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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5346_Библиотеки_им_академика_М_И_Перельмана
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248 Kai Shi
reduced expression of VCAM-1 could not be completely restored. Delfortrie et al.
have also shown that Egfl7, also known as VE-statin that is expressed in a variety
of carcinomas, promoted tumor escape by impeding the expression of VCAM-1
on tumor vascular endothelial cells [41]. The downregulation of VCAM-1 serves
most probably as a tumor protecting mechanism by attenuating the immune response
for leukocyte infiltration [42]. The proangiogenic factors produced by tumor cells,
such as bFGF and VEGF, contributed to the decreased expression of ICAM-1 in vascular endothelial cells [43].
(3) CD34, as a typical antigen protein of hematopoietic progenitor cells, is also
expressed in vascular endothelial cells. As the ligand of L-selectin, CD34 mediates
the leukocyte adhesion to specialized vascular endothelium [44]. As we all know that
the recruitment of primordial lymphocytes into secondary lymphoid organs is a multistep process that involves, as a first step, their L-selectin dependent rolling to the
specialized lymphoid vascular endothelia termed “high endothelial venules” (HEVs)
with low affinity. Then come integrin-mediated sturdy arrest and transendothelial
cell migration [45]. When CD34 is expressed in HEVs, they are appropriately
glycosylated to interact with L-selectin on lymphocytes and thereby provide ligands
for this adhesive interaction. The decreased level of CD34 hinders the rolling of
leukocytes that is dependent on CD34/L-selectin interaction, thereby impeding
the initiation of leukocyte adhesion and tumor infiltration [46, 47] (Fig. 2).
2.2 Extracellular matrix
Extracellular matrix (ECM) is a complex noncellular and dynamic structure where cells
reside, remodel and interact to allow tissue homeostasis, differentiation and histomorphogenesis [48]. The ECM is composed of locally sequestering biomacromolecules
secreted by epithelial cells and stromal cells, which is typically classified into three categories
according to their functions: ① structural proteins, including collagen and elastin, that are
organized into a fibrillar network and provide tensile strength to the skeleton of ECM. ②
connexins, including fibronectin (FN), laminin (LN) and tenascin (TN), that provide
adhesive binding sites for cell binding and thereby facilitating the process of cell adhesion,
spreading, migration and even differentiation. ③ Proteoglycan (PG) and its graft glycosaminoglycans(GAG), includinghyaluronicacid (HA),chondroitin sulfate,heparin,heparin sulfate (HS) and keratan sulfate, which indirectly sequester water molecules through a
cationic intermediary, resulting in a hydrogel-like network, and endows ECM with unique
biophysical properties such as high compressive strength, viscoelastic effects, and streaming
potentials [49]. In terms of spatial structure, ECM is typically divided into basement membrane (BM) and interstitial connective tissue (ICT) which are responsible for separating the
epithelium from the surroundingstroma.ICT primarilyconsistsof collagenI and FN, which
provides a structural scaffold for tissues and controls the differentiation of resident cells
249Stromal modulation strategies
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Fig. 2 Immune escape mechanisms in the perivascular niche. Effector T cells encounter multiple hurdles presented by the tumor endothelium and stromal cell types which are located in the perivascular
niche such as pericytes, mesenchymal stem cells, macrophages, and fibroblasts. Furthermore, migration through the noncellular basement membrane/ECM is required to establish contact with tumor
cells. Reproduced with permission from Johansson A, Hamzah J, Ganss R. More than a scaffold: stromal
modulation of tumor immunity. Biochim Biophys Acta Rev Cancer 2016;1865(1):3–13, copyright © 2016
Elsevier Ltd.
through interacting with their surface receptors. In contrast, the BM is denser than ICT and
composed of collagen IV, LN, HS and proteoglycan [50]. In addition, lysyl oxidase (LOX),
matrix metalloproteinases (MMPs) and other regulatory enzymes responsible for the posttranslational processing of ECM proteins are often considered as components of ECM.
2.2.1 Deregulated ECM remodeling
The cytoskeleton remodeling, structural plasticity and mechanical strength of ECM are
increasingly recognized as the key factors that determine the migration and spatial distribution of infiltrating immune cells. The biomechanical properties of ECM are strictly
regulated by the specific components in the matrix as well as post-translational modifications, such as glycosylation, transglutamination and crosslinking [51]. The occurrence
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of collagen crosslinking is primarily mediated by lysyl oxidase (LOX) and the LOX family
of secreted amine oxidases, which catalyze the crosslinking of collagen through the oxidative deamination of lysine residues. Concurrently, components of ECM undergo degradation by matrix-degrading enzymes, including heparanase, cathepsins, hyaluronidases,
matrix metalloproteases (MMPs), and ADAMs (a disintegrin and metalloproteinases).
