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Cell Biol Toxicol (2019) 35:407–421
/Published online: 24 January 2019
REVIEW
Current perspectives of cancer-associated fibroblast
in therapeutic resistance: potential mechanism and future
strategy
Dhruba Kadel &Yu Zhang &Hao-Ran Sun &Yue Zhao &
Qiong-Zhu Dong &Lun-xiu Qin
Received: 12 September 2018/Revised: 15 December 2018 /Accepted: 3 January 2019
#The Author(s) 2019
Abstract The goal of cancer eradication has been
overshadowed despite the continuous improvement in
research and generation of novel cancer therapeutic
drugs. One of the undeniable existing problems is drug
resistance due to which the paradigm of killing all
cancer cells is ineffective. Tumor microenvironment
plays a crucial role in inducing drug resistance besides
cancer development and progression. Recently, many
efforts have been devoted to understand the role of
tumor microenvironment in cancer drug resistance as it
provides the shelter, nutrition, and paracrine niche for
cancer cells. Cancer-associated fibroblasts (CAFs), one
major component of tumor microenvironment, reside in
symbiotic relationship with cancer cells, supporting
them to survive from cancer drugs. The present review
summarizes the recent understandings in the role of
CAFs in drug resistance in various tumors. Acknowl-
edging the fact that drug resistance depends not only
upon cancer cells but also upon the microenvironment
niche could guide us to formulate novel cancer drugs
and provide the optimal cancer treatment.
Keywords Cancer-associated fibroblast .Drug
resistance
Introduction
Various studies have already identified that the nature of
tumor does depend not only upon the malignant cancer-
ous cells themselves but also to their microenvironment
components (Kalluri 2003). The constituents of tumor
microenvironment provide the shelter as well as para-
crine niche for cancer cells that fuel the neoplastic
growth. It functions as safeguard to tumor cells either
by providing the mechanical support or secreting vari-
ous factors evading the therapeutic effect. The role of
microenvironment in promoting tumor growth and me-
tastasis has been studied to some extent in various
cancers (Kalluri and Zeisberg 2006;Lietal.2007;
Tlsty and Coussens 2006) but its role in anti-cancer
therapeutic resistance is still poorly understood
(Shekhar et al. 2007;McMillinetal.2010;Wangetal.
2009). Tumor microenvironment comprised of both
pro-tumorigenic and anti-tumorigenic components such
as stromal cells (normal fibroblasts, cancer-associated
fibroblast (CAFs), immune inflammatory cells, endo-
thelial cells, pericytes, bone marrow-derived cells, etc.),
structural elements of extracellular matrix (ECM), and
soluble factors (such as cytokines, growth factors) (Li
https://doi.org/10.1007/s10565-019-09461-z
D. Kadel :Y. Zhang :H.<R. Sun :Y. Z ha o :Q.<Z. Dong :
L.<x. Qin (*)
Department of General Surgery, Huashan Hospital & Cancer
Metastasis Institute, Fudan University, 12 Urumqi Road (M),
Shanghai 200040, China
e-mail: qinlx@fudan.edu.cn
D. Kadel :Y. Zhang :H.<R. Sun :Y. Z ha o :Q.<Z. Dong :
L.<x. Qin
Cancer Metastasis institute, Fudan University, Shanghai 200040,
China
Q.<Z. Dong (*):L.<x. Qin
Institute of Biomedical Sciences, Fudan University, 131 Dong An
Road, Shanghai 200032, China
e-mail: qzhdong@fudan.edu.cn
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
et al. 2007; Tlsty and Coussens 2006;QuailandJoyce
2013). Recent researches have suggested that these ele-
ments interact with tumor cells as well as with each
other forming a complex crosstalk network and create
either tumor-prone or tumor-suppressive microenviron-
ment, although the involved molecular mechanism is
not well understood (Quail and Joyce 2013;
Grivennikov et al. 2010; Palucka and Coussens 2016).
CAFs constitute major proportion of non-neoplastic
stromal compartment in various human tumors. Various
researches have suggested that they are capable of mod-
ulating tumor cells by forming the communication net-
work with cancer cells or with other elements and hence
susceptible to cancer drug resistance (Orimo and
Wein berg 2006; Mueller and Fusenig 2004). So, focus-
ing on both cancer cells and CAFs might provide some
new hints for cancer treatment. Here we review the role
of CAFs in cancer drug resistance, underlying molecular
mechanisms as well as the approached strategies to
overcome the potential resistance induced by CAFs.
Origin and markers of CAFs
CAFs should be considered as the structural and func-
tional alteration rather than cell type variation. Under the
various intrinsic or extrinsic influential factors, structur-
al and functional modifications on progenitor cells oc-
cur, which, to our current knowledge, are known as
CAFs. The progenitor states are transformed to CAFs
during the tumor progression, and some of the well-
known progenitors are resident fibroblast and immune
cells (Kojima et al. 2010;Erezetal.2010), bone
marrow-derived mesenchymal stem cells (Mishra et al.
2008;Quanteetal.2011;Spaethetal.2009;Jeonetal.
