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46 The Dynamics of Tumor Microenvironment and Therapeutic Targets
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48
3
The Influence of
Cancer-Associated
Fibroblasts in the Tumor
Microenvironment
and Their Effects
on Glioblastoma
Mirudula Elanchezhian, Ashwin Kumar Jainarayan,
and Arpit Kumar Pradhan
3.1 INTRODUCTION
3.1.1 defiNitioN aNd overview of CaNCer-assoCiated fibroblasts
Tumor progression is shaped by the complex interactions between cancer cells and
the surrounding stromal microenvironment. The tumor microenvironment (TME)
comprises various stromal cells, including immune cells, broblasts, and epithelial
cells. In addition to these cellular components, soluble factors such as growth fac-
tors, cytokines, capillaries, and the extracellular matrix (ECM) create a supportive
network that fuels cancer cell survival and growth.
Cancer-associated broblasts (CAFs), a type of stromal cell with a broblast-like
phenotype, exhibit unique chromosomal abnormalities not seen in normal broblasts
(NFs). These include duplications, complex rearrangements, and, in some cases, the
complete loss of chromosomes [1]. The origin and function of CAFs have been exten-
sively researched over the last three decades. In 1995, Rønnov-Jessen and colleagues
proposed that CAFs in breast cancer could arise from various sources, including
resident broblasts, vascular smooth muscle cells, and pericytes [2]. Current studies
have further identied that CAFs can originate from mesenchymal cell precursors in
the red bone marrow, endothelial and epithelial cells, local resident broblasts, and
adipocytes (detailed in the section: “Origin of CAFs”).
Fibroblasts, usually inactive, transform into myobroblasts following tissue
injury, promoting their proliferation and the release of soluble factors, and ECM
proteins to support the wound healing [3]. Upon tissue injury, various factors such
DOI: 10.1201/9781003405023-3
49Cancer-Associated Fibroblasts and Glioblastoma
as transforming growth factor-β (TGF-β), platelet-derived growth factor (PDGF),
hepatocyte growth factor (HGF), broblast growth factor 2 (FGF2), inammatory
cytokines, metalloproteinases, and reactive oxygen species are released. These sig-
nals activate broblasts, prompting them to acquire smooth muscle cell-like proper-
ties, including α-smooth muscle actin (α-SMA) expression and contractile function
[4–6]. CAFs are typically identied by their morphology, spindle-shaped appear-
ance, tissue location, and absence of markers specic to epithelial cells (epithelial
cell adhesion molecule, EpCAM), endothelial cells (CD31), immune cells (CD45),
and pericytes (NG2) [9]. Flow cytometry and single-cell RNA sequencing reveal the
heterogeneity of CAFs, which varies across cancer types and stages [10].
A signicant component of the TME, CAFs have emerged as a fascinating subject
of study, primarily due to their complex roles in tumor progression. While numerous
studies highlight their protumorigenic functions such as ECM remodeling, immune
cell interactions, promoting cancer cell proliferation, angiogenesis, and drug resis-
tance [11–17], there is growing evidence suggesting that CAFs may also exert tumor-
restraining functions [18–20]. This dual role raises intriguing questions about their
plasticity and the factors inuencing their behavior, including precursor origin, can-
cer type, and stage of tumor progression. Understanding this heterogeneity is crucial,
as it could offer new insights into how CAFs contribute to the TME.
3.1.2 importaNCe of studyiNg Cafs iN CaNCer researCh
Variations in stromal composition shape the intratumoral architecture and inuence
tumor cell behavior, underscoring the need for precise assessment of CAFs in treat-
ment planning. Studies on CAF interactions with the TME have revealed numerous
mechanisms, presenting multiple potential oncotherapy targets. However, clinical
trials targeting CAFs have often failed, sometimes accelerating cancer progres-
sion and reducing patient survival [21]. This failure is partly due to the incomplete
understanding of CAF roles in tumorigenesis and their context-dependent, plastic
functions.