This tightly regulated ECM homeostasis is sensitive to the altered expression of these proteases, and will lead to excessive ECM remodeling upon abnormal changes occur [52].
It is known that the poor diffusion in ECM together with the structural and functional
abnormalities in tumor vasculature lead to a reduced oxygen availability in the regions of
solid tumor stroma [53]. As one of the target gene products regulated by hypoxiainducible factor (HIF), the expression and activity level of LOX enzymes showed
remarkable enhancement in response to hypoxia, which in turn led to the accumulation
of abundant collagens in the tumor stroma as a result of desmoplasia [54]. The
crosslinking of collagens is primarily initiated by the LOX family of secreted enzymes,
which are usually overexpressed in a variety of tumors and negatively correlated with
the survival rate of patients. It has been found that collagen crosslinking induced by
LOX promoted the invasion of premalignant epithelium into a stiffened, cross-linked
ECM, as well as clustering of β1 integrin that facilitated focal adhesions and PI3K signaling enhancement [51]. More importantly, the excessive collagen deposition and
cross-linkage contributes to the stiffening of ECM through extensive post-translational
modifications that increase tensile strength, in addition to the building of an interstitial
matrix. The elevated hypoxia and metabolic stress caused by poor diffusion in stiff tumor
ECM lead to the upregulation of multiple immunosuppressive cytokines such as IL-10,
TGF-β, PGE2 and VEGF-A [55]. In particular, TGF-β induces anergy of infiltrating
+
CD8
cytotoxic lymphocytes (CTLs) and natural killer (NK) cells in TME by recruitment of Tregs and polarized macrophages into M2 type. VEGF-A is able to attract Tregs
expressing Nrp1, a coreceptor of VEGF, and directly inhibit the activation of T cells [56].
2.2.2 ECM determines the migration and distribution of immune cells
One of the prerequisites for immunotherapy to work is that the immunomodulatory
molecules and effector lymphocytes penetrate the tumor stroma and contact with target
tumor cells. In view of the fact that the infiltration rate is highly predictive of the immune
response, the low infiltration rate of T lymphocytes to solid tumors suggests that it has
become a major obstacle to the successful application of immunotherapy in cancer
patients, especially breast and pancreatic cancer. It is known that the infiltration rate
of lymphocytes not only depends on the strength of the immunogenicity that confers
immune responses to tumor cells, but also on the ECM shield [57]. Due to the lack
of lymphatic drainage, the distribution of immunomodulators in solid tumors mainly
occurs through diffusion. Accordingly, abundant and highly compact ECM inevitably
attenuates the infiltration of either drugs or lymphoid effector cells, resulting in only poor
paratumoral tissues being supplied by individual vessels [58]. In particular, since most of
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the immunomodulatory drugs used in clinic are therapeutic antibodies, and their large
hydrodynamic diameters hinder the effective diffusion of these biological macromolecules by dense, highly cross-linked ECM [59].
The highly stiffened ECM rich in collagen fibers not only dominates the distribution
of immunomodulatory drugs, but also confines the infiltration of immune effector cells
into tumor stroma. Upon being recruited to the tumor growth side along the chemokine
gradient, immune cells will often deviate from the original direction when facing the
dense shield of ECM around the malignant cell niche, thus following the gradient of
gradually increasing rigidity and the adhesion sites provided by ECM, resulting in the
off-target effects [60]. Studies have shown that the infiltration of T cells dependent on
chemokines occurs only in the areas of loose fibronectin and collagen, whereas impaired
within the dense interstitial fibers surrounding the tumor islets, thereby resulting in preferential stromal accumulation of T cells while limited tumor infiltration [61]. Salmon
et al. found that the migration and final distribution of T cells in the lung tumor stroma
are dominated by the aligned collagen fibers surrounding the tumor islets and perivascular
regions in the tumor stroma, which lead to the majority of immune cells accumulated in
the stroma entrapped without being able to approach the target tumor cells for killing
[62]. Treatment with collagenase alleviates this stromal capturing effect and enhances
the neoplastic infiltration of lymphocyte. In a cohort of patients with urothelial cancer,
Mariathasan et al. demonstrated the clinical significance of this shielding function of stromal ECM to keep immune cells away from malignant cells at a certain distance, where the
nonresponse to PD-L1 checkpoint inhibition is was related to the stromal embedding of
CTLs by ECM [63].
