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56 The Dynamics of Tumor Microenvironment and Therapeutic Targets
Cav-1 deciency can induce EMT, promote a malignant tumor phenotype through
metabolic symbiosis, and contribute to chemoresistance [183–186]. However, some
studies suggest that high Cav-1 expression in CAFs may indicate cancer progres-
sion, as seen in breast, pancreatic, renal, and other cancers, where it has been linked
to enhanced tumor cell invasion, metastasis, and a hardened TME [85, 187, 188].
These conicting roles of Cav-1 in CAFs suggest that therapeutic strategies target-
ing Cav-1 may need to be tailored differently depending on the cancer type and
context.
CD200 is a membrane glycoprotein expressed in various cells, including neu-
rons, lymphocytes, MSCs, and monocytes, and binds to the CD200 receptor
(CD200R1) to initiate an immunosuppressive response [189, 190]. Recent research
indicates that CD200 can also be expressed in CAFs. In LUAC patients with an
EGFR mutation, the presence of CD200
+
was linked to the improved outcomes
following getinib therapy, as these CAFs enhanced the drug’s ability to promote
cell death in cancer cells [191]. However, in pancreatic cancer, CD200 expression
in CAFs did not correlate with survival outcomes, but it did limit the effective-
ness of PD-1 inhibitors by increasing MDSC activity [192]. Early clinical trials of
samalizumab, a CD200 inhibitor, has shown promise in the treatment of chronic
lymphocytic leukemia [193].
Podoplanin (PDPN), a mucous sialoglycoprotein commonly used as a marker to
differentiate lymphatic from blood vessels, is also expressed in various cell types,
including CAFs [194, 195]. PDPN
+
CAFs, primarily derived from vascular endo-
thelial cells [69] promote tumor progression by aiding cancer cell inltration, alter-
ing the extracellular matrix, and creating an immunosuppressive microenvironment
[194, 196–200]. In LUAC, PDPN
+
CAFs are linked to poor prognosis, immune sup-
pression, and resistance to EGFR tyrosine kinase inhibitors [197, 200, 201]. However,
in CRC and breast cancers, PDPN
+
CAFs are associated with favorable prognosis,
possibly due to their protective role against cancer invasion [202, 203]. These differ-
ing roles of PDPN+ CAFs across various cancers suggest that the function of PDPN
may be context-dependent, varying by cancer type and organ.
3.3.4 other Caf markers with uNClear fuNCtioNs
Several markers are highly expressed in CAFs, but their roles in cancer are not
fully understood. MFAP5 is linked to pro-growth signaling in tongue squamous
cell carcinoma, suggesting a role in identifying oncogenic CAF subpopulations [7].
Antigen-presenting CAFs (apCAFs) express MHC class II and CD74 and may regu-
late immune responses in PDAC [204]. CD70 is highly expressed in CRC CAFs and
is associated with poor survival [205]. Markers like Transgelin (TAGLN) [95] and
COL11A1 [206] are specic to CAFs, but their functions remain unclear and need
further research.
In summary, while many CAF markers have been identied, no single marker
reliably identies CAFs across all cancers. Traditional markers like FAP and α-SMA
have limitations when used alone, and marker expression varies across cancer types.
Continued research is essential to gain a deeper understanding of CAF diversity and
improve cancer treatments by targeting both cancer cells and CAFs.
Cancer-Associated Fibroblasts and Glioblastoma 57
3.4 HETEROGENEITY AND PLASTICITY OF CAFs
The heterogeneity of CAFs is outlined by several distinct subtypes, each playing
unique roles in the tumor microenvironment. As discussed in the last section, ini-
tial studies using PDAC organoids identied two primary CAF subtypes: α-SMA
high
IL-6
low
myCAFs and α-SMA
low
IL-6
high
iCAFs [36]. Recent advancements have intro-
duced additional CAF subtypes such as apCAFs, marked by MHC class II molecules,
suggesting their role in immunomodulation [204]. In addition, single-cell sequencing
and multi-omics have identied new CAF subpopulations, including vascular CAFs
(vCAFs), cycling CAFs (cCAFs), and developmental CAFs (dCAFs). Each of these
subpopulations emerges at different stages of tumor progression and contributing
distinctively to cancer development [51].