CAF roles in tumor progression are complex, involving extensive crosstalk with
other stromal cell types via metabolites, cytokines, and signaling molecules, mak-
ing them crucial TME regulators. Despite their protumor functions, CAFs can also
exhibit tumor-restraining effects in certain contexts. Therefore, more research is
needed to explore CAFs as therapeutic targets. Targeting CAFs can involve eradica-
tion or functional impairment, focusing on specic surface markers like Endo180
(CD280) and FAP [22–24]. For example, chimeric antigen receptor (CAR) T cell
therapy targeting FAP can kill FAP+ cells, including CAFs, and improve chemother-
apy efcacy [25, 26]. Novel methods like near-infrared photoimmunotherapy (NIR-
PIT) have also shown promise in inhibiting tumor growth by removing CAFs without
adverse effects [27].
Besides elimination, another strategy is to disrupt the signaling pathways of CAFs
that drive tumor growth, invasion, and metastasis. Some anticancer drugs, like his-
tone deacetylase (HDAC) and smoothened (SMO) inhibitors, target CAF-related sig-
naling and epigenetic regulation. However, caution is needed when targeting CAFs,
50 The Dynamics of Tumor Microenvironment and Therapeutic Targets
as some subsets, like CAFs expressing estrogen receptor (ER) α in prostate cancer,
can inhibit tumor progression [28–30]. As understanding of CAF biology improves,
CAF-targeted therapies are being revitalized, with numerous clinical trials under-
way. This underscores the crucial need to study CAFs in cancer research to develop
effective therapies.
3.2 ORIGIN OF CAFs
Although generally referred to as CAFs to describe all activated broblasts within
the TME of solid cancers, these cells represent highly heterogeneous populations
that can originate from diverse precursors. The absence of precise broblast-specic
markers complicates the understanding of CAFs. Without well-dened markers for
tissue-resident NFs and CAFs, it is difcult to determine the exact cellular origin of
CAFs. To address this, research has focused on the alterations in broblast popula-
tions as carcinomas advance from hyperplasia to carcinoma [31]. These studies have
observed progressive changes in broblastic stroma, noting that an initial increase in
broblasts often precedes malignancy, and broblasts are frequently seen encircling
early or premalignant lesions [32, 33]. This gradual transition suggests that most
stromal broblasts originate from local broblasts undergoing tissue dysfunction [34,
35]. The expansion of stromal broblast numbers, although occurring at a low fre-
quency, is referred to as “stromagenesis,” which proceeds alongside and is coupled
with tumorigenesis [36, 37]. This process, supported by experimental observations,
indicates that broblasts initially exhibit a tumor-suppressive role before transition-
ing to protumorigenic roles [9, 18, 19].
To gain deeper insight into the origin of CAFs, researchers have utilized mouse
models in which cells are permanently labeled through transgenic methods. These
models employ tissue-specic expression of Cre recombinase in mice carrying
a reporter gene that becomes permanently activated in cells expressing Cre [38].
However, the lack of broblast-restricted markers complicates selecting a promoter
to drive Cre recombinase expression [39]. For example, different Cre drivers, like
collagen type Iα2 chain (Col1a2) and collagen type V α1 chain (Col5a1), have shown
distinct phenotypes in colitis models of stromal knockout of Ikkb [40, 41]. Despite
these challenges, these models provide valuable insights into how various cell types,
such as adipocytes, pericytes, endothelial cells, and mesenchymal stem cells (MSCs)
derived from bone marrow, can be transformed into CAFs. For instance, conditioned
media from breast cancer cells can drive the reprogramming of pluripotent stem cells
into cancer stem cells, which then differentiate into CAFs [42].
The cumulative evidence suggests that the CAF population arises from multiple
origins rather than originating from a single source. First, research has shown that
CAFs can derive from resident broblasts, including quiescent pancreatic stellate
cells (PSCs) and hepatic stellate cells (HSCs), which can adopt a myobroblast-like
phenotype, including α-SMA expression, in the liver and pancreas [43–46]. Activated
PSCs and HSCs sustain their activity through autocrine loops and contribute to
desmoplasia [47]. However, recent lineage-labeling studies have shown that PSCs
contribute to only a small fraction of CAFs in pancreatic ductal adenocarcinoma
51Cancer-Associated Fibroblasts and Glioblastoma
(PDAC) [48], indicating the presence of multiple CAF progenitors and necessitating
further exploration of other potential cellular origins.