2008; Direkze et al. 2004), epithelial cells (Kalluri and
Neilson 2003), endothelial cells (Zeisberg et al. 2007),
hepatic stellate cells (Yin and Evason 2013), and pan-
creatic stellate cells (Jaster 2004). Cancerous cells attract
bone marrow-derived MSCs to the tumor microenviron-
ment and convert them into CAF-like myofibroblastic
phenotype (Mishra et al. 2008; Bergfeld and Declerck
2010). These structurally altered CAFs, which formerly
recognized as MSCs, then support tumor cell survival
and angiogenesis, possess immunomodulatory function,
and lead to drug resistance (Bergfeld and Declerck
2010). Moreover, the well-known resident fibroblasts
of pancreas, pancreatic stellate cells, exhibit vitamin A
containing lipid droplets in its quiescent state. Once
communicated with tumor cells become activated and
loose the vitamin A reserving potential, which then
display contractile and secretory phenotype. The secre-
tory function of these activated pancreatic stellate cells
favors tumor survival (McCarroll et al. 2006).
CAFs are predominantly composed of activated fi-
broblast, but also with less amount of non-activated
fibroblast (Shimoda et al. 2010; Hanahan and
Coussens 2012). The activated fibroblast population in
CAFs is identified by their expression of specific
markers such as α-smooth muscle actin (α-SMA),
vimentin, desmin, fibroblast activation protein (FAP)
(Mueller and Fusenig 2004), fibroblast specific protein
(FSP) (Strutz et al. 1995), platelet-derived growth factor
receptor (PDGFR) (Pietras et al. 2003), secreted protein
acidic and rich in cystein (SPARC), chondroitin sulfate
proteoglycan (Sugimoto et al. 2006), prolyl-4 hydroxy-
lase (Kojima et al. 2010), periostin (Malanchi et al.
2012), integrin alpha 11 (Zeltz and Gullberg 2016),
and tenascin C (De Wever et al. 2004), where the ex-
pression of these markers varies from one cell to anoth-
er, suggesting the existence of heterogenic population of
CAFs. Among these markers, α-SMA showed large
labeling pattern and has long been accepted as the most
reliable marker for identifying activated fibroblast in
CAFs (Sugimoto et al. 2006). On the other hand, pro-
genitor states lack α-SMA expression and are trans-
formed to α-SMA-positive CAFs via cancer cell-
derived growth factors such as transforming growth
factor-β(TGF-β)(Orimoetal.2005), platelet-derived
growth factor (PDGF) and fibroblast growth factor-2
(FGF-2) (Elenbaas and Weinberg 2001), Wnt7a
(Avgustinova et al. 2016), sonic hedgehog (Shh)
(Bailey et al. 2008), and exosomes (Paggetti et al.
2015; Webber et al. 2015). In contrast, there is evidence
that leukemia inhibitory factor (LIF), a member of the
interleukin-6 (IL-6) pro-inflammatory cytokine family,
can transform progenitor state to pro-invasive fibroblast
independently of α-SMA expression (Albrengues et al.
2014).
Thus, the progenitor and quiescent precursor of
CAFs contributes favorable tumor microenvironment
to some extent for tumor survival when acquires pheno-
typic variation (Fig. 1). The tumor-promoting properties
of CAFs such as proliferation, angiogenesis, invasion,
and metastasis are regulated by various signaling path-
ways that include stromal cell-derived factor-1 (SDF-
1)-[C-X-C] chemokine receptor-4 (CXCR4) and
TGF-β-Smad2/3 (Kojima et al. 2010), JAK1/STAT3
(Albrengues et al. 2014; Sanz-Moreno et al. 2011;
408 Cell Biol Toxicol (2019) 35:407–421
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Albrengues et al. 2015), interleukin-1β(IL-1β)-nuclear
factor kappa B (NF-κβ) (Erez et al. 2010), PDGF-
PDGFR (Elenbaas and Weinberg 2001;Shaoetal.
2000), Yes-associated protein/Tafazzin (YAP/TAZ)
(Dupont et al. 2011; Calvo et al. 2013), Shh-
Smoothened (Smo) (Bailey et al. 2008), P62-mTORC1
(Valencia et al. 2014), loss of Timp gene (Khokha et al.
2013), and global hypomethylation of genomic DNA
(Hu et al. 2005; Jiang et al. 2008).
CAFs in tumor suppression
Even though pro-tumorigenic properties of CAFs have
been revealed by numerous studies, the inefficacy of
stromal targeted therapies in several preclinical studies
have raised the doubt in clinical application. A signifi-
cant number of possible explanations have been put
forwarded,and the interesting but insufficient evidences
suggested the possibility of tumor-suppressive function
of CAFs. The long-term administration of hedgehog
(Hh) inhibitor in genetically engineered pancreatic duc-
tal adenocarcinoma (PDAC) and chemically induced
bladder cancer mice model showed reduction in stromal
contents consequently promoting tumor growth and
malignancy, which indicated stromal cells function as
tumor suppression (Rhim et al. 2014;Shinetal.2014).
This finding was also supported by other study showing
that the depletion of CAFs resulted in suppressed im-
mune surveillance with increased CD4+FoxP3+ Tregs
and led to invasive, poorly differentiated, and enhanced
stemness of cancer cells experimented in PDAC mice
model (Özdemir et al. 2014). Contradictory to many
previous studies, a recent study verified that presence
of higher number of FAP+ CAFs (> 100/high-power
field) in PDAC stromal cells is associated with
prolonged survival (Park et al. 2017). Similarly, the
other study revealed the mechanism of CAFs in tumor
suppression via Slit2-Robo1-mediated suppression of
PI3K/AKT/β-catenin pathway in breast cancer cell lines
(Chang et al. 2012). Another example of tumor-
suppressive function of CAFs is that the deletion of
nuclear factor kappa B kinase subunit β(IKKβ)in
murine model of colitis-associated tumorigenesis result-
ed in neoangiogenesis and tumor progression showing
the tumor-suppressive role of IKKβ(Pallangyo et al.