The concept of CAF plasticity is also highlighted, with universal Pi16
+
broblasts
able to transition into specialized CAFs like LRRC15
+
CAFs under certain condi-
tions, inuencing tumor immunity and progression [207]. The continuous discov-
ery of CAF subtypes and their functions highlights the complexity of CAF biology
and emphasizes the need for further research to fully understand their diversity and
develop targeted therapies.
3.4.1 moleCular meChaNisms regulatiNg Caf heterogeNeity
CAF heterogeneity arises from several factors, including genetic evolution, epigen-
etic changes, and metabolic reprogramming. Tumor cells inuence CAFs through
various growth factors and chemokines like TGF-β, EGF, PDGF, FGF, IL-6, and
IL-1β. These molecules drive CAFs toward specic subsets by activating crucial reg-
ulatory pathways [208]. For instance, TGF-β induces a myobroblastic phenotype,
whereas IL-6 promotes an immune-modulating phenotype [209]. The genetic prole
of tumor cells, such as mutations in p53, can also shape the CAF phenotype, with dif-
ferent p53 statuses resulting in distinct stromal characteristics and inuencing tumor
progression through paracrine signaling and exosomal cargo [210, 211].
Epigenetic changes in CAFs, although less commonly associated with genetic
mutations, include consistent alterations in DNA methylation patterns [212]. These
changes occur predominantly at regulatory regions and transcription factor-binding
sites, leading to activation of broblasts with specialized functions [209, 213–215].
For example, DNA methylation of the SOCS1 promoter affects STAT3 signaling
and promotes cancer growth [216]. Additionally, nicotinamide N-methyltransferase
(NNMT) contributes to a tumor-supportive phenotype in CAFs by decreasing
global methylation and increasing the production of tumor-promoting factors [217].
Epigenetic changes also affect CAF behavior in metastatic sites, with distinct DNA
methylation patterns observed in liver and lung metastases, which might be inuenc-
ing the aggressive nature of the cancer [218].
In CAFs, metabolic reprogramming involves a shift from oxidative phosphory-
lation to aerobic glycolysis, aligning with the “reverse Warburg effect.” This shift
allows CAFs to produce lactate, which tumor cells utilize for oxidative phos-
phorylation [219] Factors such as HIF-1α and oncogenic c-Myc regulate glycolytic
enzyme expression in CAFs, resulting in a pro-glycolytic phenotype [220–223].
58 The Dynamics of Tumor Microenvironment and Therapeutic Targets
The metastatic potential of cancer cells also inuences the metabolic reprogram-
ming of CAFs, with highly metastatic tumors inducing a more aggressive CAF
phenotype [224].
3.4.2 fuNCtioNal heterogeNeity of Cafs
CAFs have long been recognized as key players in fueling tumor growth and resis-
tance. Traditionally cast as the villains of the tumor microenvironment, CAFs were
known for their roles in promoting tumor cell proliferation, aiding angiogenesis, and
creating an immune-suppressive shield [15–17, 225] However, emerging research has
unveiled a more nuanced picture: CAFs can also act as unexpected allies in the ght
against cancer. For instance, depleting αSMA+ myobroblasts in pancreatic cancer
can lead to more aggressive tumors and reduced survival [19]. Moreover, type Icol-
lagen produced by certain CAF subpopulations has been shown to curb tumor spread
in both CRC and PDAC [20]. These ndings highlight the remarkable functional
diversity of CAFs, revealing that they are neither simply benecial nor detrimental
but possess a dual nature.
Despite this complexity, the predominant view remains that CAFs largely contrib-
ute to tumor progression through several mechanisms:
• Facilitating Proliferation: CAFs can alter cancer cell metabolism, provid-
ing nutrients and inuencing cellular behaviors to support proliferation.
They also inuence cancer metabolism via exosomes, such as long non-
coding RNA SNHG3, which suppresses mitochondrial function, accelerates
glycolysis, and boosts breast cancer cell growth [226, 227]. Additionally,
the prostaglandin E2 (PGE2) pathway in CAFs has been linked to tumor
growth and resistance to therapies [228, 229]. The CXCL12/CXCR4 signal-
ing cascade in FAP
+
CAF and the methyltransferase NNMT in the TME
further contribute to tumor proliferation, highlighting the multifaceted
involvement of CAFs in tumor progression [68, 217].
