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Citation: Oncul, S.; Cho, M.S.
Interactions between Platelets and
Tumor Microenvironment
Components in Ovarian Cancer and
Their Implications for Treatment and
Clinical Outcomes. Cancers 2023,15,
1282. https://doi.org/10.3390/
cancers15041282
Academic Editor: David Wong
Received: 13 January 2023
Revised: 7 February 2023
Accepted: 13 February 2023
Published: 17 February 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
cancers
Review
Interactions between Platelets and Tumor Microenvironment
Components in Ovarian Cancer and Their Implications for
Treatment and Clinical Outcomes
Selin Oncul and Min Soon Cho *
Section of Benign Hematology, Department of Pulmonary Medicine, The University of Texas MD Anderson
Cancer Center, Houston, TX 77030, USA
*Correspondence: mscho@mdanderson.org; Tel.: +1-713-792-3987
Simple Summary:
Despite initially responding to treatment, many ovarian cancers recur because of
tumor cell heterogeneity, chemoresistance, and the cancer-promoting and immunosuppressive tumor
microenvironment. Recurrent tumors account for the reduced overall and progression-free survival
of patients with ovarian cancer. Ovarian cancer is commonly accompanied by thrombocytosis
and thrombotic events, which implies that platelets may participate in cancer progression via their
association with cancer cells and the tumor microenvironment. This review focuses on platelets’
interactions with cellular and acellular components of the tumor microenvironment, including
endothelial cells, mesenchymal stem cells, adipocytes, pericytes, immune cells, and extracellular
matrix elements, and discusses how these interactions support the proliferation and metastasis of
ovarian cancer cells. It also provides an overview of potential therapeutic strategies that obstruct
platelets’ protumor effects by reprogramming the tumor microenvironment.
Abstract:
Platelets, the primary operatives of hemostasis that contribute to blood coagulation and
wound healing after blood vessel injury, are also involved in pathological conditions, including
cancer. Malignancy-associated thrombosis is common in ovarian cancer patients and is associated
with poor clinical outcomes. Platelets extravasate into the tumor microenvironment in ovarian cancer
and interact with cancer cells and non-cancerous elements. Ovarian cancer cells also activate platelets.
The communication between activated platelets, cancer cells, and the tumor microenvironment is via
various platelet membrane proteins or mediators released through degranulation or the secretion of
microvesicles from platelets. These interactions trigger signaling cascades in tumors that promote
ovarian cancer progression, metastasis, and neoangiogenesis. This review discusses how interactions
between platelets, cancer cells, cancer stem cells, stromal cells, and the extracellular matrix in the
tumor microenvironment influence ovarian cancer progression. It also presents novel potential
therapeutic approaches toward this gynecological cancer.
Keywords:
ovarian cancer; platelet; tumor microenvironment; metastasis; angiogenesis; thrombosis;
immune system
1. Introduction
Ovarian cancer is the fifth most common cause of death among women and the most
lethal gynecological malignancy in the United States [
1
]. Epithelial ovarian cancer, which
accounts for 90% of ovarian cancers, is further categorized into serous, endometrioid, muci-
nous, and clear cell types, in addition to other rare or non-specified subgroups [
2
]. The most
prevalent type of epithelial ovarian cancer, high-grade serous ovarian cancer (HGSOC),
originates in the fallopian tubes or ovarian surface epithelium and disseminates to the
ovaries and peritoneum [
3
]. HGSOC, which carries a poor prognosis, is often aggressive,
diagnosed in its late stages, and has a high capacity for metastasis and ascites formation [
2
].
Cancers 2023,15, 1282. https://doi.org/10.3390/cancers15041282 https://www.mdpi.com/journal/cancers
Cancers 2023,15, 1282 2 of 37
Non-epithelial ovarian cancers (e.g., germ cell and sex cord–stromal) constitute approxi-
mately 10% of all ovarian cancers and are generally less aggressive than epithelial ovarian
cancer [
4
]. Risk factors for ovarian cancer include genetic alterations, including germline
mutations of breast cancer genes 1 and 2 (BRCA1 and BRCA2) [
5
] and alternative mutations
of DNA damage repair-associated genes such as BRIP1,RAD51, and ATM/ATR [
6
,
7
]; Lynch
syndrome [
8
]; and various environmental factors such as hormone replacement therapy [
9
],
not giving birth and/or not breastfeeding [
10
], being overweight [
11
], and frequent tobacco
smoking [
12
]. The conventional therapy for ovarian cancer is surgical excision of the tumor
along with neoadjuvant or adjuvant platinum- or taxane-based chemotherapy [
13
]. Addi-
tional treatments include using agents that target proangiogenic factors, poly (ADP-ribose)
polymerase (PARP), and immune system components [3].
Despite marked improvements in the efficacy of treatments, ovarian cancer is asso-
ciated with high mortality because of late diagnosis due to its anatomical location and
mostly indistinguishable symptoms, high recurrence rate [
2
], primary or acquired resis-
tance to chemotherapy [
3
,
4
], and tumor heterogeneity [
5
]. Thus, more specific and effective
approaches are in demand to inhibit tumor growth and prolong patient progression-free
survival and overall survival. Because the tumor microenvironment (TME) is a princi-
pal contributor to cancer progression and poor therapeutic response [
6
,
7
], targeting TME
components holds excellent potential for more effective cancer management.
The TME comprises cancer cells; cancer stem cells (CSCs); stromal cells such as
fibroblasts; endothelial cells; immune cells; and proteins of the extracellular matrix (ECM)
such as collagen and fibronectin [
8
]. Crosstalk among these components constitutes a
complex signaling network that promotes malignancy and metastasis [
9
]. Accumulating
evidence indicates that TME has a role in the development and progression of ovarian
cancer [
10
,
11
], and many studies manipulate TME in the treatment of ovarian cancer [
12
,
13
].
One of the components of TME in ovarian cancer is extravasated platelets [
14
,
15
]. Mem-
brane proteins on activated platelets, including P-selectin [
16
], GPIb
α
[
17
], GPIIb/IIIa [
18
],
and C-type lectin-like receptor 2 (CLEC-2) [
19
], mediate the binding of platelets to various
elements in the TME. The released contents of granules from activated platelets, such as
growth hormones [
20
], cytokines [
21
], and chemokines [
22
], also affect the TME. Addition-
ally, platelet microparticles [
23
], mitochondria [
24
], and nucleic acids [
25
,
26
] can reshape
the TME response in cancer. The major molecules on platelets or in their granules are
listed in Table 1. We also summarize the protumorigenic and antitumorigenic influences
of various platelet-associated molecules in the TME in Table 2. The interactions between
platelets and the TME components of ovarian cancer are illustrated in Figure 1.
