. 83, 1247–1256
(2013).
101. Mpekris, F. et al. Sonic-​hedgehog pathway inhibition
normalizes desmoplastic tumor microenvironment to
improve chemo- and nanotherapy. J. Control. Release
261, 105–112 (2017).
102. Stokes, J. B. et al. Inhibition of focal adhesion kinase
by PF-562,271 inhibits the growth and metastasis of
pancreatic cancer concomitant with altering the tumor
microenvironment. Mol. Cancer Ther. 10, 2135–2145
(2011).
103. Babiker, H. M. et al. Cardiotoxic effects of
chemotherapy: a review of both cytotoxic and
molecular targeted oncology therapies and their
effect on the cardiovascular system. Crit. Rev. Oncol.
Hematol. 126, 186–200 (2018).
104. Nemeth, B. T., Varga, Z. V., Wu, W. J. & Pacher, P.
Trastuzumab cardiotoxicity: from clinical trials
to experimental studies. Br. J. Pharmacol. 174,
3727–3748 (2017).
105. Shah, C. P. & Moreb, J. S. Cardiotoxicity due to
targeted anticancer agents: a growing challenge.
Ther. Adv. Cardiovasc. Dis. 13, 1753944719843435
(2019).
106. Hajari, C. A. & Johnson, P. Clinical use of nintedanib in
patients with idiopathic pulmonary fibrosis. BMJ Open
Respir. Res. 4, e000192 (2017).
107. Jensen, S. A. & Sørensen, J. B. Risk factors and
prevention of cardiotoxicity induced by 5-fluorouracil
or capecitabine. Cancer Chemother. Pharmacol. 58,
487–493 (2006).
108. Mifková, A. et al. Synthetic polyamine BPA-​C8 inhibits
TGF-​β1-mediated conversion of human dermal
fibroblast to myofibroblasts and establishment
of galectin-1-rich extracellular matrix in vitro.
Chembiochem 15, 1465–1470 (2014).
109. Daniels, C. E. et al. Imatinib mesylate inhibits the
profibrogenic activity of TGF-​beta and prevents
bleomycin-​mediated lung fibrosis. J. Clin. Invest. 114,
1308–1316 (2004).
110. Schultz, J. E. Fibroblast growth factor-2 mediates
pressure-​induced hypertrophic response. J. Clin. Invest.
104, 709–719 (1999).
111. Millanvoye, E. et al. Growth rate and phospholipase C
activity in cardiac and aortic spontaneously
hypertensive rat cells. J. Hypertens. Suppl. 6,
S369–S371 (1988).
112. Klett, C. P., Palmer, A., Gallagher, A. M.,
Rioseco-​Camacho, N. & Printz, M. P. Differences in
cultured cardiac fibroblast populations isolated from
SHR and WKY rats. Clin. Exp. Pharmacol. Physiol.
Suppl. 22, S265–S267 (1995).
113. Oka, T. et al. Genetic manipulation of periostin
expression reveals a role in cardiac hypertrophy
and ventricular remodeling. Circ. Res. 101, 313–321
(2007).
114. Xia, Y. et al. Endogenous thrombospondin 1 protects
the pressure-​overloaded myocardium by modulating
fibroblast phenotype and matrix metabolism.
Hypertension 58, 902–911 (2011).
115. Leslie, K. O., Taatjes, D. J., Schwarz, J., vonTurkovich,
M. & Low, R. B. Cardiac myofibroblasts express alpha
smooth muscle actin during right ventricular pressure
overload in the rabbit. Am. J. Pathol. 139, 207–216
(1991).
116. Baicu, C. F. et al. Time course of right ventricular
pressure-​overload induced myocardial fibrosis:
relationship to changes in fibroblast post-​synthetic
procollagen processing. Am. J. Physiol. Heart Circ.
Physiol. 303, H1128–H1134 (2012).
117. Corsa, C. A. The action of discoidin domain receptor 2
in basal tumor cells and stromal cancer-​associated
fibroblasts is critical for breast cancer metastasis.
Cell Rep. 15, 2510–2523 (2016).
118. Sonnenberg, M. et al. Highly variable response to
cytotoxic chemotherapy in carcinoma-​associated
fibroblasts (CAFs) from lung and breast. BMC Cancer
8, 364 (2008).