• Promoting Angiogenesis: CAF contributes to tumor angiogenesis through
both VEGF-related and alternative pathways [230–232]. They overexpress
pro-angiogenic factors and angiogenesis regulators, which aid in recruit-
ing myeloid cells, attracting endothelial cells, and supporting blood vessel
development with tumors [19, 21, 233, 234]. Additionally, CAFs play a role
in forming vascular mimicry (VM) networks via the Notch2-Jagged1 path-
way, with resistance to anti-VEGF treatments often associated with VM
[235]. Additionally, CTGF secreted by CAFs is linked to tumor angiogene-
sis and worse clinical outcomes in malignant mesothelioma, while CHI3L1
secreted by CAFs promotes angiogenesis in CRC [236–238]. CAF-secreted
exosomes containing miRNAs, such as miR-21, further stimulate angiogen-
esis through autocrine and paracrine signaling, contributing to the tumor’s
pro-angiogenic environment [239, 240].
• Driving Metastatic Progression: CAFs are central to driving cancer pro-
gression, particularly in promoting tumor invasion, metastasis, and ECM
remodeling. They enhance tumor cell migration by aligning bronectin and
59Cancer-Associated Fibroblasts and Glioblastoma
increasing contractility, contributing to the directed migration of cancer
cells like those in prostate and pancreatic cancers [112]. CAFs also facili-
tate tumor metastasis by producing cytokines and chemokines, which pro-
mote cancer cell survival, invasion, and recruitment of immune cells like
neutrophils [112, 241–243]. Additionally, CAFs remodel the ECM, mak-
ing tumor tissues stiffer and more conducive to cancer cell invasion [244].
They secrete enzymes like MMPs that degrade ECM, enabling metastasis,
while their secretion of factors like lysyl oxidase-like 2 (LOXL2) aligns the
ECM, aiding cancer cell migration [245–249]. CAFs also contribute to the
development of premetastatic niches through exosome-mediated transfer
of non-coding RNAs, further promoting distant metastasis [250, 251]. The
heterogeneity of CAFs, such as those differentiated by CD146 expression,
and their interaction with cancer cells, underscores their role in driving the
invasive and metastatic characteristics of tumors [252–254].
• Contributing to Treatment Evasion: Studies on CAFs reveal their critical
role in inducing resistance to therapeutic approaches such as chemother-
apy, radiotherapy, immunotherapy, and hormone therapy. CAFs contrib-
ute to therapeutic resistance through mechanisms like ECM remodeling,
enhanced paracrine signaling, promotion of stem-like traits, and immune
evasion [112, 255–260]. For example, CAFs secrete cytokines like IL-6 that
protect cancer cells from drugs such as doxorubicin [261], and CAF-derived
exosomes, including miR-22 and miR-106b, promote resistance to tamoxi-
fen and gemcitabine [262, 263], respectively. Additionally, CAFs form phys-
ical barriers that hinder drug delivery and create tumor immune barriers
that reduce immunotherapy effectiveness [264–266].
• Modulating Immune Surveillance: CAFs contribute signicantly to
immunosuppression within the TME. They employ various mechanisms to
escape immune surveillance and support tumor progression. CAFs secrete
cytokines like TGF-β and chemokines such as CXCL12, which inhibit T
lymphocyte activation and recruitment, and induce T cell transformation
into regulatory T cells (Tregs) [267–270]. They can also induce MDSCs and
enhance immune checkpoint ligand expression like PD-L1, which further
impairs antitumor immunity [271–274]. Additionally, CAFs facilitate resis-
tance to immune checkpoint blockade (ICB) and inuence T cell responses,
leading to a more immunosuppressive microenvironment [24, 272, 275,
276]. Despite advances in understanding CAF-induced immunosuppres-
sion, many underlying mechanisms remain to be fully elucidated.
• Although much research has concentrated on the protumor functions of
CAFs, their potential antitumor effects should also be considered. Recent
studies have identied CD9
+
CAF-derived exosomes that inhibit malignant
melanoma proliferation, correlating with longer patient survival rates [277].