Healthy individuals have platelet counts of between 150,000 and 450,000 per micro-
liter of blood. In contrast, roughly one-third of newly diagnosed ovarian cancer patients
have platelet counts exceeding 450,000 per microliter [
27
]. In patients with ovarian cancer,
thrombocytosis is an adverse prognostic factor associated with elevated serum carcinoma
antigen 125 (CA-125) levels, advanced disease stage, and poor clinical outcomes [
27
,
28
],
as well as the diminished efficacy of secondary cytoreductive surgery [
29
] and chemother-
apy [
30
]. Aside from contributing to the formation of venous thromboembolisms, platelets
contribute to cancer progression via distinct mechanisms, including increasing prolifera-
tion [
31
], epithelial–mesenchymal transition (EMT) [
32
], and anoikis resistance in cancer
cells [
33
]; promoting the formation of the premetastatic niche and metastasis [
33
]; en-
hancing angiogenesis [
27
] and the integrity of tumor vasculature [
34
]; inducing immune
tolerance [35]; and reducing the impact of chemotherapy [30].
Cancers 2023,15, 1282 3 of 37
Cancers 2023, 15, x FOR PEER REVIEW 4 of 38
junctional adhesion molecule; LPA: lysophosphatidic acid; MCP-1: monocyte chemoattractant pro-
tein 1; MIP: migration inhibitory protein; MMP: matrix metalloproteinase; NAP-2: neutrophil-acti-
vating peptide 2; PAF: platelet-activating factor; PAI-1: plasminogen activator inhibitor 1; PAR: pro-
tease-activated receptor; PD-L1: programmed death ligand 1; PDGF: platelet-derived growth factor;
PECAM-1: platelet endothelial cell adhesion molecule 1; PF4: platelet factor 4; PGD2: prostaglandin
D2; PGE2: prostaglandin E2; PGI2: prostaglandin I2; polyP: polyphosphate; RANTES: regulated
upon activation and normal T cell expressed and secreted; S1P: sphingosine 1-phosphate; SDF-1:
stromal-derived factor 1; TGF-β: transforming growth factor-beta; TIMP: tissue inhibitor of metal-
loproteinases; TLR: Toll-like receptor; TNF-α: tumor necrosis factor-alpha; TxA2: thromboxane A2;
uPA: urokinase-type plasminogen; VEGF: vascular endothelial growth factor; vWF: von Willebrand
factor.
Figure 1. The tumor microenvironment (TME) of ovarian cancer. Tumor cell-induced activated
platelets engage with endothelial cells, pericytes, mesenchymal stem cells (MSCs), cancer-associated
fibroblasts (CAFs), adipocytes, immune cells, and extracellular matrix (ECM) elements through di-
rect interaction or by releasing various modulatory factors and platelet microparticles. Platelets pro-
mote the extravasation, differentiation, and activation of these cells, which, in turn, contribute to the
hyper-responsiveness of platelets and thrombosis in a positive feedback loop.
This review focuses on the interactions between platelets and TME components, the
contribution of these interactions to the progression of ovarian cancer, and the plausible
approaches to interrupting this interwork to improve the prognosis of patients with ovar-
ian cancer.
2. Interactions of Platelets with TME Compartments: Endothelial Cells, Pericytes, and
Cancer-Associated Fibroblasts
2.1. Interactions with Endothelial Cells
Figure 1.
The tumor microenvironment (TME) of ovarian cancer. Tumor cell-induced activated
platelets engage with endothelial cells, pericytes, mesenchymal stem cells (MSCs), cancer-associated
fibroblasts (CAFs), adipocytes, immune cells, and extracellular matrix (ECM) elements through direct
interaction or by releasing various modulatory factors and platelet microparticles. Platelets promote
the extravasation, differentiation, and activation of these cells, which, in turn, contribute to the
hyper-responsiveness of platelets and thrombosis in a positive feedback loop.
Table 1. The major components reside on activated platelets or are released from platelet granules.
Location General Function Examples References
Surface
molecules
Integrins α
2
β
1 (GPIa/IIa),
α
5
β
1,
α
6
β
1,
α
L
β
2 (ICAM-2),
αIIbβ3 (GPIIb/IIIa), αVβ3[36]
Selectins P-selectin (CD62P), CLEC-2 [37,38]
Leucine-rich repeat
receptors GPIb-IX-V, TLR1, TLR2, TLR4, TLR6, MMPs [36,39,40]
ADP receptors P2Y1, P2Y12 [41]
Thrombin receptors PAR1, PAR4, GPIbα[42,43]
Tetraspanins CD63, CD9, CD53 [36]
Prostaglandin receptors PGD2 and PGE2 receptors [44]
Prostacyclin receptors PGI2 receptors [44]
Thromboxane receptors TxA2 receptors [45]
Lipid receptors PAF and LPA receptors [46,47]
Ig receptors GPVI, FcγRIIA (CD32), FcεRI (CD23) [48,49]
JAMs JAM-1, JAM-2, JAM-3, PECAM-1 (CD31) [50,51]
Tyrosine kinase receptors Thrombopoietin, leptin, insulin,
PDGF receptors [36]
Immune checkpoints PD-L1, GITRL, OX40L [52–54]
Other receptors
Serotonin receptors, GPIV (CD36), IAP (CD47)
complement receptors, CD40, CD40L (CD154) [55–59]
Cancers 2023,15, 1282 4 of 37
Table 1. Cont.