2015); however, opposite results were shown in the
same model by other research group (Koliaraki et al.
2015). The contradictory results observed in two differ-
ent studies with similar model could be explained as (1)
IKKβwas deleted in type-I-collagen fibroblast by the
first research group and in type-VI-collagen fibroblast
by the latter one; (2) besides genetic background of the
mice, timing of IKKβdeletion and (3) existence of
heterogeneous fibroblast subpopulation in tumor stroma
might play a role in different findings (Wagner 2016).
Inconsistent outcomes of CAFs in pro- and anti-
tumorigenicity might be due to its wide sources as well
as diversity in its secretory function and establishing
different communication network with tumor cells.
The origin of CAFs determining its nature could be
illustrated as CD271+. Pancreatic stellate cells showed
anti-tumorigenic properties (Fujiwara et al. 2012)while
CD10+ pancreatic stellate cells were identified as pro-
tumorigenic nature (Ikenaga et al. 2010). Whereas the
secretory function characterizing CAFs was also shown
by various studies. One study verified the dual function
of periostin secreted by CAFs as its slight overexpres-
sion significantly reduced epithelial-mesenchymal tran-
sition (EMT), whereas higher overexpression enhanced
EMT in human pancreatic cells (Kanno et al. 2008).
Moreover, one of the major ECM factors secreted by
CAFs is hyaluronan (HA), whose role in cancer has
been studied well. Large number of clinical analysis
have shown that tumor progression and poor outcome
in various cancers is associated with higher accumula-
tion of HA either in stroma or in tumor parenchyma (Wu
et al. 2017; Turley et al. 2016;Satoetal.2016;Chanmee
et al. 2016; Bourguignon et al. 2017). Studies have
shown that CAFs secreted HA played crucial role in
migratory interaction of CAFs and tumor cells. So, the
mitogenic properties of highly motile CAFs are based
on HA concentration (Costea et al. 2013). Apart from
promoting CAF motility, a major susceptible factor for
cancer supporting role of HA might be its participation
in EMT program. Studies have shown that HA accumu-
lation either by HAS3 overexpression or by hypoxia
inducible factor-1α(HIF-1α) leads to induction of
EMT (Zhang et al. 2013; Misra et al. 2008; Kultti
et al. 2014; Gao et al. 2005). However, some recent
studies have recognized HA as tumor-suppressing stro-
mal component (Bohaumilitzky et al. 2017;Fisher
2015; Triggs-Raine 2015;Tianetal.2013). The cancer
resistance properties of HAwere first noted in naked rat
mole, where authors observed that naked rat mole fibro-
blasts secreted extremely high molecular mass HA, cells
possessed higher affinity to HA signaling, and HA-
degrading enzyme showed less activities (Tian et al.
2013). The elaborative study pointed that high
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molecular HA has ability to hypersensitize cells to con-
tact inhibition and stimulate p16 (INK4a locus) expres-
sion resulting in cell cycle arrest (Tian et al. 2015).
Consistent to this, another study revealed that excess
HA production was found to be associated with inhibi-
tion to G1-S transition in cell cycle rather than acting as
tumorigenesis (Bharadwaj et al. 2011). Supporting to
this, hyaluronidase showed tumor growth suppression
and facilitated cancer drug treatment (Wong et al. 2017;
Melanie and Simpson 2008). These observations can
conclude that high-weight HA with less tendency for
degradation could provide the cancer resistance
properties.
The dynamic nature of CAFs during the cancer pro-
gression focuses on further need for discussion to rec-
ognize it as friend or foe. In author’s view, categorizing
the specific subpopulation of CAFs would more pre-
cisely characterize their role in cancer environment. A
study identified two distinct subpopulations of CAFs as
inflammatory fibroblast (iCAFs) and myofibroblast
(myCAFs), where they observed that myCAFs lack
tumor-promoting chemokines and cytokines (Öhlund
et al. 2017). Furthermore, another study also identified
the two distinct subpopulation of stromal types based on
gene expression as normal (expressing high CAF
markers such as α-SMA, vimentin, and desmin) and
activated (expressing more gene-related macrophage)
stroma (Moffitt et al. 2015), as shown in Fig. 2.This
can hypothesize that normal stromal cell can be
considered as good stroma and may show tumor-
suppressive function. Combining the aforementioned
studies, a detail study can be carried out to identify if
good stroma only secretes high molecular mass HA.
Thus, it alarms the preservation of tumor-suppressing
stromal cells when generating stromal-targeted therapies
for cancer treatment.