251Stromal modulation strategies
2.2.3 ECM remodeling mediated immune escape
As the major process of ECM remodeling, the cleavage of ECM components is of great
significance to regulate the abundance, composition and structure of ECM, as well as to
release bioactive regulatory substances. ECM acts as a reservoir of immunomodulatory
cytokines and growth factors, which are released upon their proteolytic degradation
[64]. The lysates of the ECM can exert influence on immune surveillance by themselves.
Pancreatic ductal adenocarcinoma (PDAC) typically produces a collagen-rich fibrotic
extracellular matrix (ECM) referred to as “desmoplastic reaction,” through which the
expression of membrane-type 1-matrix metalloproteinase (MT1-MMP) is elevated.
By proteolytic processing TGF-β-binding protein-1 (LTBP-1), MT1-MMP releases
latent TGF-β1 from the ECM, which leads to the enhanced collagen production by
PDAC stellate cells and thereafter an aggravated fibrotic tumor stroma [65].
In addition, many ECM proteins also contain domains similar in structure to
chemokines and cytokines, which can be exposed by stromal remodeling enzymemediated proteolysis, and the cleavage liberates a variety of biologically active peptide
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fragments, namely matrikines [66]. They are able to act as chemokines or cytokines to
modulate processes of tumor progression, including migration, differentiation and
immune surveillance. Matrix metalloproteinases (MMPs) are a group of zinc/calciumdependent endogenous proteolytic enzyme family involved in the degradation of
ECM, which are synthesized and secreted by fibroblasts, neutrophils, macrophages
and tumor cells [67]. Their activities are usually negligible under normal physiological
conditions, whereas significantly elevated during the process of stromal remodeling or
inflammation. Upon secreted into the ECM as the form of zymogens, MMPs are activated to cleave the components of ECM including interstitial collagen, proteoglycans and
glycoproteins, resulting in the release of matrikines. Besides, MMPs and ADAMs are also
involved in the shedding of major histocompatibility complex type I chain-associated
molecule A (MICA) from tumor cells, a surface ligand that specifically activates receptor
of NKG2D in immune effector cells, thereby allowing tumor cells to evade immune surveillance [68, 69].
2.3 Cancer-associated fibroblasts
In most types of cancers, fibroblasts are the predominant cellular component of tumor
stroma. The cancer-related fibroblasts (CAFs), also known as tumor-associated fibroblasts
(TAFs), myofibroblasts or active stromal fibroblasts, refer to a population of activated
fibroblasts in the tumor stroma [70]. Compared with resting fibroblasts in normal adult
tissues, this cell population has undergone significant changes in morphological characteristics and functional protein expression as well as other biological characteristics. The
main manifestations are that the cells are spindle-shaped, larger in size, and the nucleus has
obvious depressions or notches. Moreover, a variety of contractile filaments and tension
filaments were found in the cytoplasm, and rich in the rough endoplasmic reticulum [71].
Therefore, they are more similar to those transiently present in the developing fetus and
wound healing process. Like their wounds or fetal counterparts, CAFs exhibit enhanced
motility and proliferation, and provide essential functions to promote tumor survival and
growth [72].
2.3.1 Heterogeneity of CAFs
CAFs are a highly heterogeneous cell population, which mainly originates from five types
of precursor cells: (1) Resident fibroblasts, which are derived from normal fibroblasts
within the surrounding stroma under the stimulation of TGF-β and PDGF secreted
by tumor cells [73]. (2) Vascular smooth muscle cells and adventitia cells migrate from
the vascular basement membrane to the mesenchyme and then transdifferentiate into
CAFs. (3) Bonemarrow-derived mesenchymal stem cells (BMSC) can migrate to the
tumor stroma and differentiate into CAFs, promoting the growth and migration of tumor
cells [74]. (4) Tumor epithelial cells and endothelial cells can transform into CAFs
through an epithelia-mesenchymal transition (EMT) and endothelial-mesenchymal
transition (EndMT) respectively, in which TGF-β is the main driving force. (5) Adipo-
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cytes or adipose tissue-associated fibroblasts have similar molecular characteristics and
secretion phenotypes (such as increased expression of EGF, ECM and MMP), which
changes the microenvironment of adjacent epithelium and promote the proliferation
and tumorigenicity of epithelial cells, and even tumorigenicity, which may be another
source of CAFs [75].