Location General Function Examples References
α-granules
Adhesion molecules vWF, αIIbβ3 (GPIIb/IIIa), αVβ3, P-selectin
(CD62P), fibrinogen, fibronectin,
thrombospondin [36,60,61]
Proangiogenic factors VEGF, angiopoietin-1, SDF-1 (CXCL12), S1P,
TGF-β, IL-6, PF4 (CXCL4) [61]
Angiostatic factors Endostatin, angiostatin, thrombospondin-1 [56,61]
Growth factors VEGF, PDGF, EGF, FGF, HGF,
IGF-1, CTGF, TGF-β[61–64]
Coagulation-associated components Prothrombin, fibrinogen, factor V, factor VIII,
factor XI, protein S [61,65,66]
Fibrinolytic factors α2-macroglobulin, uPA, PAI-1 [61]
MMPs MMP-1, MMP-2, MMP-3, MMP-9 [67,68]
Metalloproteinases ADAM-10, ADAM-17, ADAMTS-13 [69]
TIMPs TIMP-1, TIMP-2, TIMP-4 [69]
Inflammamodulatory molecules
CXCL1, PF4 (CXCL4), CXCL5, CXCL7
(NAP-2), IL-1β, IL-6, IL-8 (CXCL8), SDF-1
(CXCL12), CCL2 (MCP-1), CCL3 (MIP-1α),
CCL5 (RANTES), CCL7, PAF, LPA, TGF-β,
TNF-α, GM-CSF
[61,70–75]
Immunologic molecules Complement factors, IgG, IgA,
IgM, thymosin-β4[61,76–78]
Other components Albumin, α1-antitrypsin,
HMWK [61]
δ-granules
Nucleotides ADP, ATP, GDP, GTP [79]
Bioactive amines Serotonin, histamine, epinephrine [60]
Ions Calcium, magnesium, phosphate,
pyrophosphate [61]
Polyphosphates Polyphosphate (polyP) [60]
Lysosomes
Proteases Cathepsin D/E, carboxypeptidase A/B,
glycohydrolases, collagenase, elastase [79,80]
Phosphatases Acid phosphatase [79]
Phospholipases Phospholipase A [61]
ADAM: a disintegrin and metalloproteinase; CCL: chemokine (C-C motif) ligand; CD40L: CD40 ligand;
CLEC-2: C-type lectin-like receptor 2; CTGF: connective tissue growth factor; CXCL: chemokine (C-X-C mo-
tif) ligand; EGF: epidermal growth factor; FGF: fibroblast growth factor; GITRL: glucocorticoid-induced tu-
mor necrosis factor receptor-related protein ligand; GM-CSF: granulocyte-monocyte colony-stimulating factor;
GP: glycoprotein; HGF: hepatocyte growth factor; HMWK: high-molecular-weight kininogen; IAP: integrin-
associated protein; ICAM-2: intercellular adhesion molecule 2; Ig: immunoglobulin; IGF-1: insulin-like growth
factor 1; IL: interleukin; JAM: junctional adhesion molecule; LPA: lysophosphatidic acid; MCP-1: monocyte
chemoattractant protein 1; MIP: migration inhibitory protein; MMP: matrix metalloproteinase; NAP-2: neutrophil-
activating peptide 2; PAF: platelet-activating factor; PAI-1: plasminogen activator inhibitor 1; PAR: protease-
activated receptor; PD-L1: programmed death ligand 1; PDGF: platelet-derived growth factor; PECAM-1: platelet
endothelial cell adhesion molecule 1; PF4: platelet factor 4; PGD2: prostaglandin D2; PGE2: prostaglandin E2;
PGI2: prostaglandin I2; polyP: polyphosphate; RANTES: regulated upon activation and normal T cell expressed
and secreted; S1P: sphingosine 1-phosphate; SDF-1: stromal-derived factor 1; TGF-
β
: transforming growth factor-
beta; TIMP: tissue inhibitor of metalloproteinases; TLR: Toll-like receptor; TNF-
α
: tumor necrosis factor-alpha;
TxA2: thromboxane A2; uPA: urokinase-type plasminogen; VEGF: vascular endothelial growth factor; vWF: von
Willebrand factor.
This review focuses on the interactions between platelets and TME components, the
contribution of these interactions to the progression of ovarian cancer, and the plausi-
ble approaches to interrupting this interwork to improve the prognosis of patients with
ovarian cancer.
Cancers 2023,15, 1282 5 of 37
2. Interactions of Platelets with TME Compartments: Endothelial Cells, Pericytes, and
Cancer-Associated Fibroblasts
2.1. Interactions with Endothelial Cells
2.1.1. In Angiogenesis
Tumor angiogenesis involves degradation of the vascular endothelial matrix, the pro-
liferation and migration of endothelial cells, the branching of endothelial cells to generate
vascular rings, and the establishment of new basement membranes [
81
]. Tumor blood
vessels, which tend to be erratic, branched, and leaky, are dissimilar to normal blood vessels
in terms of shape, integrity, and permeability. Moreover, perivascular cells are reduced in
number and are less likely to be associated with endothelial cells [
82
,
83
]. Blood flow in
tumor-associated vessels is inconsistent and may lead to maladjusted circulation [
82
,
84
].
Consequently, tumors cannot receive adequate oxygen and nutrients, and discharge excess
carbon dioxide and other metabolites generated by the glycolytic pathway. The TME
becomes more hypoxic, acidic, and ischemic [
85
]. In addition, the hyperpermeability of the
tumor vasculature enhances extravascular clotting, fibrin gel clot formation, and endothe-
lial and stromal cell expansion [
86
]. Angiogenesis is a poor prognostic factor in ovarian
cancer [
87
], and antiangiogenic therapeutics demonstrate a moderate effect on overall and
progression-free survival [88,89].
Platelets preferentially attach to tumor-associated vessels rather than normal vascula-
ture, amplifying the delivery of tumorigenic mediators to the TME [
90
]. Tumor cell-induced
platelet activation (TCIPA) leads to the translocation of P-selectin (also known as CD62P), a
cell adhesion molecule stored in the
α
-granules [
37
], to the platelet surface. The binding
of P-selectin to the P-selectin glycoprotein ligand (PSGL-1) on leukocytes governs leuko-
cyte rolling in activated endothelial cells [
91
] and the generation of platelet—cancer cell
complexes [
92
]. Adhesion molecules, including integrins, von Willebrand factor (vWF), fib-
rinogen, fibronectin, and coagulation factors, and several members of the a disintegrin and
metalloproteinase (ADAM) protein family accommodate the activation, tethering, rolling,
and firm adhesion of platelets to endothelial cells [
93
]. Activated platelets degranulate and
release various factors that affect angiogenesis. More than 30 components associated with
platelets that influence angiogenesis have been described [
94
]. Platelets generate angiostatic
factors such as endostatin, angiostatin, and thrombospondin-1 (TSP-1), and angiogenic fac-
tors including vascular endothelial growth factor (VEGF), angiopoietin-1, stromal-derived
factor 1 (SDF-1, also known as the chemokine (C-X-C motif) ligand [CXCL]12), sphingosine
1-phosphate (S1P), transforming growth factor-beta (TGF-
β
), interleukin (IL)-6, and platelet
factor 4 (PF4; also known as CXCL4) [
61
]. Platelet-derived growth factor (PDGF) supports
the function of cancer-associated fibroblasts (CAFs), vascular pericytes, and smooth muscle
cells in angiogenesis [
95
]. Platelets also support the recruitment of endothelial progenitor
cells (EPCs) [
96
]. Platelet integrin GPIIb/IIIa promotes endothelial cell proliferation and
function [
97
]. The activation of platelets and the release of their granular content, such
as angiopoietin-1 and serotonin, prevent intratumoral bleeding [
98
]. ATP released from
the
δ
-granules of platelets activates endothelial P2Y
2
receptors, causing the retraction of
endothelial cells and promoting the transendothelial migration of cancer cells (intravasation
and extravasation) and metastasis [
99
]. Platelet microparticles increase the expression of
matrix metalloproteinases (MMPs) on endothelial cells [
100
], assisting in the generation of
new vessels [61].