Roles of CAFs in drug resistance
Drug resistance via revascularization and reactivating
MAPK and Akt
One of the problems in eradication of cancer is the drug
resistance. Tumor cells follow different paths to become
resistance to cancer treatment depending upon the in-
trinsic properties or external stimuli from microenviron-
ment (Hata et al. 2016). Many researchers are focusing
on various external stimuli from tumor microenviron-
ment inducing drug resistance. Numerous studies have
tried to explore the role of stromal cells, especially
fibroblasts and CAFs in drug resistance in different
tumors (Straussman et al. 2012; Mao et al. 2013;
Paraiso and Smalley 2013). Majority of studies have
proven that the secretory function of CAFs, which es-
tablishes the crosstalk with tumor cells, is responsible
for drug resistance. One study revealed that CAFs ex-
tracted from anti-VEGF resistance murine lymphoma
Fig. 1 Heterogeneous origin of CAFs and its markers. Cancer-
associated fibroblasts are originated from various sources, which
are in quiescent state and convert into CAFs after communicating
with malignant cells and express different markers differentiating
from its progenitor state
410 Cell Biol Toxicol (2019) 35:407–421
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cell line (EL4) could effectively resist the anti-VEGF
therapy in otherwise sensitive murine myeloma cell line
(TIB6) via platelet-derived growth factor-C (PDGF-C)
mediation (Crawford et al. 2009). Authors observed the
upregulation of PDGF-C in CAFs and hence inducing
the revascularization, which ultimately led to anti-
angiogenic therapy resistance. Most of the patients treat-
ed with anti-angiogenesis such as sorafenib, sunitinib,
and bevacizumab appeared to be low/no response after
certain period of treatment with only modest benefit in
clinical outcomes (Jayson et al. 2016). This could sug-
gest that there might be morphologic and functional
changes of CAFs after exposure to anti-angiogenic treat-
ment recreating the angiogenic environment and becom-
ingrefractorytodrugtherapy.Anotherexperiment
showed that stromal fibroblast could induce resistance
to epidermal growth factor receptor (EGFR) tyrosine
kinase inhibitors via hepatocyte growth factor (HGF)
mediated crosstalk between tumor cells and stromal
cells in lung cancer (Wang et al. 2009). Furthermore,
the study carried out in tumor microenvironment in-
duced drug resistance showed that various BRAF mu-
tated melanoma and ERBB2+ breast cancer cell lines
when co-cultured with different fibroblasts affected the
sensitivity to vemurafenib and lapatinib, respectively,
via HGF/c-MET pathway (Straussman et al. 2012). This
result was alsosupported by another study revealing that
most cancer cells could be rescued from drug by simply
exposing to one or more receptor tyrosine kinase (RTK)
ligands (Wilson et al. 2012). It is well known that HGF/
c-MET signaling activates MAPK cascades enhancing
cancer cell proliferation and Akt cascades increasing the
anti-apoptotic effects, which could eventually increase
the drug tolerance capacity in various cancers (Xiao
et al. 2001).
Drug resistance in hypoxic environment
Many studies have pointed out the ability of CAFs to
modulate drug sensitivity in hypoxic environment.
CAFs secrete different angiogenic factors and promi-
nent one being the VEGF, whose production is even
increased in hypoxic state (Beckermann et al. 2008;
Masamune et al. 2008). However, a recently published
study verified that endothelial cell sprouting was ob-
served more with hypoxic CAFs even upon blocking
VEGFA, which indicated presence of other angiogenic
agent (Kugeratski et al. 2016). Further study on proteo-
mic analysisof hypoxic CAFs revealed the upregulation
of proteins related to glycolysis and downregulation of
proteins related to mitochondrial metabolism. A detail
study is needed to unveil the other associated factors
responsible for angiogenesis. Furthermore, hypoxia
stimulated pancreatic fibroblast and promoted angio-
genesis via expression of VEGF receptors,
angiopoetin-1 and Tie-2, and these pancreatic fibro-
blasts induced pancreatic cancer cell motility via IGF1/
IGF1R signaling (Masamune et al. 2008; Hirakawa
et al. 2016).
Acidic environment created by hypoxia produces the
lactic acid within ECM without changing the intracellu-
lar PH that blocks the accumulation of drugs within the
cancer cells (Harrison and Blackwell 2004; Vukovic and
Tannock 1997). In some drugs such as doxorubicin,
which is oxygen-dependent, effect is obviously reduced
in hypoxic environment (Harrison and Blackwell 2004).
Hypoxic environment drives the hypoxia-inducible fac-
tor 1 (HIF-1) to upregulate the drug resistance genes
encoded ATP-binding cassette transporters (ABC)
(Wartenberg et al. 2003). Proteins of ABC family have
been well studied and their functions are well known,
Fig. 2 The dual nature of CAFs.
Two distinct subpopulation of
CAFs that are based on its
secretory function and expression
markers and play the subsequent
role in tumor microenvironment
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Cell Biol Toxicol (2019) 35:407–421
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which play a major role in drug resistance through
multiple functions including efflux of drug from cancer
cells (Fletcher et al. 2010). Moreover, as mentioned
previously, HIF-1αsignaling is associated with HA
accumulation promoting EMT and ultimately to drug
resistance (Zhang et al. 2013; Gao et al. 2005). A study
pointed out the possible way to overcome this by de-
pleting HA accumulation, which inhibits HIF-1α-snail
signaling and suppresses EMT (Kultti et al. 2014). The
role of hypoxia in generating the tumor drug resistance
has been well reviewed and suggested to target hypoxia
in treating cancer to get the better outcome (Wilson and
Hay 2011). These studies provided the sufficient proofs
that the regulation of drug sensitivity of cancer cells by
CAFs, especially in hypoxic environment, is also inev-
itable. However, hypoxic CAFs secreted key player to
induce the resistance may not have been characterized
yet and continuous effort is needed to unravel it.
Contradictory to this, a study reported that the
prolonged hypoxia can cause the deactivation of CAFs
and diminishes the role of CAFs (Madsen et al. 2015). A
detail study is needed to clarify it more.