In addition to the heterogeneity of origin, CAFs are also heterogeneous in phenotype.
Molecular markers such as vimentin, type I collagen, fibronectin and prolyl 4-hydroxylase
are often observed in interstitial fibroblasts. Upon activated into CAFs, the expression of
some molecules will be specifically up-regulated, such as α-smooth muscle actin (α-SMA),
tenascin C, chondroitin sulfate proteoglycan (CSPG), platelet-derived growth factor
receptor α/β (PDGFRα/β), fibroblast specific protein-1 (FSP-1), paladin, podoplanin,
etc. [76]. Concurrently, the expression of epithelial cell markers such as cytokeratin and
endothelial cell markers such as CD31 disappeared in CAFs. These differentially expressed
molecules can be used as molecular markers of CAFs, but they are not specific markers and
are also expressed to varying degrees in other stromal cells [77].
2.3.2 CAFs regulate immunity via paracrine pathway
As the main stromal cells of the TME (the proportion in some tumor interstitial tissues is
as high as 90%), CAFs are mainly distributed in the front of tumor invasion, tumor mesenchymal interface or adjacent to the vascular endothelial cells in the tumor stroma and
surround the cancer nest [78]. They maintain interaction with tumor cells and endothelial
cells, and thus play an important regulatory role in tumor occurrence, development and
metastasis. In recent years, a considerable number of research reports have clarified the
relationship between CAFs and tumors, providing a theoretical basis for CAFs as a new
target for tumor therapy. CAFs not only promote the growth and metastasis of tumor
cells through paracrine, but also regulate angiogenesis and tumor immunity through
interaction with other cells [79].
Once activated into CAFs, fibroblasts can secrete a considerable amount of soluble
cytokines, such as chemokine ligand 12 (CXCL12), chemokine ligand 7 (CCL7), transforming growth factor β (TGF-β), hepatocyte growth factor (HGF), insulin-like growth
factor (IGF), etc. [80]. These secreted cytokines can crosstalk with the corresponding
receptors or ligands expressed on adjacent tumor cells, and promote the malignant behavior of tumor cells through a complex paracrine signal network. Among them, TGF-β is
particularly concerned, and HGF and CXCL12 are also molecules that have been studied
more. The TGF-β secreted by CAFs induces epithelial-mesenchymal transition (EMT) of
tumor cells through the TGF-β/Smad signaling pathway, which leads to remodeling of the
extracellular stroma, thereby creating a permissive microenvironment for tumor invasion
and distant metastasis [81]. Studies have shown that Wnt7a secreted by aggressive breast
cancer cells could enhance the activity of the TGF-β receptors, and the activation of
253Stromal modulation strategies
254 Kai Shi
TGF-β pathway facilitated the conversion of fibroblasts into CAFs [82]. HGF secreted by
CAFs regulates the growth, proliferation, and invasion of a variety of tumor cells by acting
on the c-met receptor on tumor cells and thereafter activating the tyrosine signaling
cascade [83]. As a chemokine highly expressed in CAFs, CXCL12 induced tumor cells
to undergo EMT in breast and prostate cancer upon binding with CXCR4 ligand
expressed on tumor cells, thereby promoting the proliferation of breast cancer cells and
metastasis of prostate cancer. In addition, CXCL12 also mediates the recruitment of endothelial progenitor cells by CAFs, thus stimulating neovascularization [84].
2.3.3 CAFs regulate immunity by remodeling ECM
The differentiation and function of related immune cells in the TME depend to a large
extent on the structure and physicochemical characteristics of the surrounding tissues,
especially the hardness, density and plasticity of the ECM. The activated CAFs can
secrete a large amount of enzymes and proteins related to extracellular matrix remodeling, such as Fas-associated phosphatase (FAP), MMP as well as fibronectin and type
I collagen [85]. As a membrane-bound glycoprotein, FAP can activate related growth
factors in the ECM, thereby promoting tumor cell proliferation and angiogenesis.