NFs activated through signals from tumor cells also give rise to CAFs in PDAC,
gastrointestinal ca ncer, and breast cancer [49 –51]. Local broblasts are heterogeneous,
consisting of distinct populations [52]. For example, Gli1-expressing broblasts, but
not Hoxb6-expressing ones, form a portion of PDAC CAFs [53]. Additionally, intes-
tinal pericryptal leptin receptor (Lepr) lineage cells have been detected as a source
of CAFs marked by melanoma cell adhesion molecule (MCAM) [50].
Second, CAFs can also originate from epithelial and endothelial cells via pro-
cesses such as epithelial-to-mesenchymal transition (EMT) and endothelial-to-
mesenchymal transition (EndMT) [54–56]. Further, both in vitro and in vivo tracing
studies have shown that CAFs can also originate from bone-marrow-derived MSCs
[57]. Additionally, while adipocytes have been reported to convert into CAFs, this
process does not seem to occur consistently across all tumor types [58, 59]. The
depletion or absence of adipocytes in pathological tissue may be due to the interfer-
ence of activated broblasts with adipocyte differentiation [60]. In cases where adi-
pocytes persist, they can interact with crosstalk with cancer cells and offer metabolic
support without undergoing conversion into CAFs [61]. In non-small-cell lung can-
cer (NSCLC), CAFs can originate from macrophages through a process known as
macrophage-myobroblast transition (MMT), which is also associated with brotic
nephropathy [62, 63].
In addition to the previously mentioned sources, other origins of CAFs include
pericytes, mesothelial cells, and smooth muscle cells [51, 64–66]. This diversity
results in multiple subpopulations of CAFs across different tumor types, which
evolve in tandem with genetic changes in epithelial cells during cancer progression,
inuencing in the temporal and spatial distribution of CAFs [51, 67]. Acomprehen-
sive understanding of full spectrum of CAFs and the mechanisms underlying their
transformation from normal precursors is essential for unraveling the complexities of
the TME and developing targeted cancer therapies.
3.3 CAF BIOMARKERS
The expression of biomarkers by CAFs varies signicantly depending on their cel-
lular origins, reecting diverse biological properties. Recent clinical observations
underscore the distinct roles played by CAF subgroups expressing different mark-
ers in various cancers, categorized into cancer-promoting, cancer-restraining, and
bidirectional functions. Therefore, studying CAF markers is crucial for advancing
precision targeted therapies. In recent years, advancements in molecular techniques,
such as single-cell sequencing, have greatly enhanced our understanding of CAF
markers and their role in tumorigenesis. In this section, we rst focus on cancer-
promoting CAF markers, including broblast-activating protein (FAP), α-SMA,
periostin (POSTN), platelet-derived growth factor receptor (PDGFR), broblast-spe-
cic protein (FSP-1), palladin, Twist1, glutamine-fructose-6-phosphate transaminase
2 (GFPT2), galectin1 (Gal1), vimentin, CD90, CD10, GPR77, Tenascin C (TNC),
adipocyte enhancer-binding protein 1 (AEBP1), and osteopontin (OPN). Next, we
52 The Dynamics of Tumor Microenvironment and Therapeutic Targets
explore CAF markers with cancer-restraining functions, such as mein and CD146.
Following that, we cover CAF markers with dual role, including caveolin-1 (Cav-
1), CD200, and podoplanin (PDPN). Finally, we briey discuss several other CAF
markers whose roles in different cancers are yet to be claried.
3.3.1 CaNCer-promotiNg Caf biomarkers
FAP is highly expressed in CAFs derived primarily from NFs [68, 69]. FAP con-
tributes to the advancement of various cancers by promoting metastasis in phyl-
lodes tumors, enhancing the aggressiveness of high-grade urothelial carcinoma of
the bladder, facilitating invasion and growth of prostate cancer cells, and promoting
cancer progression through EMT mediated by the Wnt/β-catenin signaling pathway
in gastric cancer [70–72]. Further, FAP
+
CAFs contribute to an immunosuppres-
sive TME, leading to resistance to immunotherapy by promoting interactions with
immune cells such as macrophages and myeloid-derived suppressor cells (MDSCs)
[73–76]. FAP
+
CAFs also inuence the density and function of T cells in cancers,
impacting immune response and tumor progression [77]. These ndings underscore
FAP as a potential biomarker for predicting immunotherapy resistance and highlight
it as a therapeutic target in solid tumors, with strategies focusing on depleting FAP
+
CAFs through various approaches including antibodies [78, 79], genetic methods
[80], pharmacological inhibitors [81, 82], and innovative immunotherapies [25, 26,
83] such as DNA vaccination and CAR-T cell therapy.