The co-localization of GPIIb (CD41), platelet endothelial cell adhesion molecule-1
(PECAM-1; also known as CD31), and VEGF in ovarian cancer tissues suggests the in-
volvement of platelets in angiogenesis and tumor growth [
101
]. An increased level of
VEGF can be considered a biomarker of ovarian cancer [
102
] and an indicator of advanced
disease, ascites formation, metastasis, and reduced survival [
103
,
104
]. Moreover, the levels
of PDGF-BB and VEGF were found to be positively correlated in the TME and ascites, and
the pharmacological inhibition of their receptors increased the efficacy of chemotherapy in
patients with ovarian cancer [
105
]. The co-localization of regulator of G-protein signaling 5
(RGS5), a signal transduction molecule upregulated in endothelial cells in the TME, with
Cancers 2023,15, 1282 6 of 37
PECAM-1 and PDGF receptor (PDGFR)-
β
, has been reported in various types of cancer,
including ovarian cancer [
106
]. The participation of activated platelets in angiogenesis is
displayed in Figure 2.
Cancers 2023, 15, x FOR PEER REVIEW 6 of 38
Figure 2. The pro-angiogenic role of platelets in cancer. The interaction between platelets, endothe-
lial cells, and pericytes supports the extravasation of immune cells, mesenchymal stem cells (MSCs),
endothelial precursor cells (EPCs), and tumor cells. Platelets also release proangiogenic factors that
promote new blood vessel formation and facilitate tumor growth. The newly formed cancer-associ-
ated blood vessels are branched, leaky, and less supported by pericytes. Insufficient oxygen and
nutrient supplies lead to hypoxic and necrotic areas in the tumor. Platelet-targeting strategies can
restrict neoangiogenesis.
Platelet GPIb-IX receptor complex, a receptor for vWF, and GPIIb/IIIa, the receptor
for fibrinogen, promote platelet aggregation [107] and adhesion to endothelial cells. Ad-
ditionally, platelet P-selectin and GPIIb assist in the adhesion of platelets to cancer cells.
Hence, platelets assist in the clinging of cancer cells to the endothelium and metastasis
[108,109]. Targeting platelet surface proteins might show therapeutic benefits in cancer.
Antiplatelet agent-directed platelet inhibition diminishes the proliferative capability of
ovarian cancer cells [31]. In addition, focal adhesion kinase (FAK) promotes platelet infil-
tration into the TME, and targeting FAK suppresses ovarian tumor growth. Dual therapy
using antiplatelet agents and antiangiogenic drugs prevents rebound tumor growth after
discontinuing antiangiogenic agents [20].
Figure 2.
The pro-angiogenic role of platelets in cancer. The interaction between platelets, endothelial
cells, and pericytes supports the extravasation of immune cells, mesenchymal stem cells (MSCs),
endothelial precursor cells (EPCs), and tumor cells. Platelets also release proangiogenic factors
that promote new blood vessel formation and facilitate tumor growth. The newly formed cancer-
associated blood vessels are branched, leaky, and less supported by pericytes. Insufficient oxygen
and nutrient supplies lead to hypoxic and necrotic areas in the tumor. Platelet-targeting strategies
can restrict neoangiogenesis.
Platelet GPIb-IX receptor complex, a receptor for vWF, and GPIIb/IIIa, the receptor for
fibrinogen, promote platelet aggregation [
107
] and adhesion to endothelial cells. Addition-
ally, platelet P-selectin and GPIIb assist in the adhesion of platelets to cancer cells. Hence,
platelets assist in the clinging of cancer cells to the endothelium and metastasis [
108
,
109
].
Targeting platelet surface proteins might show therapeutic benefits in cancer. Antiplatelet
agent-directed platelet inhibition diminishes the proliferative capability of ovarian cancer
Cancers 2023,15, 1282 7 of 37
cells [
31
]. In addition, focal adhesion kinase (FAK) promotes platelet infiltration into the
TME, and targeting FAK suppresses ovarian tumor growth. Dual therapy using antiplatelet
agents and antiangiogenic drugs prevents rebound tumor growth after discontinuing
antiangiogenic agents [20].
2.1.2. In Lymphangiogenesis
Lymphangiogenesis is the formation of new lymphatic vessels and occurs during
embryonic development and in pathological conditions involving inflammation and tumor
metastasis [
110
]. Platelets are essential for the proper partitioning of blood and lym-
phatic vessels during development, mainly by coordinating endothelial cells’ expansion,
relocation, and tube formation. This phenomenon occurs following the engagement of
platelet CLEC-2 with its ligand podoplanin on lymphatic endothelial cells [
111
]. Although
platelets do not necessarily contribute to the maintenance of the separation of the two
circulatory systems post-development in normal conditions, in certain situations, including
wound healing or tumor growth, platelets again participate in lymphangiogenesis [
112
].
Platelets stimulate lymphangiogenesis by secreting proangiogenic factors such as VEGF,
angiopoietin-1, PDGF, and insulin-like growth factor 1 (IGF-1) [
61
,
113
], and through the
interaction of CLEC-2 and podoplanin [111].