MMP is a group of endopeptidase that can directly decompose the cadherin in the extracellular domain to cause the disintegration of normal epithelium, which in turn leads to
the occurrence of EMT and the destruction of the histological barrier against tumor cell
invasion, thereby contributing to the infiltration and metastasis of malignant tumors [86].
As a major regulatory enzyme of collagen secretion, the expression level of lysyl oxidase
(LOX) in CAFs was significantly increased, which can promote the synthesis of collagen
by CAFs and enhance the hardness of ECM, so that the ECM could facilitate tumor cell
metastasis while inhibiting immune cell infiltration [87]. In human pancreatic cancer, the
hardness of ECM and the rich content of type I collagen can promote the excessive secretion of chemokines CCL2 and CSF-1 by tumor cells and CAFs, resulting in abundant
infiltration of TAMs [88].
Another important consequence of the ECM remodeled by CAFs in the TME is to
further aggravate the hypoxic environment [89]. The existence of Warburg effect in
tumor cells and a large number of abnormal blood vessels cause a decrease in the partial
pressure of oxygen in the TME. Studies have shown that decreased oxygen partial pressure can increase the expression levels of collagen related genes in fibroblasts, so it is a
positive regulation of collagen secretion by CAFs [90]. The hypoxic TME plays an
important role in preventing immune surveillance, which can induce the secretion of
chemokines and promote the recruitment of immunosuppressive cells including TAMs
and MDSCs [91, 92]. In addition, CAFs-mediated signaling pathways can regulate the
cytoskeleton, promote the generation of tension in the tumor stroma, and enhance
the stiffness of ECM to support the malignant process [93].
2.3.4 CAFs regulate immunity by promoting tumor angiogenesis
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Tumor vasculatures are the channels of tumor nutrition supply and tumor cell dissemination, which play an important role in tumor growth and metastasis. CAFs induce
the formation of vascular endothelial cell networks in the tumor stroma by secreting vascular endothelial cell growth factors such as VEGF and FGF, or recruiting CXCR4
positive endothelial progenitor cells, thereby promoting tumor angiogenesis [94] . The
TGF-β and SDF-1 secreted by CAFs can also elevate the expression of E-cadherin,
MMP-2 and laminin-5γ2 through TGF-βR1 and CXCR4 axis of tumor cells, thereby
ultimately promoted the formation of vascular mimicry [95]. Studies have shown that
stromal-derived WNT2 promotes the angiogenesis in colorectal cancer (CRC) by
increasing EMT molecules related to angiogenesis, such as ANG-2, IL-6, G-CSF, and
PGF [96]. CAFs can be induced by autocrine CXCL14 to secrete FGF-2, VEGF and
other cytokines to promote tumor angiogenesis [97]. The activation of Ets2 (v-ets erythroblastosis virus E26 oncogene homolog 2) in breast stromal fibroblasts can also induce
the expression of a large number of tumor-related genes such as MMP9, VEGF-A, etc.,
and recruit endothelial progenitor cells to jointly induce and promote the process of
tumor angiogenesis [98].
It is known that the increase in the number of tumor vasculatures is closely related to
the degree of immune cells infiltrating into the TME. Therefore, CAFs can regulate
tumor immunity by promoting angiogenesis theoretically. The angiogenic effect of
CAFs can also enhance the infiltration of CD8
+
lymphocyte, which contributes to
the antitumor response of the immune system to a certain extent [99]. However, studies
have shown that CAF can also facilitate the immune escape and metastasis of tumor cells
by promoting the growth of blood vessels. In addition, the platelet-derived growth factor
(PDGF) secreted by CAFs can cause leakage of tumor microvessels, resulting in higher
interstitial fluid pressure within the tumor stroma, which will not only create mechanical
obstacles to chemotherapy drugs, but also facilitate the metastasis of immunosuppressive
cells in tumor stroma [100].
255Stromal modulation strategies
2.3.5 Regulatory effects of CAFs on innate immune cells
In recent years, CAFs have attracted more and more attention due to their ability to regulate the recruitment and functions of immune cells in the tumor stroma [101] (Fig. 3).
(1) TAMs
TAMs are macrophages that infiltrate in the tumor stroma, performing the same
kinds of functions as alternatively activated M2 macrophages, for instance, secreting
immunosuppressive cytokines as well as growth factors that inhibit T cell proliferation
and activation, promoting tumor cell growth, participating in tumor angiogenesis,
and facilitating tumor invasion and metastasis [102]. While in the presence of Th1
cytokines, they can be reprogrammed toward the classically activated M1 phenotype
that holds the responsibility for promoting inflammation and tumor inhibition [103].