α-SMA is a cytoskeletal protein prevalent in CAFs, distinguishing them as key
players in cancer progression [84, 85]. These CAFs primarily originate from NFs
but can also arise from various other cell types—including stellate cells and MSCs
[69, 85–87]. α-SMA
+
CAFs contribute to enhanced colony formation, proliferation,
and invasiveness in cancers like pancreatic cancer [88] and cholangiocarcinoma
[89]. These CAFs exhibit diverse roles across different cancer types: in pancreatic
cancer, they include myobroblastic CAFs (myCAFs) near cancer cells expressing
high α-SMA and FAP, inuencing the TME through ECM deposition and TGF-
driven pathways. Conversely, inammatory CAFs (iCAFs), further from cancer cells,
secrete inammatory cytokines like IL-6, promoting tumor progression [36]. In lung
tumors, α-SMA
+
CAFs are categorized into distinct subpopulations, such as myosin
heavy chain 11 (MYH11)
+
SMA
+
CAFs in early-stage tumors and FAP
+
SMA
+
CAFs
in advanced stages, impacting immune cell activity and suggesting potential targets
for enhancing immunotherapy efcacy [90]. Clinical studies link α-SMA
+
CAF pres-
ence with poorer prognoses in various cancers [91–94], including breast cancer, oral
tongue squamous cell carcinoma, colon cancer, and prostate cancer.
POSTN, a matricellular protein originally identied in osteoblasts, plays signif-
icant roles in CAFs, which are primarily derived from NFs [95]. POSTN
+
CAFs
contribute to cancer progression by enhancing invasion and metastasis through inter-
actions with integrin receptors [96–98]. POSTN promotes EMT via the PI3K/Akt
pathway in esophageal adenocarcinoma and ovarian cancer, facilitating cancer cell
migration and invasion [99, 100]. In gastric cancer POSTN-expressing CAFs degrade
the ECM and attract pro-metastatic immune cells [101]. POSTN also supports cancer
53Cancer-Associated Fibroblasts and Glioblastoma
stem cell characteristics in head and neck squamous cell carcinoma (HNSCC) [102]
and colorectal cancer (CRC) [103]. In addition, POSTN
+
CAFs appear to play a role
in enhancing drug resistance in melanoma [104] and chemoresistance in epithelial
ovarian cancer [105]. Clinically, POSTN
+
CAFs correlate with adverse prognostic
factors and poorer outcomes in multiple cancers [99–101, 103, 106, 107], suggesting
POSTN as a potential therapeutic target through antibody-based neutralization or
DNA inducers [102, 108]
PDGFR, found on broblasts, neural precursor cells, astrocytes, and pericytes,
includes PDGFRα and PDGFRβ, which bind to PDGF family members, initiating
coagulation, stimulating angiogenesis, and promoting tumor growth and metastasis
[109, 110]. PDGFRα/β
+
CAFs primarily originate from NFs, with smaller proportions
from pericytes and vascular smooth muscle cells. PDGFRβ colocalizes with integrin
A11 to activate JNK signaling in breast cancer [109], driving cancer cell aggressive-
ness, and stimulates tumor growth in cervical cancer by enhancing the expression
of heparin-binding epidermal growth factor (HB-EGF) [111. Additionally, PDGFR
binds with integrin α5β1 in prostate cancer to organize the ECM, facilitating cancer
cell migration [112]. PDGFRα/β
high
CAFs are associated with lymph node metastasis,
lymphovascular invasion, and worse clinical outcomes in multiple cancers [109, 113,
114] Inhibiting PDGFR signaling can reduce angiogenesis and proliferation [115],
with dasatinib potentially restoring cancer-associated CAFs to a more quiescent
broblast state in lung adenocarcinoma (LUAC) [116].