Specic CAF subsets, such as CD200
+
CAFs, enhance drug sensitivity to
EGFR-tyrosine kinase inhibitors in lung cancer [191]. In addition, IGF and
IGF-binding proteins secreted by CAFs in NSCLC are linked to increased
drug sensitivity [278], while IL-8 secreted by CAFs can suppress prolifera-
tion in certain cell lines [279]. Furthermore, apCAFs are involved in antigen
60 The Dynamics of Tumor Microenvironment and Therapeutic Targets
presentation to CD4+ T cells, suggesting an antitumor role [204]. Overall,
these ndings underscore the complex and potentially benecial functions
of CAFs in cancer.
3.5 TUMOR MICROENVIRONMENT IN GLIOBLASTOMA
Glioblastoma (GBM) is the most aggressive and lethal form of primary brain
tumor, despite extensive molecular analyses of GBM cells. Recent research has
highlighted the crucial role of the tumor microenvironment (TME) in GBM pro-
gression, resistance to therapy, and recurrence. However, fully understanding the
complex cellular and molecular components of the TME and their interactions
remains a challenge for the development of effective treatments. GBM is classied
as an IDH-wildtype astrocytoma, characterized by microvascular proliferation,
high stemness, invasiveness, and a predisposition to necrosis [280]. It predomi-
nantly occurs in the frontal and temporal lobes but is rarely found in the brainstem,
cerebellum, or spinal cord. Despite advancements in cancer biology, GBM remains
an intractable disease with a median survival of only 15 months [281]. The inci-
dence of GBM in the United States is 3.22 per 100,000 persons, with a median
diagnosis age of 64 years [282].
One of the primary challenges in treating GBM is the heterogeneous composition
of the TME. The TME in GBM is made up of various cell types, including tumor-
associated macrophages (TAMs), microglia, astrocytes, and endothelial cells, all of
which play a signicant role in the tumor’s growth, invasion, and evasion of immune
surveillance [282]. Additionally, the permeability of the blood–brain barrier (BBB)
and the immunosuppressive nature of the TME pose severe obstacles for therapeutic
interventions.
Immune Suppression and the Tumor Microenvironment—The TME of GBM is
highly immunosuppressive, limiting the effectiveness of immune-based therapies.
Tumor-associated macrophages (TAMs) and microglia are abundant in GBM and
often adopt an M2-like, protumorigenic phenotype, secreting anti-inammatory
cytokines like IL-10 and TGF-β, which promote immune evasion [283]. In addition,
regulatory T cells (Tregs) are recruited to the TME, further suppressing cytotoxic T
cell responses and contributing to immune escape. This immune-suppressive envi-
ronment prevents the body’s natural defenses from effectively attacking and elimi-
nating the tumor.
Tumor Heterogeneity and Therapeutic Resistance—The intratumor heterogene-
ity of GBM presents a signicant challenge for treatment. GBM cells exhibit vari-
ability at the molecular level, inuenced by genetic and epigenetic alterations that
drive resistance to conventional therapies such as surgery, radiation, and chemother-
apy. Neoplastic cells within the tumor adapt to their surroundings, modulating the
TME to create a supportive environment for growth and survival [284]. For instance,
hypoxia in the TME promotes angiogenesis and the maintenance of glioma stem
cells (GSCs), which are highly resistant to standard therapies and are responsible for
tumor recurrence after treatment.
New Therapeutic Strategies and Overcoming Barriers—Conventional treat-
ment for GBM primarily involves surgical resection of the tumor mass, followed by
61Cancer-Associated Fibroblasts and Glioblastoma
radiation and chemotherapy. However, due to the heterogeneity of the TME, these
approaches are often insufcient, and recurrence is common. Modern research has
introduced new therapeutic strategies aimed at overcoming the barriers posed by
the TME. One area of focus is on developing methods to improve drug delivery
across the blood–brain barrier (BBB), which remains a signicant obstacle to effec-
tive treatment [283]. Several new approaches, including the use of nanoparticles and
focused ultrasound, aim to temporarily disrupt the BBB to allow chemotherapeutic
agents and other treatments to reach the tumor more effectively. However, the fea-
sibility and safety of these techniques must be validated in clinical settings before
widespread use.
Other emerging therapies include targeting specic components of the TME, such
as inhibiting TAMs or using immune checkpoint inhibitors to boost the antitumor
immune response. The success of these approaches may depend on their ability to
reprogram the immune-suppressive environment into one that favors tumor elimi-
nation. Additionally, novel treatments targeting the signaling pathways that drive
GBM cell survival and proliferation, such as VEGF inhibitors to block angiogenesis,
are under investigation, though resistance mechanisms often limit their long-term
ef cacy.