Drug resistance by secreting soluble factors
As mentioned earlier, tumor microenvironment, notably
fibroblasts and CAFs, elicits drug resistance via secre-
tion of various soluble factors. Among these proteins,
Wnt family member wingless-type MMTV integration
site family member 16B (WNT16B), which is regulated
by NF-κβ after DNA damage, activates the canonical
Wnt program in tumor cells and induces cytotoxic che-
motherapy resistance in prostate cancer (Sun et al.
2012). They showed that WNT16B was upregulated in
chemotherapy administered prostate, breast, and ovarian
cancers and verified both in vitro and in vivo that
WNT16B secreted by fibroblast was responsible for
inhibiting the chemotherapy-induced apoptosis. Anoth-
er study revealed that fibroblasts secreted frizzled-
related protein 2 (SERP2) after genotoxic treatment
could augment β-catenin activities initiated by
WNT16B and enhanced chemotherapy resistance in
prostate cancer (Sun et al. 2016). Moreover, other pro-
teins, cytokines and chemokines, secreted by CAFs can
switch the tumor cells genotypically and phenotypically
exhibiting the drug resistance properties. Interleukin-
17A (IL-17A) secreted by chemotherapy-treated human
CAFs promoted the colorectal cancer initiating cell
(CIC) self-renewal and tumor growth displaying the
conventional chemotherapy resistance features (Lotti
et al. 2013). Authors noted the significant increase of
CAFs after the chemotherapy, which further suggested
the possibilities of alteration of CAF features induced by
various drugs. This speculation was supported by an-
other study showing that initially well responded
BRAF-mutant melanoma cells to PLX4720 became
tolerant after certain period of treatment by reactivating
ERK/MAPK in the areas of high stromal density (Hirata
et al. 2015). This is due to activation of stromal fibro-
blast, elevation of matrix production, and remodeling
leading to elevated integrin β1/FAK/Src signaling in
melanoma cells associated with BRAF inhibitor,
PLX4720. These findings suggested that chemotherapy
or radiotherapy could enhance the secretions of stromal
derived factors besides killing cancer cells, and provide
the survival benefit to cancer cells and resulting in drug
resistance. This concept was also supported by other
two independent studies (Acharyya et al. 2012;
Nakasone et al. 2012). Therefore, approaches to curative
treatment to cancer became likely insufficient due to
avoiding the fact of therapy-derived functional switch
of stromal cells.
Drug resistance via stromal modification
Desmoplastic stroma also could sufficiently hinder the
drug delivery by inducing vascular collapse. A study in
PDAC mouse model refractory to gemcitabine was
observed poor vascularization with poor perfusion, but
when co-administered with IPI-926, hedgehog cellular
signaling inhibitor, significantly increased both vascu-
larization and perfusion by reducing tumor-associated
stromal tissue (Olive et al. 2010). Moreover, HA was
also found to be responsible for generating high inter-
stitial fluid pressure (IFP) inducing vascular collapse
and acted as barrier for drug perfusion and diffusion in
PDAC mice model (Provenzano et al. 2012). Re-
searchers found that enzymatic breakdown of stromal
hyaluronic acid before administration of cancer drug
therapy resulted in remodeling of microenvironment,
normalized IFP, and reestablished the microvascular
structure, which ultimately enhanced the therapeutic
effect. This study was further supported by the research
published in following year, observed that stromal
hyaluronic acid depletion by PEGylated recombinant
PH20 hyaluronidase (PEGPH20) tested in PDAC mice
model could successively increase the intratumoral de-
livery of chemotherapeutic drugs, doxorubicin and
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gemcitabine (Jacobetz et al. 2013). Apart from HA,
CAFs also modulated the drug delivery in cancer cells
via mechanism of PDGFR involved increased IFP
(Heldin et al. 2004). The role of PDGFR in drug resis-
tance by increasing IFP have been supported by other
independently published data showing that PDGFR in-
hibitor could reduce the vascular intercellular pressure
and facilitate the drug transport into the cancer cells
(Pietras et al. 2003; Östman and Heldin 2007). These
findings suggested that desmoplastic stroma and
hypoperfused tumor generated by CAFs could hinder
the effective drug perfusion leading to drug resistance.
Moreover, matrix remodeling by CAFs can form the
chemoprotective niche and hence blocks the effective
delivery of chemotherapeutic drugs to the cancer cells
via cell adhesion-mediated drug resistance (CAM-DR),
contributing its role in evading cancer cells to treatment
(Meads et al. 2009). Researchers have described the
presence of number of molecules on the cell membrane
of CAFs such as cell surface proteoglycans, integrin,
and non-integrin collagen receptors, which participate in
cell adhesion mechanism that protect cancer cells from
drug-induced apoptosis (Zeltz and Gullberg 2016;
Multhaupt et al. 2016). One study explained the role of
CAM-DR on modulation of cancer cell adhesion on
ECM in multiple myeloma showing that the adhesion
resulted in increased p27kip1 levels that associated with
cell cycle arrest and resistance to melphalan (Hazlehurst
and Dalton 2001). The role of focal adhesion molecule
including integrins, integrin-associated proteins, and
growth factor receptors have been highlighted in recent-
ly reviewed article (Eke and Cordes 2015). These find-
ings suggested that cell-matrix interaction caused reor-
ganization of cytoskeleton and induced the multiple
signaling pathways, which was sufficient to cause drug
resistance. However, the experiment on mouse model of
pancreatic cancer showed that desmoplastic response
and fibrosis could be restored by the inhibition of Hh-
Smo pathway and permitted the well distribution of
drugs in the cancer cells (Olive et al. 2009). So, there
is still dim hope to overcome the cancer drug resistance
due to stromal modification, and continue study to un-
derstand the mechanism in detail is needed.