In patients with ovarian cancer, the upregulation of lymphangiogenic markers is
associated with more aggressive disease and shorter overall survival [
114
]. Podoplanin
overexpression in the malignant stroma of ovarian cancer patients predicts lymphatic
spread and poor clinical outcomes [
115
]. Blocking podoplanin—CLEC-2 contact between
ovarian cancer cells and platelets forestalls lymph vessel proliferation [
116
]. Likewise,
VEGF and PDGF released by platelets promote lymph vessel generation in epithelial
ovarian cancer [
117
]. Treatment with antiangiogenic agents might attenuate lymphangio-
genesis in ovarian cancer [
118
]. Notably, inhibiting the TGF-
β
signaling cascade prevents
lymphangiogenesis and subsequent VEGF-mediated ascites generation in ovarian cancer
patients [119].
2.2. Interactions with Pericytes
Pericytes are perivascular cells embedded in the basement membrane surrounding
the microvasculature [
120
]. Pericytes might prevent the intravasation of cancer cells and
metastasis [
121
]; however, they might also facilitate micrometastasis by supporting the
formation of tumor vasculature [
122
]. Tumor vessels have atypical coverage of pericytes,
whose contact with endothelial cells is disrupted [
122
]. The tumor vasculature has an excess
of pericytes that loosely interact with endothelial cells, deteriorating the integrity of the
vessels and resulting in hemorrhage [
123
]. In ovarian cancer, abnormal pericyte numbers
and expression signatures are associated with tumor growth, aggressive metastasis, and
poor clinical outcomes [124].
Podoplanin, which is highly expressed on pericytes, mediates platelet binding to
pericytes via CLEC-2 [
125
]. Furthermore, platelet-derived TGF-
β
, angiopoietin, and PDGF
also stimulate pericyte differentiation, colonization, and their interaction with endothelial
cells [
64
]. TGF-
β
strongly influences the proliferation of pericytes [
126
] and their associa-
tion with endothelial cells through the TGF-
β
—matrix protein axis [
127
]. The activation
of the TGF-
β
signaling cascade impacts the density and lumen size of tumor microves-
sels [
127
]. Angiopoietin overexpression is linked with pericyte impairment and tumor
vessel instability [
128
]. Blocking TGF-
β
or angiopoietin signaling inhibits tumor growth
and neovascularization [
127
,
129
]. PDGF released from platelets and other cells [
130
] is
essential for pericytes recruitment and function during tumor neoangiogenesis. Preventing
PDGF isoforms from binding to their receptors and hindering angiogenesis with antiangio-
genic agents such as bevacizumab may interfere with the incorporation of pericytes into
new blood vessels [131].
Cancers 2023,15, 1282 8 of 37
TSP-1 is a matricellular glycoprotein with antiangiogenic properties that counters the
proliferative effects of growth factors on endothelial cells [
132
,
133
]. TSP-1 is released from
the granules of activated platelets, prompting platelet aggregation and tethering [
56
]. In
ovarian cancer, binding of the TSP-1 three type 1 repeats (3TSR) domain of TSP-1 to GPIV
(CD36) normalizes the tumor vasculature and exhibits antitumor function [
134
]. Treating
patients with 3TSR in combination with chemotherapeutics [
135
] or oncolytic viruses [
136
]
can improve the efficacy of anticancer therapies. 3TSR alone, or fused with the Fc region
of human IgG1 for improved stability, increases the number of pericyte-covered blood
vessels, reduces the proliferative capacity of endothelial cells, and contributes to vascular
normalization [134].
Platelets release IL-6 [
73
] and also trigger IL-6 secretion from tumor cells by releasing
several factors, such as lysophosphatidic acid (LPA) [
137
]. The protumorigenic cytokine
IL-6 is significantly elevated in ovarian cancer patients with confirmed thrombocytosis [
27
].
High IL-6 levels promote neoangiogenesis with abnormal pericyte coating. Anti-VEGF and
anti-IL-6 agents reduce vessel sprouting and leakiness of the vasculature by reinstating the
pericyte lining [
138
]. Combining chemotherapeutic agents and pazopanib, a multitargeted
tyrosine kinase inhibitor, can help restore pericyte coverage and restrict tumor microvessel
density [
139
] in patients with ovarian cancer. The antiplatelet action of pazopanib [
140
]
might further inhibit tumor growth and angiogenesis [20].
2.3. Interactions with Cancer-Associated Fibroblasts
Fibroblasts are a heterogeneous population of connective tissue cells with a presum-
ably mesenchymal origin [
141
]. Fibroblasts can differentiate into particular mesenchymal
cell types, including osteoblasts, adipocytes, and chondrocytes [
142
]. In the TME, CAFs
promote disease progression by releasing various molecules; rearranging the ECM to facili-
tate cancer cell motility, invasion, and EMT; and stimulating angiogenesis, tumor growth,
and metastasis. CAFs modulate the function of immune cells and the metabolism of cancer
cells to promote tumor survival [
143
]. CAFs also release extracellular vesicles that support
cancer progression [
144
] and chemoresistance [
145
]. Although fibroblasts play a role in
tumorigenesis, they may also restrict tumor development by activating the tumoricidal
immune response or consolidating the ECM to prevent tumor dissemination [146].
Extravasated platelets promote EMT by releasing mediators such as TGF-
β
, SDF-1,
and PDGF. The same mediators also induce the differentiation, migration, and proliferation
of CAFs [
147
,
148
]. PDGF and TGF-
β
induce mesenchymal stem cell (MSC) differentiation
into CAFs [
149
]. Integrin
α
11 is a CAF marker, and its expression is related to myofibrob-
last differentiation and ECM alteration. CAFs expressing integrin
α
11 and PDGFR-
β
are
associated with poor clinical outcomes in ovarian cancers and other malignancies [
150
].
Platelet-originated CLEC-2 induces the migration and proliferation of CAFs in the TME [
15
].
The binding of platelet-derived CLEC-2 to podoplanin on CAFs and cancer cells promote tu-
mor growth and venous thrombosis in patients with ovarian cancer [
125
,
151
]. LPA derived
from ovarian cancer cells promotes the differentiation of fibroblasts into CAFs through
a hypoxia-inducible factor 1 alpha (HIF-1
α
)-dependent mechanism [
152
]. LPA activates
platelets [
153
], which, in turn, release LPA [
137
]. Moreover, LPA promotes the secretion of
VEGF and SDF-1 from MSCs, further supporting ovarian cancer progression [
154
]. Under
oxidative stress, platelets release their mitochondria, which are picked up by MSCs [
24
].
Mitochondria originating in platelets and engulfed by MSCs promote fatty acid synthesis
and ATP production and stimulate the release of angiogenic components, such as VEGF
and hepatocyte growth factor (HGF), from MSCs [24].