The Need for Integrated Approaches—Given the complexity of the GBM TME,
a multipronged approach targeting both the tumor cells and the supportive microen-
vironment is likely required for more effective treatments. This includes combining
therapies that target the TME’s immune components, angiogenesis, and the meta-
bolic adaptations of the tumor cells. Integrating such strategies may help to overcome
the intrinsic resistance mechanisms of GBM and improve patient outcomes.
3.6 CANCER-ASSOCIATED FIBROBLASTS IN GLIOBLASTOMA
Cancer-associated broblasts (CAFs) play a pivotal role in shaping the TME in a
variety of cancers, including GBM. While CAFs are well-characterized in other
cancers, their presence and function in the brain have only recently been iden-
tied, challenging the previous assumption that broblasts do not exist in brain
tumors [13, 56, 233]. Excessive ECM deposition, driven by CAFs, is a hallmark of
many solid tumors, including gliomas. This dense ECM creates a physical barrier
that impedes drug delivery, thereby contributing to chemoresistance [285, 286].
Additionally, the plasticity and heterogeneity of glioma cells within the TME fur-
ther complicate treatment outcomes. Nontumor cells in the TME, such as CAFs,
interact with glioma cells to form a protective niche that promotes tumor survival
and drug resistance [287, 288]. Despite their recognized role in other solid tumors,
the isolation and study of CAFs in gliomas have been limited due to a lack of
appropriate methodologies. Most stromal broblasts in the brain have been dif-
cult to isolate in pure form from patient-derived tissues, thus hindering research
into their specic interactions with glioma cells [289]. Recent advances in single-
cell RNA sequencing and spatial transcriptomics have enabled more detailed char-
acterization of CAF populations within GBM, revealing their potential to mediate
tumor-supporting interactions and their signicant contribution to the glioma
microenvironment.
62 The Dynamics of Tumor Microenvironment and Therapeutic Targets
The role of CAFs in GBM is becoming increasingly clear. Proteomic analysis of
GBM-derived CAFs revealed bronectin (FN1) as a critical factor in facilitating the
migration and invasion of GBM cells [289]. In fact, CAFs are more abundant in
mesenchymal-like states of GBM, where they are thought to play a signicant role in
tumor invasion and metastasis [289]. These ndings suggest that CAFs contribute not
only to tumor growth but also to the invasive characteristics of GBM.
CAFs, now identied as glioma-associated broblasts (GAFs) in the GBM TME,
contribute signicantly to the chemoresistance observed in glioblastoma [290].
Through the secretion of ECM components, cytokines, and other growth factors,
CAFs create a niche that protects glioma cells from chemotherapy, particularly
temozolomide (TMZ) chemotherapy [290]. While the precise mechanisms by which
CAFs confer resistance are still being elucidated, there is growing evidence that
these cells can directly inuence the survival of GBM cells through the modulation
of ECM stiffness, barrier function, and the sequestration of therapeutic agents [287,
291]. Another critical aspect of CAFs in glioblastoma is their contribution to therapy
resistance. CAFs are involved in the secretion of growth factors such as hepatocyte
growth factor (HGF) and vascular endothelial growth factor (VEGF), which promote
angiogenesis and enhance the survival of tumor cells under stress conditions such as
chemotherapy and radiation [292]. Additionally, CAFs can shield glioblastoma cells
from therapeutic agents by forming dense brotic barriers, further complicating the
delivery of drugs to the tumor [293, 294].
Given their signicant role in glioblastoma progression and therapy resistance,
CAFs present a promising therapeutic target. Current approaches to targeting CAFs
include the inhibition of key signaling pathways, such as TGF-β, PDGF, and CXCL12/
CXCR4, which are critical for CAF activation and function [225]. Additionally, dis-
rupting the ECM produced by CAFs using ECM-degrading enzymes or blocking
CAF-secreted factors that promote tumor survival are also being explored as ther-
apeutic strategies [295]. However, given the heterogeneity and plasticity of CAFs,
more research is required to fully understand their role and to develop effective CAF-
targeting therapies in glioblastoma.