Perspectives
119. Morris, J. C. et al. Phase I study of GC1008
(fresolimumab): a human anti-​transforming growth
factor-​beta (TGFβ) monoclonal antibody in patients
with advanced malignant melanoma or renal cell
carcinoma. PLOS ONE 9, e90353 (2014).
120. Rijavec, E. et al. Belagenpumatucel-​L for the treatment
of non-​small cell lung cancer. Expert. Opin. Biol. Ther.
15, 1371–1379 (2015).
121. Nemunaitis, J. et al. Summary of bi-​shRNA/GM-​CSF
augmented autologous tumor cell immunotherapy
(FANG™) in advanced cancer of the liver. Oncology 87,
21–29 (2014).
122. Scott, A. M. et al. A phase I dose-​escalation study
of sibrotuzumab in patients with advanced or
metastatic fibroblast activation protein-​positive
cancer. Clin. Cancer Res. 9, 1639–1647 (2003).
123. Welt, S. et al. Antibody targeting in metastatic colon
cancer: a phase I study of monoclonal antibody F19
against a cell-​surface protein of reactive tumor stromal
fibroblasts. J. Clin. Oncol. 12, 1193–1203 (1994).
124. Yamamoto, K. et al. Stromal remodeling by the BET
bromodomain inhibitor JQ1 suppresses the
progression of human pancreatic cancer. Oncotarget
7, 61469–61484 (2016).
125. Guan, J. et al. Retinoic acid inhibits pancreatic cancer
cell migration and EMT through the downregulation of
IL-6 in cancer associated fibroblast cells. Cancer Lett.
345, 132–139 (2014).
126. Moatassim-​Billah, S. et al. Anti-​metastatic potential of
somatostatin analog SOM230: indirect pharmacological
targeting of pancreatic cancer-​associated fibroblasts.
Oncotarget 7, 41584–41598 (2016).
127. Sanchez-​Lopez, E. et al. Targeting colorectal cancer
via its microenvironment by inhibiting IGF-1
receptor-​insulin receptor substrate and STAT3
signaling. Oncogene 35, 2634–2644 (2016).
128. Sweeny, L. et al. Inhibition of fibroblasts reduced head
and neck cancer growth by targeting fibroblast growth
factor receptor. Laryngoscope 122, 1539–1544
(2012).
129. Arpin, C. C. et al. Applying small molecule signal
transducer and activator of transcription-3 (STAT3)
protein inhibitors as pancreatic cancer therapeutics.
Mol. Cancer Ther. 15, 794–805 (2016).
130. Chang, J. et al. Pre-​clinical evaluation of small
molecule LOXL2 inhibitors in breast cancer.
Oncotarget 8, 26066–26078 (2017).
131. Wang, L. et al. Terminating the criminal collaboration
in pancreatic cancer: nanoparticle-​based synergistic
therapy for overcoming fibroblast-​induced drug
resistance. Biomaterials 144, 105–118 (2017).
132. Zhao, J. et al. Simultaneous inhibition of hedgehog
signaling and tumor proliferation remodels stroma
and enhances pancreatic cancer therapy. Biomaterials
159, 215–228 (2018).
133. Henke, A. et al. Reduced contractility and motility of
prostatic cancer-​associated fibroblasts after inhibition
of heat shock protein 90. Cancers (Basel) 8, E77
(2016).
Acknowledgements
The authors are supported by the National Heart, Lung, and
Blood Institute of the National Institutes of Health under
award numbers R01HL130972 and 3R01HL130972-
01A1S1 and a Merit Award from the Veterans Affairs Health
Administration. The content is solely the responsibility of the
authors and does not necessarily represent the official views
of the National Institutes of Health or the Veterans Affairs
Health Administration. The authors thank R. Sargent,
Sargent Illustration & Design, LLC, and S. Riffle, University of
South Carolina School of Medicine, for assistance with
the figures.
Author contributions
K.E.O. and F.G.S. made substantial contributions to research-
ing data for the article, discussions of content and the writing
of the manuscript. All the authors reviewed and edited the
manuscript before submission.
Competing interests
The authors declare no competing interests.
Peer review information
Nature Reviews Cardiology thanks I. Dixon, Z. Kassiri and the
other, anonymous, reviewer(s) for their contribution to the peer
review of this work.
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