CAFs originating from MSCs release platelet-activating factor (PAF), promoting
platelet activation and aggregation [
155
], which further supports ovarian cancer progres-
sion and induces ovarian cancer development through the PAF/PAF receptor signaling
pathway [
34
]. Exosomes from ovarian cancer cells induce the generation of CAFs from
MSCs in the tumor stroma [
156
]. CAF-released IL-6 causes EMT in ovarian cancer cells, tu-
mor growth, and ECM reorganization, mainly by mediating STAT3 phosphorylation [
157
].
Cancers 2023,15, 1282 9 of 37
The increased concentrations of IL-6 in the stroma or ascites can activate platelet function
and aggregation and lead to thrombosis [158].
Most patients with metastatic ovarian cancer have peritoneal dissemination, which
indicates a poor prognosis. It starts with the emigration of cancer cells into the peritoneal
fluid, forming floating masses that attach to peritoneal mesothelial cells throughout the
peritoneal cavity [
159
]. Alternatively, the cancer cells can initiate an inflammatory reaction
in the peritoneal stroma, promoting the generation of a fibrin mesh that can be used for
adhesion to the peritoneal surface. Fibrin mesh can also potentiate the colonization of
fibroblasts and endothelial cells. Fibroblasts that differentiate into CAFs promote ovarian
cancer invasion through the upregulation of several markers such as alpha-smooth muscle
actin (
α
-MA), PDGFR, and podoplanin [
151
]. A subset of CAFs originating from mesothe-
lial cells through mesothelial-to-mesenchymal transition (MMT) contribute to peritoneal
metastasis [
160
]. Ovarian cancer cells that have been relocated to the peritoneal cavity
promote ascites, and the ascitic fluid contains various cytokines and growth factors [
161
].
TGF-
β
derived from ascites and activated platelets is one of the main stimulating factors
for MMT [
160
,
162
]. In addition, tissue factor (TF), present in high amounts in ascites,
cancer cell masses, and cancer cell-derived microparticles, induces thrombin generation,
which activates platelets and produces fibrin [
163
]. Activated platelets further increase the
expression of TF, prompting ovarian cancer migration [
164
]. The activation of mesothelial
cells by TGF-
β
released from platelets is partially responsible for ECM remodeling during
metastasis [165].
Like fibroblasts, mesothelial cells and adipocytes in the omentum and peritoneum
can be prompted by cancer cells to differentiate into CAFs [
166
]. Periostin is a secretory
protein that is overexpressed by stromal fibroblasts in multiple cancers, including ovarian
cancer, and its overexpression is associated with poor clinical outcomes in patients with
epithelial ovarian cancer. TGF-
β
modulates periostin expression and promotes ovarian
cancer growth and chemotherapy resistance [
167
]. Similarly, the aberrant expression and
release of connective tissue growth factor (CTGF), a stromal factor, induces the colonization
and peritoneal adhesion of ovarian cancer cells [
168
]. Platelets store a large quantity of
CTGF [
63
], suggesting that platelet activation and the release of CTGF may participate in
ovarian cancer seeding in the peritoneum.
Inhibitors of the TGF-
β
signaling pathway can diminish CAFs’ function in ovarian
cancer [
169
]. Anti-VEGF therapy can inhibit ovarian cancer progression, metastasis, and
malignant ascites formation promoted by the release of VEGF from CAFs, along with vari-
ous other cell types [
170
]; however, synchronous anti-PDGF treatment might be necessary
to target CAFs resistant to VEGF-neutralizing agents [
171
]. It has been reported that aspirin
therapy suppresses chemotherapy-induced CAF formation in colorectal cancer [
172
] and
the impact of CAFs on ovarian cancer.
3. Interplay of Platelets with the Tumor Immune Microenvironment
3.1. Interplay with Tumor-Associated Neutrophils
Most inflammatory cells in solid tumors are tumor-associated neutrophils (TANs)
that promote or inhibit tumor growth and angiogenesis, depending on various circum-
stances. In the initial stages of tumor growth, TANs tend to exert tumoricidal functions
(N1 neutrophils), whereas in later stages of tumor growth, they become protumorigenic
(N2 neutrophils). Permissive N2 neutrophils enhance the proliferation and metastasis
of malignant cells by releasing growth factors (e.g., TGF-
β
and VEGF), MMPs, and re-
active oxygen species (ROS) [
173
]. In addition, they can suppress antitumor immune
responses [
174
]. Neutrophils assist cancer cells in escaping the antitumor immune response
through the overexpression of immune checkpoint molecules, including programmed
death ligand 1 (PD-L1) [
175
], glucocorticoid-induced tumor necrosis factor receptor-related
protein-ligand (GITRL) [
176
], and V-domain Ig suppressor of T cell activation (VISTA) [
177
].
In patients with ovarian cancer, elevated neutrophil counts, neutrophil-lymphocyte ratios
(NLRs), and platelet counts indicate a poor prognosis and shorter overall survival [
178
,
179
].
Cancers 2023,15, 1282 10 of 37
Adhesion molecules on the surface of neutrophils include L-selectin (CD62L), PSGL-
1, macrophage-1 antigen (Mac-1; also known as CD11b/CD18), and leukocyte function-
associated antigen 1 (LFA-1; also known as CD11a/CD18), which are essential for the rolling
of neutrophils on the endothelium, as well as their firm adhesion and transendothelial
migration [
180
]. Inflammation promotes the expression of surface adhesion molecules on
platelets and endothelial cells. Platelets help recruit neutrophils to the tissues via direct
or indirect interaction. Neutrophils and platelets interact mainly through the binding of
P-selectin to PSGL-1 [
181
]. The binding of GPIb on platelets to Mac-1 [
182
] on neutrophils,
and that of the intercellular adhesion molecule 2 (ICAM-2) on endothelial cells to LFA-
1 [
183
] on neutrophils, provide additional adhesive interactions under flow conditions. At
baseline, Mac-1 has low expression on neutrophils in the peripheral blood; however, it is
significantly upregulated in inflammation [
184
]. Neutrophils in the peripheral blood of
ovarian cancer patients have higher levels of Mac-1.