The discovery of CAFs in glioblastoma opens new avenues for therapeutic strate-
gies. Targeting CAFs or disrupting their interaction with glioma cells may prove to
be an effective approach to improving treatment outcomes in GBM patients. Novel
techniques for isolating and characterizing CAFs, such as single-cell sequencing and
proteomics, are critical for advancing our understanding of these cells and their role
in GBM progression and chemoresistance. By uncovering the molecular features and
functions of CAFs, researchers may identify new therapeutic targets aimed at over-
coming the challenges posed by the GBM TME.
3.7 THERAPEUTIC TARGETING OF CAFs
CAFs as discussed earlier are center to the progression of cancer. Therapeutic inter-
ventions targeting CAFs have been studied over years and have entered clinical tri-
als. Broadly, these targeting can be categorized into the following:
(A) Direct targeting, which includes inhibiting their inltration, preventing their
activation, depleting the CAFs, targeting signaling pathways associated with CAFs,
63Cancer-Associated Fibroblasts and Glioblastoma
and reprogramming them. Small-molecule inhibitors like Scriptaid have shown prom-
ise in repressing CAF differentiation via TGF-β signaling. Scriptaid not only reduces
CAF-mediated extracellular matrix (ECM) secretion but also diminishes cellular
stiffness and contraction, impairing tumor invasion and growth [296]. Targeting the
CXCL-CXCR2 axis has proven effective in reducing CAF and tumor cell migration,
inhibiting angiogenesis, and prolonging survival by suppressing immune-suppressive
cells such as myeloid-derived suppressor cells (MDSCs) and tumor-associated mac-
rophages (TAMs). Additionally, strategies targeting brinogen-like protein 2 (FGL2)
have demonstrated decreased CAF activation and tumor growth by limiting MDSC
aggregation [297]. Emerging insights into the Wnt/β-catenin pathway suggest that
inhibiting BCL9/BCL9L cofactor activity can shift CAFs toward a phenotype that
enhances T-cell-mediated antitumor immunity [298]. Other approaches, such as
using pirfenidone to decrease CAF invasiveness and immune suppression, highlight
the potential of CAF-targeted therapies in modifying the tumor microenvironment
(TME) to impede cancer progression [299]. These ndings underscore the impor-
tance of directly targeting CAF-specic pathways to disrupt their multifaceted role
in tumor development.
(B) Indirect targeting of CAFs which includes restoring the quiescent broblast
phenotype, addressing ECM proteins produced by CAFs, focusing on the tumor
immune microenvironment (TIME), shifting CAFs toward a suppressive phenotype,
and targeting key downstream effectors essential for CAF activity. The Trojan horse
camouage technique involves coating nanoparticles with cancer-associated bro-
blast (CAF) membranes, exploiting their innate characteristics like self-recognition
and immune evasion to bypass biological barriers and deliver therapeutics efciently
[300]. For instance, an AF membrane-coated semiconducting polymer nanoparticle
(SPN) with a near-infrared-absorbing core was developed to selectively bind homol-
ogous CAF membranes, enhancing the precision of tumor-targeted phototherapy.
Additionally, advanced nanodelivery systems improve drug solubility, stability, and
bioavailability while reducing systemic toxicity. These nanoparticles are engineered
to disrupt CAF biofunctions, inhibit tumor-promoting activities, and aggregate
within the tumor core.
REFERENCES
1. Hosein AN, Wu M, Arcand SL, Lavallée S, Hébert J, Tonin PN, et al. Breast carcinoma–
associated broblasts rarely contain p53 mutations or chromosomal aberrations. Cancer
Res. 2010;70:5770–5777.
2. Rønnov-Jessen L, Petersen OW, Koteliansky VE, Bissell MJ. The origin of the myo-
broblasts in breast cancer: Recapitulation of tumor environment in culture unravels
diversity and implicates converted broblasts and recruited smooth muscle cells. J Clin
Invest. 1995;95:859–873.
3. Shinde AV, Humeres C, Frangogiannis NG. The role of α-smooth muscle actin in
broblast-mediated matrix contraction and remodeling. Biochim Biophys Acta (BBA)-
Molecular Basis Dis. 2017;1863:298–309.
4. Knowles LM, Stabile LP, Egloff AM, Rothstein ME, Thomas SM, Gubish CT, et al.
HGF and c-Met participate in paracrine tumorigenic pathways in head and neck squa-
mous cell cancer. Clin Cancer Res. 2009;15:3740–3750.