FSP-1
+
CAFs, originating from NFs, vascular endothelial cells, epithelial cells,
and adipocytes [54, 85, 117, 118], drive angiogenesis and enhance cell motility and
metastasis by secreting ECM proteins and cytokines [59, 119, 120]. FSP-1 is linked
to lymph node metastasis in cholangiocarcinoma [121] and breast cancer [122]. In
rodent models of breast cancer, FSP-1 increases cell motility and invasion, leading to
lung metastasis [123], and in transgenic mice, FSP-1
+/+
broblasts create a microen-
vironment conducive to metastasis [124]. Given their role in metastasis, FSP-1
+
CAFs
are considered a potential target for anticancer therapy, with anti-FSP-1 monoclonal
antibodies showing effectiveness in reducing T cell inltration and metastatic burden
in experimental models [125].
Palladin
+
CAFs primarily originate from NFs and stellate cells [126, 127]. Palladin
inuences ECM protein gene expression, promoting a pro-invasive CAF phenotype
[128]. In PDAC, CAFs with high ISO3/ISO4 expression release cytokines that sup-
press the immune response, maintain inammatory CAF characteristics, and pro-
duce desmoplastic ECMs supporting tumor cell viability and growth [129]. High
palladin expression in CAFs also facilitates cancer cell invasion by altering the ECM
via the small GTPase Cdc42 [127]. In breast cancer, palladin acts as an Akt1-specic
substrate, and its downregulation by miR-96/miR-182 in CAFs reduces cancer cell
migration and invasion [130].
Twist1 in CAFs marks tumor progression, with its expression in NFs inducing
their transdifferentiation into CAFs via STAT3 phosphorylation. In gastric cancer,
increased Twist1 expression in CAFs correlates with tumor progression, while silenc-
ing Twist1 in CAFs negates their tumor-promoting effects [131]. Additionally, Twist1
is expressed in cancer cells as well as CAFs in invasive ductal breast carcinoma,
54 The Dynamics of Tumor Microenvironment and Therapeutic Targets
correlating with shorter survival, making it a potential prognostic marker [132]. In
CRC, Twist1 is mainly in the tumor stroma, enhancing matrix stiffness through the
induction of collagen α1 and palladin, thus promoting cell migration and invasion
[133].
GFPT2 is a crucial enzyme in the hexosamine biosynthesis pathway (HBP),
responsible for glycosylation [134]. HBP activation alters O-GlcNAcylation and
N-/O-glycosylation of transcription factors and kinases, stabilizing proteins like
c-Myc and β-catenin, which promote tumor growth, invasion, metastasis, and resis-
tance to drugs [135–140]. GFPT2
+
CAFs mainly originate from NFs. In LUAC,
TGF-β induces GFPT2 expression in CAF-like cells, enhancing glucose uptake and
regulating tumor metabolic reprogramming, correlating with poor prognosis [134]
GFPT2
+
CAFs are associated with immunosuppressive cell populations and T cell
exhaustion, with high GFPT2 expression in CAFs correlating with unfavorable path-
ological features and reduced overall survival in CRC patients [141].
Gal1 regulates cell proliferation in a manner that is both cell-specic and depen-
dent on its concentration. It enhances angiogenesis through the vascular endothelial
growth factor receptor 2 (VEGFR2) pathway, and modulates immune responses by
inducing T cell apoptosis while inhibiting the proliferation of T cells and activation
of antigen-presenting cells [142]. Under TGF-β induction, stellate cells can convert
into Gal1
+
CAFs [143]. In breast cancer, CAF-derived Gal1 shapes an immunosup-
pressive microenvironment by promoting a Th2 cytokine prole and expanding Treg
cells [144]. In PDAC, Gal1
+
CAFs contribute to tumor cell growth, angiogenesis,
invasion, metastasis, and inammation [126, 143].
Vimentin+ CAFs mainly originate from MSCs, with other sources including vas-
cular endothelial cells and epithelial cells [69, 87]. These CAFs are linked to tumor
development, metastasis, relapse, resistance to drugs, and unfavorable outcome in
various cancers [145–148]. For instance, in CRC, vimentin expression in CAFs cor-
relates with higher tumor malignancy, recurrence, and shorter survival [145], and in
PDAC, vimentin+ CAFs lacking α-SMA co-expression act as independent indicator
of poor prognosis [148].