In ovarian cancer patients, neutrophils overexpress Mac-1, which improves the ad-
hesion of neutrophils to endothelial cells and modifies the endothelium for improved
cancer cell migration [
185
]. Of note, the PSGL-1–L-selectin interaction is also important
for neutrophil adherence to endothelium [
186
]. The interaction between cancer cells and
neutrophils through Mac-1 and L-selectin can promote cancer cell migration through blood
vessels [
184
,
187
]. Other interactions, including those between CD40–CD40 ligands (CD40L,
also known as CD154) [
188
] and between platelet PSGL-1 and neutrophil L-selectin [
189
],
might also support neutrophil interactions in the TME.
Platelets and neutrophils communicate indirectly through intermediary molecules.
For instance, platelet GPIIb/IIIa and neutrophil Mac-1 both bind to fibrinogen [
190
]. In
addition, platelets’ secretion of chemokines and cytokines, such as PF4 [
70
], CXCL7 (also
known as neutrophil-activating peptide 2 (NAP-2)) [
71
], and TGF-
β
[
191
], following their
interaction with cancer cells reinforces neutrophils’ attachment to the endothelium and
their transendothelial migration. In ovarian cancer, IL-8 (CXCL8) recruits neutrophils to
the TME [
192
]. IL-8 released from the activated platelets [
193
] or platelet-activated cancer
cells [
194
] can help increase the number of neutrophils in the TME. IL-8 receptor CXCR2
is upregulated in the neutrophils of patients with ovarian cancer compared to healthy
individuals [
195
]. Moreover, the elevated concentration of IL-8 in peritoneal lavage in
ovarian cancer is associated with shorter overall survival [
196
]. Cytokines and chemokines,
such as granulocyte colony-stimulating factor (G-CSF), granulocyte-monocyte colony-
stimulating factor (GM-CSF), CXCL1, CXCL2 (also known as migration inhibitory protein
2 alpha (MIP-2
α
)), CXCL5, and CCL3 (chemokine (C-C motif) ligand 3) (MIP-1
α
) recruit
neutrophils to the TME [
197
]. TGF-
β
and G-CSF are important for neutrophil differentiation
into the N2 phenotype [
173
]; thus, platelet-derived TGF-
β
[
198
] and GM-CSF [
75
] create an
immunotolerant environment for ovarian cancer.
Neutrophil extracellular trap (NET) formation (NETosis) is a defense mechanism
against inflammation [199]. The activated neutrophils secrete antimicrobial proteases and
release chromatins and cytosolic and granular proteins, such as myeloperoxidase and
neutrophil elastase, to trap and kill pathogens [
200
]. The presence of lipopolysaccharide
(LPS) activates platelets in endotoxemia, and hyperactive platelets bind to adherent neu-
trophils via Toll-like receptor (TLR) 4, causing neutrophil activation and NETosis. LPS is
not adept at directly stimulating NET formation [
40
]. In return, NETs trigger thrombosis
because histone proteins and DNA released from neutrophils, in addition to NET-linked
cathepsin G, activate platelets [
201
]. NETs bind to factor XII or P-selectin to initiate blood
coagulation [
202
]. Neutrophil and the NET-dependent release of neutrophil elastase cleaves
E-cadherin and enhances EMT in ovarian cancer cells [
203
]. Cathepsin G and neutrophil
elastase activate platelets via GPIIb/IIIa and induce platelet aggregation in the presence of
exogenous fibrinogen [204].
Mitochondrial DNA (mtDNA) and formylated peptides are among the mitochondrial
damage-associated molecular patterns discharged from various cells. These molecules
stimulate neutrophil function via the adhesion of TLR9 and formylated peptide receptors
Cancers 2023,15, 1282 11 of 37
and promote NETosis [
205
]. NETs support cancer-related thrombosis through factors such
as extracellular chromatin and tissue factor [
206
]. NETs also play a role in ovarian cancer
cell invasion and premetastatic niche formation in the omentum [
207
]. The amount of
platelet-derived mtDNA and the number of microparticles in ascites correlate with poor
clinical outcomes in ovarian cancer patients [
208
]. The fibrin deposits in the TME further
assist in ovarian cancer invasion by providing an adhesion surface for platelets, promot-
ing their aggregation, and stimulating monocyte differentiation into tumor-associated
macrophage (TAM)-like cells [
209
]. The pharmacological suppression of NETosis-related
genes, including the protein arginine deiminase 4 (PAD4) gene, which encodes a histone
protein-citrullinating enzyme, can delay ovarian cancer cell invasion of the peritoneal
cavity [207].
3.2. Interplay with Tumor-Associated Macrophages
Mononuclear cells extravasate into tumor tissues and differentiate into macrophages.
Macrophages polarize into two distinct subtypes that have pro- or anti-inflammatory char-
acteristics. Classically activated macrophages, also termed M1 macrophages, are stimulated
by molecules such as LPS, interferon-gamma (IFN-
γ
), tumor necrosis factor-alpha (TNF-
α
),
and GM-CSF, as well as by target pathogens and tumor cells. In contrast, alternatively
activated macrophages (M2 macrophages) are induced by molecules such as TGF-
β
, IL-
10, and macrophage colony-stimulating factor (M-CSF), and display protumorigenic and
immunomodulatory features [210].
In the ovarian cancer TME, a population of TAMs from both the M1 and M2 pheno-
types is observed [
211
]. As cancer progresses, TAMs polarize into M2 macrophages via
the upregulation of multiple markers, including CD163, CD206, PD-L1, and arginase 1
(ARG1) [
210
]. epithelial ovarian cancers support M2 polarization by releasing mediators
such as M-CSF [
212
]. The number of TAMs escalates as the tumor spreads, so much so
that half of the cells in the peritoneal TME and ascites can be TAMs with tolerogenic
functions [
213
,
214
]. M2 macrophages in ascites induce the transcoelomic metastasis of
ovarian cancer cells. M2 macrophages secrete multiple mediators that induce ovarian
cancer spheroid formation, encourage attachment to the metastasis site, and escape from
the cytolytic immune response [
215
,
216
]. An elevated M2/M1 macrophage ratio correlates
with reduced overall survival in ovarian cancer patients [217].
Platelet—monocyte aggregates are more potent markers for platelet activation than the
expression of P-selectin [
218
]. The activated macrophages release cytokines such as TNF-
α
,
IL-1
β
, IL-6, and IL-8 [
219
]. The interaction between monocytes and platelets enhances the
procoagulant effect of macrophages and ROS generation. Activated platelets adhere to
monocytes via P-selectin and promote monocyte function and ROS release [
220
]. A high
concentration of ROS differentiates TAMs to the M2 phenotype, and this effect is annihilated
when macrophages are polarized to the M1-like phenotype, rather than M2 [221].