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Fig. 3 CAFs-mediated immunosuppression: CAFs shape the immune microenvironment in tumors
toward a protumorigenic and immunosuppressive milieu by affecting the recruitment and function
of various innate and adaptive immune cells. Reproduced with permission from and produced by
Monteran L, Erez N. The dark side of fibroblasts: cancer-associated fibroblasts as mediators of immunosuppression in the tumor microenvironment. Front Immunol 2019;10:1835.
Accumulated evidence indicates that CAFs exert functions of driving epithelialmesenchymal transition (EMT) and cross-talking with M2 macrophages, thereafter
promoting the occurrence and development of malignant tumors [104].
In order to identify the role of CAFs in the recruitment of monocytes as well as
the polarization of macrophages in mammary cancer, the research work by Gok
Yavuz et al. showed that CAFs, distinguished from normal fibroblasts (NFS), could
highly express α-SMA and effectively recruit monocytes mediated by cytokines of
monocyte chemotactic protein-1 (MCP-1) and stromal cell-derived factor-1
(SDF-1) [105]. Once recruited by CAFs into the tumor stroma, monocytes differentiate into M2-like macrophages, and then exert their immunosuppressive effects
through the PD-1/PD-L1 axis. Different from the ones educated by NFS, CAFs
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induced monocytes not only showed a prominent immunosuppressive effect
manifested as a significant suppression of T cell proliferation, but also up-regulated
the expression levels of Snail, Slug and Twist genes associated with EMT, as well
as promoting their metastasis and invasion. The study has also revealed that CAFs were
able to repolarize differentiated M1 macrophages into M2-like ones, which were
characterized by the elevated expression of CD163 and production of antiinflammatory cytokines such as IL-10, while the decreased level of proinflammatory
cytokines such as IL-12. Analysis of tumor tissue sections derived from breast cancer
patients suggested that the degree of CAFs infiltration was highly correlated with the
density of TAMs and the proliferation of tumor cells. When addressing the cross-talk
mechanism between CRC-derived CAFs and TAMs, Zhang et al. proposed a model
involving immunosuppression occurring in the microenvironment of colorectal
carcinomas [106]. Their results showed that CAFs were responsible for recruiting
monocytes into tumor stroma by secreting IL-8, rather than SDF-1. The infiltrated
monocytes were then repolarized into M2-like macrophages mediated with the IL-8/
CXCR2 pathway. Alongside, CAFs enhanced the phosphorylation of ERK1/2 and
the expression of VCAM-1 in colorectal cancer (CRC) cells via IL-6 secretion,
thereby facilitating the adhesion of recruited monocytes. Accordingly, the synergy
of CAFs and TAMs contributed to the dysfunction of NK cells, which was manifested
as the attenuated expression of CD27 and CD107a, two marker receptors indicating
the cytokines secretion and degranulation during NK cells killing.
The Jak/STAT axis initiated by IL-4 and IL-13 has been recognized as necessary
signaling to regulate M2 polarization of macrophages [107]. Comito et al. showed
that SDF-1, a stromal cell-derived factor that is indispensable for crosstalk between
CAFs and other cells in the tumor stroma, could recruit monocytes and differentiate
them into the M2 phenotype via SDF-1/CXCR4 [108]. Although MCP-1 produced by pancreatic cancer cells was also able to drive monocytes to recruit to tumor
sites, it can hardly induce their polarization toward the M2-macrophage phenotype.
Alongside, IL-6 produced by invasive pancreatic cancer cells and CAFs did not has
the function of recruiting monocytes, but can polarize them into the M2 phenotype.
In addition, there exists a reciprocal relationship between M2 polarized macrophages
and CAFs, where M2 macrophages were able to activate human prostate fibroblasts
through mesenchymal-mesenchymal transition and polarize them into myofibroblasts or CAFs, which possessed functions of promoting the invasiveness,
EMT and stemness of pancreatic cancer cells.
The signal transduction mediated by myeloid growth factor (CSF1) and its
receptor CSF1R plays a key role in regulating the differentiation and function of
TAM. The employment of CSF1R antagonists has shown the potential to eliminate
tumor-associated macrophages (TAM), while they just showed a limited ability to
257Stromal modulation strategies
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