64 The Dynamics of Tumor Microenvironment and Therapeutic Targets
5. Kumar D, New J, Vishwakarma V, Joshi R, Enders J, Lin F, et al. Cancer-associated
broblasts drive glycolysis in a targetable signaling loop implicated in head and neck
squamous cell carcinoma progression. Cancer Res. 2018;78:3769–3782.
6. Kuzet S-E, Gaggioli C. Fibroblast activation in cancer: When seed fertilizes soil. Cell
Tissue Res. 2016;365:607–619.
7. Gascard P, Tlsty TD. Carcinoma-associated broblasts: Orchestrating the composition
of malignancy. Genes Dev. 2016;30:1002–1019.
8. Miyai Y, Esaki N, Takahashi M, Enomoto A. Cancer-associated fibroblasts that
restrain cancer progression: Hypotheses and perspectives. Cancer Sci. 2020;111:
1047–1057.
9. Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M, Evans RM, et al. A
framework for advancing our understanding of cancer-associated broblasts. Nat Rev
Cancer. 2020;20:174–186.
10. Lavie D, Ben-Shmuel A, Erez N, Scherz-Shouval R. Cancer-associated broblasts in
the single-cell era. Nat Cancer. 2022;3:793–807.
11. Bif G, Tuveson DA. Diversity and biology of cancer-associated broblasts. Physiol
Rev. 2020;101(1):147–176. doi:10.1152/physrev.00048.2019.
12. Yoshida GJ. Regulation of heterogeneous cancer-associated broblasts: The molecular
pathology of activated signaling pathways. J Exp Clin Cancer Res. 2020;39:112.
13. Kalluri R. The biology and function of broblasts in cancer. Nat Rev Cancer. 2016;16:
582–598.
14. Mao X, Xu J, Wang W, Liang C, Hua J, Liu J, et al. Crosstalk between cancer-associated
broblasts and immune cells in the tumor microenvironment: New ndings and future
perspectives. Mol Cancer. 2021;20:1–30.
15. Affo S, Nair A, Brundu F, Ravichandra A, Bhattacharjee S, Matsuda M, et al. Promotion
of cholangiocarcinoma growth by diverse cancer-associated broblast subpopulations.
Cancer Cell. 2021;39:866–882.
16. Unterleuthner D, Neuhold P, Schwarz K, Janker L, Neuditschko B, Nivarthi H, et al.
Cancer-associated broblast-derived WNT2 increases tumor angiogenesis in colon
cancer. Angiogenesis. 2020;23:159–177.
17. Su S, Chen J, Yao H, Liu J, Yu S, Lao L, et al. CD10+ GPR77+ cancer-associated bro-
blasts promote cancer formation and chemoresistance by sustaining cancer stemness.
Cell. 2018;172:841–856.
18. Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA, et al. Stromal
elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer
Cell. 2014;25:735–747.
19. Özdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu C-C, Simpson TR,
et al. Depletion of carcinoma-associated broblasts and brosis induces immuno-
suppression and accelerates pancreas cancer with reduced survival. Cancer Cell.
2014;25:719–734.
20. Bhattacharjee S, Hamberger F, Ravichandra A, Miller M, Nair A, Affo S, et al. Tumor
restriction by type I collagen opposes tumor-promoting effects of cancer-associated
broblasts. J Clin Invest. 2024;131.
21. Chen Y, McAndrews KM, Kalluri R. Clinical and therapeutic relevance of cancer-
associated broblasts. Nat Rev Clin Oncol. 2021;18:792–804.
22. Jungwirth U, van Weverwijk A, Evans RJ, Jenkins L, Vicente D, Alexander J, et al.
Impairment of a distinct cancer-associated broblast population limits tumour growth
and metastasis. Nat Commun. 2021;12:3516.
23. Wienke D, Davies GC, Johnson DA, Sturge J, Lambros MBK, Savage K, et al. The
collagen receptor Endo180 (CD280) is expressed on basal-like breast tumor cells and
promotes tumor growth in vivo. Cancer Res. 2007;67:10230–10240.
65Cancer-Associated Fibroblasts and Glioblastoma
24. Jenkins L, Jungwirth U, Avgustinova A, Iravani M, Mills A, Haider S, et al. Cancer-
associated broblasts suppress CD8+ T-cell inltration and confer resistance to
immune-checkpoint blockade. Cancer Res. 2022;82:2904–2917.