CD90 regulates cell–matrix and cell–cell interactions, playing a crucial role in
neural regeneration, cell migration, adhesion, and brosis [149]. CD90
+
CAFs mainly
originate from MSCs, with stellate cells as another source [87, 150]. These CAFs
promote tumor malignancy by serving as a major source of IL-6, which preserves
the stemness of CRC cells and promotes an immune response that supports tumor
growth [151]. In a KrasG12D-driven LUAC mouse model, CD90
+
CAFs enhance
tumor cell–endothelial cell attachment, promoting invasion [152]. Further, CD90
+
CAFs can also differentiate prostate cancer-associated stroma and benign stroma,
making it a potential biomarker for prostate cancer [153].
CD10
+
CAFs primarily originate from bone-marrow-derived MSCs, with pre-B
lymphocytes also differentiating into this population [17, 69]. In breast cancer, CD10
+
CAFs are associated with ER-negative invasive tumor, while CD10
−
CAFs are linked
to luminal-type invasive breast cancer [154]. GPR77
+
CAF is primarily sourced from
bone marrow-derived MSCs and polymorphonuclear neutrophils [69]. CD10 and
GPR77 serve as markers to identify distinct CAF subpopulations; high expression
55Cancer-Associated Fibroblasts and Glioblastoma
of these markers is correlated with chemotherapy resistance and poor prognosis in
patients with lung and breast cancer [17].
TNC
+
CAFs mainly originate from MSCs [87] and are linked to lymph node
metastasis in breast and prostate cancers, as well as with more advanced clinical
stages, increased microvessel density, and the presence of tumor-associated macro-
phages in prostate cancer [93]. High TNC expression in CAFs serves as an distinct
prognostic factor for several cancers, including breast, bladder, and prostate [93, 155,
156].
AEBP1 is closely associated with EMT, suggesting that epithelial cells are the
primary origin of AEBP1
+
CAFs [157]. In the tumor stroma, AEBP1 plays a sig-
nicant role in cancer progression and is linked to various malignancies. In CRC,
overexpression of AEBP1 in CAFs promotes proliferation, invasion, migration, and
metastasis through the activation of NF-κB signaling. Elevated levels of AEBP1 in
CAFs is associated with broblast biomarker expression and EMT-related gene sig-
natures in both melanoma and CRC [158, 159].
OPN is a secreted phosphoprotein that functions as a cell adhesion protein and
cytokine, signaling through integrin V-3 and CD44 to contribute in tumorigenesis
[160–163]. The origin of OPN
+
CAFs is currently unclear. Treatment with an anti-
OPN monoclonal antibody, either alone or in combination with carboplatin, signi-
cantly reduces lung metastasis growth, highlighting OPN’s involvement in tumor
metastasis and progression [164].
3.3.2 CaNCer-restraiNiNg Caf biomarkers
Mein, encoded by the ISLR gene, is specically expressed in CAFs in both human
and mouse PDAC [8, 165–168]. Mein
+
CAFs also play a crucial role in tissue repair
and brosis inhibition in non-neoplastic brotic diseases [169–171]. Mein interacts
with proteins like BMP7 and Lox, counteracting brosis and promoting tissue repair
[169, 172–175]. Mein is also associated with CAFs that have undergone reversal,
resulting in enhanced responsiveness to treatment, and its presence can enhance che-
mosensitivity by converting α-SMA
+
mein
−
CAFs (tumor promoting CAFs) back to
mein
+
tumor-restraining CAFs [176].
CD146, primarily sourced from vascular endothelial cells [69], distinguishes two
CAF subgroups in ER
+
breast cancers: CD146
+
CAFs maintain ER expression, pro-
mote estrogen-driven proliferation, and increase tamoxifen sensitivity, while CD146
−
CAFs have the opposite effect [177]. While in PDAC, lower CD146 expression in
CAFs is associated with worse prognosis and enhanced tumor progression due to
increased CAF activation and secretion of protumor factors [178].
3.3.3 Caf biomarkers with a dual role
Derived from adipocytes, vascular endothelial cells, and NFs, Cav-1
+
CAFs exhibit
a dual role in cancer [69]. While Cav-1 downregulation in the TME can transform
NFs into CAFs [179], its deciency in CAFs has been associated with poor prognosis
in cancers such as breast, prostate, and gastric cancers [180–182]. Mechanistically,