Role in endocrine treatment resistance
The endocrine treatment resistance is widely observed
even in estrogen receptor-positive (ER+) breast cancers.
A research performed in ER+ MCF-7 cells showed that
CAF was the source of tamoxifen and fulvestrant resis-
tance and also protected cancer cells from doxorubicin
and PARP inhibitor (Martinez-outschoorn et al. 2011).
They found that tamoxifen promoted the upregulationof
TP53-induced glycolysis and apoptosis regulator
(TIGAR), P53regulated gene that can inhibit glycolysis,
autophagy, and apoptosis and reduces ROS generation,
in CAF co-cultured MCF-7 cells enhancing the oxida-
tive mitochondrial metabolism, which provided the sur-
vival benefit to cancer cells. The inhibition of mitochon-
drial activities by metformin or arsenic trioxide led to
increase in glucose uptake by mitochondria resulting in
metabolic imbalance between cancer cells and CAFs
that resensitized tamoxifen treatment. Another indepen-
dent research on MCF-7 cells showed that soluble fac-
tors secreted by fibroblast rescued the tumor cells from
tamoxifen by the mechanisms that involved EGFR and
matrix metalloproteinases (Pontiggia et al. 2012)]. They
verified that stromal factors as the modulators of ER
activity showing that fibroblasts were able to phosphor-
ylate ER at serine-118. In contrast to this, a research
performed by Shekhar et al. showed that sensitive pre-
malignant EIII8 and tumorigenic MCF-7 cells when co-
cultured with the fibroblast derived from ER−/proges-
terone receptor (PR)−human breast tumors conferred
the tamoxifen resistance independently of EGFR
(Shekhar et al. 2007). They observed the non-
correlation between tamoxifen resistance and level of
EGFR or phospho-EGFR and endocrine sensitivity.
However, some studies have concluded that the
in vitro EGFR sensitivity in neck squamous cell carci-
noma and lung cancer is modulated by co-cultured
fibroblast, indicating that the role of fibroblast in cancer
drug resistance via EGFR mechanism should not be
neglected (Wang et al. 2009; Johansson et al. 2012).
Role in immunotherapy resistance
The hope to treat cancer patients is becoming dim with
the increased report of immunotherapy resistance. Im-
mune system is complex to understand but various
researches have tried to explore the role of immune
system in cancer development and put forward the idea
of dual function of immune cells, pro- and anti-tumor
progression (DeNardo et al. 2010). In fact, the role of
microenvironment components in tumor promotion or
suppression somehow depends on the nature ofinfiltrat-
ed immune cells in the microenvironment (Ostrand-
Rosenberg 2008). Tumor microenvironment is
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infiltrated by various immune cells in response to in-
flammation and secret growth factors such as TGF, FGF,
VEGF, and some members of the interleukin family,
which can act as driving force for fibroblast activation
(De Visser et al. 2006; Calvo and Sahai 2011). In the
other hand, fibroblasts are also able to modulate the
tumor immune system. The role of fibroblast in altering
the immune-controlled tumor growth was described in
transgenic Lewis lung carcinoma and subcutaneous
PDAC mouse model, where it was observed that deple-
tion of FAP-expressing cells enhanced the hypoxic ne-
crosis of both tumor and stromal cells by a process
involving interferon-γ(IFN-γ)andtumornecrosis
factor-α(TNF-α) (Kraman et al. 2010). This result
was further supported by another research showing
FAP-expressing CAF as the main source for the resis-
tance of two immunological checkpoint antagonists:
anti-cytotoxic T lymphocyte-associated protein-4 (α-
CTLA4) and α-programmed cell death ligand 1 (α-
PD-L1), in PDAC mice model (Feig et al. 2013). The
failure of these checkpoint inhibitors was driven by
CAF-secreted chemokine [C-X-C motif] ligand 12
(CXCL12). Administration of CXCL12 receptor inhib-
itor enhanced the T cell accumulation at cancer site and
acted synergistically to those immunological checkpoint
antagonists. These research findings alarmed that CAFs
are consistently supporting cancer cells to evade a po-
tential curative therapy of cancer, immunotherapy, re-
quiring to further explore the function of CAFs.
Drug resistance via epigenetic modification
Various researches have pointed that the epigenetic
modification of cancer cells induced by CAFs is respon-
sible for drug resistance. Some studies have reported
that DNA methylation status of stroma associated with
the methylation profile of adjacent malignant cells (Hu
et al. 2005; Hanson et al. 2006). Consistent to this,
soluble factors secreted by CAFs upregulated wide pat-
terns of genes (372 genes) in breast cancer cells that are
epigenetically modified by DNA hypermethylation at
transcription start site and shore regions. This effect was
silenced on inhibition of DNA methylation (Mathot
et al. 2017). This was further supported by another
research showing that CAF secreted factors were re-
sponsible for combinatorial DNA hyper/hypomethyla-
tion, which induced EMT and stemness phenotype in
prostate cancer cell (Pistore et al. 2017). They observed
that methylation was DNM3TA dependent and its
knockdown prevented EMT program. Many researches
have already verified that EMT and stemness were also
one major contributory factor for cancer drug resistance.