25. Kakarla S, Chow KKH, Mata M, Shaffer DR, Song X-T, Wu M-F, et al. Antitumor
effects of chimeric receptor engineered human T cells directed to tumor stroma. Mol
Ther. 2013;21:1611–1620.
26. Wang L-CS, Lo A, Scholler J, Sun J, Majumdar RS, Kapoor V, et al. Targeting broblast
activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit
tumor growth and augment host immunity without severe toxicity. Cancer Immunol
Res. 2014;2:154–166.
27. Akai M, Noma K, Kato T, Nishimura S, Matsumoto H, Kawasaki K, et al. Fibroblast
activation protein-targeted near-infrared photoimmunotherapy depletes immunosup-
pressive cancer-associated broblasts and remodels local tumor immunity. Br J Cancer.
2024;130:1647–1658.
28. Younes A, Berdeja JG, Patel MR, Flinn I, Gerecitano JF, Neelapu SS, et al. Safety,
tolerability, and preliminary activity of CUDC-907, a rst-in-class, oral, dual
inhibi
tor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or
multiple myeloma: An open-label, dose-escalation, phase 1 trial. Lancet Oncol.
2016;17:622–631.
29. Slavin S, Yeh C-R, Da J, Yu S, Miyamoto H, Messing EM, et al. Estrogen receptor α
in cancer-associated broblasts suppresses prostate cancer invasion via modulation of
thrombospondin 2 and matrix metalloproteinase 3. Carcinogenesis. 2014;35:1301–1309.
30. Yeh C-R, Slavin S, Da J, Hsu I, Luo J, Xiao G-Q, et al. Estrogen receptor α in cancer
associated broblasts suppresses prostate cancer invasion via reducing CCL5, IL6 and
macrophage inltration in the tumor microenvironment. Mol Cancer. 2016;15:1–14.
31. Paulsson J, Micke P. Prognostic relevance of cancer-associated broblasts in human
cancer. Semin Cancer Biol. 2014;25:61–68, Elsevier.
32. Lockwood DSR, Yeadon TM, Clouston AD, Crawford DG, Fawcett J, Callaghan SA,
et al. Tumor progression in hepatocellular carcinoma: Relationship with tumor stroma
and parenchymal disease. J Gastroenterol Hepatol. 2003;18:666–672.
33. Abbas O, Mahalingam M. Desmoplasia: Not always a bad thing. Histopathology.
2011;58:643–659.
34. Kretzschmar K, Weber C, Driskell RR, Calonje E, Watt FM. Compartmentalized epi-
dermal activation of β-catenin differentially affects lineage reprogramming and under-
lies tumor heterogeneity. Cell Rep. 2016;14:269–281.
35. Arina A, Idel C, Hyjek EM, Alegre M-L, Wang Y, Bindokas VP, et al. Tumor-associated
broblasts predominantly come from local and not circulating precursors. Proc Natl
Acad Sci. 2
016;113:7551–7556.
36. Öhlund D, Handly-Santana A, Bif G, Elyada E, Almeida AS, Ponz-Sarvise M, et al.
Distinct populations of inammatory broblasts and myobroblasts in pancreatic can-
cer. J Exp Med. 2017;214:579–596.
37. Beacham DA, Cukierman E. Stromagenesis: The changing face of broblastic microen-
vironments during tumor progression. Semin Cancer Biol. 2005;15:329–341, Elsevier.
38. Alcolea MP, Jones PH. Tracking cells in their native habitat: Lineage tracing in epithe-
lial neoplasia. Nat Rev Cancer. 2013;13:161–171.
39. Ping Q, Yan R, Cheng X, Wang W, Zhong Y, Hou Z, et al. Cancer-associated broblasts:
Overview, progress, challenges, and directions. Cancer Gene Ther. 2021;28:984–999.
40. Pallangyo CK, Ziegler PK, Greten FR. IKKβ acts as a tumor suppressor in cancer-
associated broblasts during intestinal tumorigenesis. J Exp Med. 2015;212:2253–2266.
41. Koliaraki V, Pasparakis M, Kollias G. IKKβ in intestinal mesenchymal cells promotes
initiation of colitis-associated cancer. J Exp Med. 2015;212:2235–2251.