Furthermore, a study revealed that EMT and metastasis
were promoted by TGF-βsecreted by CAFs, which
catalyzed the global DNA hypermethylation changes
in epithelial ovarian cancer cell (Cardenas et al. 2014).
Authors further observed that DNMT inhibitor knock
down the hypermethylation and EMT effect.
Similarly, few studies are available showing that
posttranscriptional histone modification of cancer-
associated CAFs caused cancer-promoting behavior. A
study showed that expression of both the histone mark
H3K27me3 and enhancer of zeste homolog 2 (EZH2)
was decreased in breast CAFs and promoted cancer
invasion by overexpression of thrombospondin type 1
(Bracken et al. 2006; Tyan et al. 2012). Epigenetic
modification on cancer cells induced by CAFs causing
drug resistance is outgrowing topic, and a detailed study
is needed to address the drug resistance issues. In our
knowledge, a better result could be expected by combi-
nation of demethylating agent and targeting agent to
CAF secreted factor responsible for epigenetic
modification.
Anti-fibroblastic therapies
Many studies are available examining the anti-
fibroblastic therapies in cancer treatment. Analyzing
the various related published research work, the current
focus being either to deplete the stroma or inactivate
CAFs. The most potential one is targeting to HA, stro-
mal component secreted by CAFs. A phase Ib clinical
study showed that doxorubicin increased median
progression-free survival and overall survival when ap-
plied in combination withPEGPH20 (7.2 and 13 months
in high HA and 3.5 and 5.7 months in low HA tissue
level, respectively) (Hingorani et al. 2016). This was in
consistent with another phase II study, which showed
that nab-paclitaxel/gemcitabin in combination with
PEGPH20 obviously increased progression-free surviv-
al in patients with metastatic PDAC as compared to nab-
paclitaxel/gemcitabine [hazard ratio (HR) 0.73, P=
0.049 and in patient with high HA tumors HR 0.51,
P= 0.048] (Hingorani et al. 2018)]. As mentioned pre-
viously, PEGPH20 degraded HA and nab-paclitaxel
also believed to be depleting agent of stromal compo-
nent (Jacobetz et al. 2013; Von Hoff et al. 2013). Sim-
ilarly, a recently published article showed the increased
414 Cell Biol Toxicol (2019) 35:407–421
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
concentration of carboxymethyl cellulose docetaxel
nanoparticle (CellaxTM-DTX) at SMA CAFs
degrading the stromal component. Whereas, the latest
studies have also verified the possibility of reverting
activated CAFs. A study showed that the anti-cancer
compound minnelide, water-soluble pro-drug of
triptolide extracted from Chinese plant Tripterygium
wilfordii,disruptedTGF-βsignaling and hence reverted
activated CAFs to quiescent form by decreasing α-SMA
expression, reducing ECM secretion, and increasing
vitamin A-containing lipid droplets (Dauer et al.
2018)]. Moreover, another study also supported the
strategy to revert activated CAFs showing that applica-
tion of all-transretinoic acid (ATRA) promoted the qui-
escence form of pancreatic stellate cells resulting in
Wnt-beta-catenin signaling and reduced tumor progres-
sion (Froeling et al. 2011).
Thus, newly recognized CAFs targeted molecules
like PEGPH20, nab-paclitaxel, CellaxTM-DTX,
minnelide, and ATRA could be regarded as the novel
cancer therapeutic agent in the modern era. However, it
should also be noted that the various researches have
pointed that simple depletion of stroma could promote
spreading of cancer cells rather than only facilitating
drug delivery. A study reported that simple blocking of
serum amyloid A1 (SAA1), poor prognostic marker in
pancreatic cancer cells, did not inhibit tumor growth
and they verified two subtypes: saa3-competent and
saa3-null CAFs, which showed pro-tumorigenic and
anti-tumorigenic effect, respectively (Djurec et al.
2018). So, in author’s view, selective depletion of
stroma would provide the better result in cancer
treatment.
As mentioned previously, one reason behind the re-
sistance of a new hope of cancer treatment, an immu-
notherapy, is induced by CAFs. But, dim hope still
remains with continuous exploration and understanding
its mechanism. CAF-induced resistance of two check-
point inhibitors (α-CTLA4 and α-PD-L1) was blocked
by CXCL12 receptor inhibitor (Feig et al. 2013)]. Sim-
ilarly, Janus Kinase 2 (JAK2) inhibitor, which can mod-
ify the stroma, also decreased PD-L1 expression and
enhanced the anti-cancer treatment as demonstrated in
in vitro cancer cells (Wörmann et al. 2016; Doi et al.
2017)]. Consistent to this, another research showed
possible enhancement of anti-PD-L1 treatment via
inhibiting the IL-6, a JAK activator (MacE et al.
2018). Hence, all these evidences verify that targeting
stroma can enhance the immunotherapy.
Discussion
Despite the continuous progress in current cancer re-
search and development of novel drugs, the problems
against cancer drug resistance were not vanquished.
Earlier, great efforts were given to resolve the cancer
drug resistance focusing on the properties of cancer cells
themselves, but recently, the role of microenvironment
in drug resistance becomes the emerging topic for many
researchers. Among the microenvironment components,
CAFs have been long studied in exploring the mecha-
nism of initiation of cancer, cancer progression, and
metastasis (Kalluri and Zeisberg 2006). As discussed
previously, CAFs should be regarded as the transitioned
state rather than distinct cell type, but instead of know-
ing progenitors of CAFs, we are still unable to find the
distinctive markers that can differentiate between differ-
ent states. CAFs reside in the microenvironment as
symbiotic relationship with cancer cells and provide
the shelter, nutrition, and paracrine niche for tumor
growth and function as backbone of microenvironment.
Breakdown of this correlation is warranted to defeat
cancer, and this can be achieved by understanding the
structure and function of each of the constituents of
microenvironment. Here we have reviewed the role of
CAFs, pillar of tumor microenvironment, in drug resis-
tance, and its underlyingmechanism and highlighted the
feasible way of reversal. As shown in Fig. 3,wehave
tried to summarize the CAF’scontributionindrugre-
sistance by different aspects such as participating in
revascularization, immune modulation, ECM remodel-
ing, and providing the alternative pathway for cancer
cells to induce drug resistance. Knowing these facts
would help in determining the better strategy for the
treatment of cancer patients and provides certain guide-
lines in the generation of next cancer drugs avoiding
potential risk of therapy resistance.
Some of the researches have also pointed out the
tumor-suppressive function of CAFs, which has been
briefed above in this review, and suggested no need to
pursue them while treating cancer to get the better
outcome. The controversial study published regarding
the tumor-suppressive role of CAFs has been discussed
in detail in respective segment. But to our knowledge,
failure to recognize CAFs as friend or foe is due to (1)
unable to identify its specific origin (for, e.g., differ-
ences in CD271+ and CD10+ pancreatic stellate cells
originated CAFs) (Fujiwara et al. 2012; Ikenaga et al.
2010), (2) inadequate knowledge to characterize its
415
Cell Biol Toxicol (2019) 35:407–421
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
secreted factors (for, e.g., different function of CAFs
secreted high- and low-weight HA), and (3) improper
characterization of CAFs (for, e.g., existence of differ-
ent subpopulation of CAFs as iCAFs and myCAFs).
Moreover, the existence of heterogenic properties of
CAFs also keeps us in dilemma in its appropriate
characterization, which can be further elaborated as,
as described above, CAFs are able to express various
markers, and none of the markers are completely over-
lapped; CAFs’contents are relatively higher in highly
dense breast, pancreatic, and prostate cancer while
lower contents are detected in brain and renal tumors
(Prakash 2016). CAFs are the phenotypic and func-
tional switch from normal stromal cells, also termed as
progenitors of CAFs within this review, and study
reported that CAFs are much more competent in
supporting tumor growth and metastasis than normal
stromal fibroblasts (Orimo et al. 2005). One research
has pointed out the importance of functional state of
stromal cells, where they showed that the stromal sig-
natures were more reliable than whole tissue signatures
for predicting the clinical outcome in breast cancer
patients (Finak et al. 2008). Drug sensitivity of cancer
cells in the presence of CAFs also depends on the
cancer types and microenvironment (Sonnenberg
et al. 2008). Further study regarding identification
and classification of CAFs is needed to better explain
these existing problems.
One previous study showed that despite the heteroge-
neity of CAFs, they are genetically more stable than
cancer cells. Therefore, targeting CAFs in cancer treat-
ment would have smaller possibilities to develop drug
resistance (Kerbel 1997)]. Recently published data have
suggested the strategies to modulate CAFs either by
inhibiting the activation pathway of CAFs or by breaking
the drug delivery barrier created by CAFs. Preclinical
studies showed that inhibiting TGF-β, angiotensin recep-
tor, and Hedgehog signaling could reduce CAFs and
ECM contents and improve the drug delivery (Olive
et al. 2009;Liuetal.2012). Similarly, suppression of
CAF mediated secretion of IL-6 by inhibiting mTOR
pathway via somatostatin analogue reversed the
chemoresistance in pancreatic tumor (Duluc et al.
2015). Moreover, one recently published article showed
that application of micro-RNA (miRNA) was possible in
reverting the CAF phenotype to non-CAF phenotype
(Kuninty et al. 2016). Detail discussion of targeted stro-
maltherapyhasbeendiscussedinthisreview.Toour
knowledge, reversing the phenotype of CAFs rather than
depleting may provide better solution for drug resistance.
In conclusions, CAFs, the building block of micro-
environment, have a crucial role in modulating cancer
drug sensitivity and understanding in detail could min-
imize the existing challenge of drug resistance and direct
the future innovation of cancer drug by avoiding or
overcoming the drug resistance.
Fig. 3 Roles of CAFs in drug resistance. CAFs play important role in cancer drug resistance via secretion of different factors and
modulation of tumor microenvironment resulting reduction of drug efficacy or activation of cancer cells by alternating pathway
416 Cell Biol Toxicol (2019) 35:407–421
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Financial support statement This research is supported by the
National Key Research and Development Program of China
(2017YFC1308604 and 2017YFC0908402), the B973^State
Key Basic Research Program of China (2014CB542101 and
2013CB910500), National Natural Science Foundation of China
(81772563, 81672820, and 81372647), and China National Key
Projects for Infectious Disease (2012ZX10002-012).
OpenAccess This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://
creativecommons.org/licenses/by/4.0/), which permits unrestrict-
ed use, distribution, and reproduction in any medium, provided
you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons license, and indicate if
changes were made.
Publisher’snote Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional
affiliations.
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