The upregulation of platelet-derived TGF-
β
, the subsequent overexpression of cy-
clooxygenase 2 (COX-2), and the generation of prostaglandin E2 (PGE2) in monocytes
modulate CD16 levels. The activation of CD16 on monocytes induces M2 polarization [
222
].
COX-2-positive TAMs increase cancer cell proliferation and metastasis because the PGE2
generated by COX-2 activates the protein kinase C/A and TGF-
β
signaling pathways [
223
].
COX-2 expression is elevated in macrophages that infiltrate epithelial ovarian cancer tu-
mors [
224
], and the resulting increased levels of PGE2 support tolerogenic M2 polarization
and ovarian cancer cell chemoresistance [225].
The platelet-directed differentiation of monocytes into the immunogenic phenotype via
IL-1
β
and IL-8 potentiates NF-
κ
B signaling and supports thrombosis [
226
]. Macrophages
with high levels of podoplanin expression migrate toward vascular endothelial cells, bind to
CLEC-2 on the surface of platelets, activate platelets [
38
,
227
], and promote thrombosis [
38
,
227
].
Additionally, podoplanin is upregulated in ovarian cancer cells, and extracellular vesicles
released from these cells increase the likelihood of thrombosis [125].
Cancers 2023,15, 1282 12 of 37
Platelet microparticles regulate the function of macrophages recruited to the inflam-
mation site by chemotactic components such as PF4, TGF-
β
, and PDGF-
β
[
23
]. These
microparticles can drive macrophages toward the protumorigenic phenotype by suppress-
ing TNF-
α
, CCL4, and M-CSF production and increasing their phagocytic efficacy [
228
].
Conversely, platelet microparticles may direct macrophage activation, which can inhibit
tumor growth through cytokines such as TNF-related apoptosis-inducing ligand (TRAIL),
CCL2 (also known as monocyte chemoattractant protein 1 (MCP-1)) and IL-8 [229].
Cancer cells and activated monocytes can release extracellular vesicles containing
TF that contribute to venous thromboembolism [
163
,
230
]. Moreover, the coincubation of
platelets with extracellular vesicles upregulates the TF activity of monocytes [
231
]. Cancer
cell-derived extracellular vesicles also trigger platelet activation and cause the release
of procoagulant platelet microparticles [
232
]. The extracellular vesicles of platelets with
phosphatidylserine attach to monocytes and monocyte extracellular vesicles and promote
their procoagulant effects [
233
,
234
]. TAMs express the coagulation factors II, V, VII, and X,
stimulating thrombin formation and platelet activation [
235
]. The TF-dependent throm-
bin formation promotes several cellular interactions in the TME [
236
]. For instance, the
TF-related activation of protease-activated receptor (PAR)-2 and integrin ligation enhance
tumor growth and angiogenesis [
237
]. Moreover, TF supports the intravasation and in-
travascular survival of cancer cells, and the formation of metastatic niches, to provide an
environment for the interaction of monocytes and macrophages with tumor-associated
microthrombi [
238
]. The thrombin receptors PAR1, PAR4, and GPIb
α
on the surface of
platelets can facilitate metastasis [
42
,
43
]. By disrupting the TF-accompanying pathways,
PAR inhibitors might diminish the proliferation and metastasis of ovarian cancer cells [
237
].
The network between platelets, cancer cells, endothelial cells, and smooth muscle
cells attracts monocytes into the early metastatic niches through chemokines such as
CCL2 and CCL5 (known as regulated on activation, normal T cell expressed and secreted
(RANTES)) [
238
]. The CCL5-induced attraction of monocytes to metastatic cancer cells
indicates that CCL5 is indirectly critical to the organization of metastasis rather than
directly acting on cancer cells [
239
]. Similarly, platelets’ secretion of SDF-1 is decisive in the
recruitment of macrophages to tumors and in the migration of CXCR4
+
cancer cells [
240
]. In
addition, SDF-1 mediates the migration of TAMs into the hypoxic TME and the polarization
of monocytes toward the tolerogenic phenotype [
241
]. The blockade of the SDF-1—CXCR4
interaction, combined with anti-programmed death 1 (PD-1)-based immunotherapy, results
in a higher M1/M2 ratio, which is associated with better clinical outcomes in patients with
ovarian cancer [242].
PAFR activation stimulates macrophages to differentiate toward the M2 phenotype,
whereas the absence of PAFR drives tumor-infiltrating macrophages to demonstrate an-
titumor properties [
243
]. PAFR ligands support tumor development by reprogramming
the TAM phenotype and increasing the frequency of M2 macrophages rather than M1
macrophages. This specific polarization of macrophages through apoptotic cells results in a
tolerogenic environment that supports tumor growth [
243
]. Thus, PAFR antagonists may
be a therapeutic option for patients with ovarian cancer [244].
Ovarian cancer cell-derived M-CSF stimulates the polarization of macrophages to
the M2 subtype, which supports EMT and the peritoneal metastasis of ovarian cancer
cells [
216
]. M-CSF can also trigger platelet aggregation [
245
] and provoke thrombosis in
cancer patients. M2 macrophages release high concentrations of epidermal growth factor
(EGF) and induce angiogenesis and the invasion and metastasis of cancer cells through the
activation of an EGF receptor (EGFR) [
246
]. EGF stimulation facilitates the activation of
platelets and the release of IL-1
β
[
72
]. Moreover, EGF-triggered ovarian cancer cells secrete
PAF and contribute to the hyper-responsiveness of platelets. The blockade of EGFR might
abolish EGF’s promotion of ovarian cancer progression [247].
Cancers 2023,15, 1282 13 of 37
In the ovarian cancer TME, LPA is produced from phospholipids by TAM- and platelet-
derived phospholipase A2 (PLA2) and autotaxin [
248
,
249
]. LPA promotes ovarian cancer
growth and metastasis through diverse networks [
250
,
251
]. It also induces platelet activa-
tion [
252
]; thus, the pharmacological inhibition of LPA and the application of antiplatelet
agents might interfere with ovarian cancer development [249,253].
3.3. Interplay with T Cells
3.3.1. CD4+Helper T Cells
CD4
+
helper T (Th) cells are major contributors to adaptive immunity. Their antitu-
mor effect can be exerted directly by targeting tumor cells or indirectly by triggering the
expansion of cytotoxic CD8
+
T cells [
254
]. An increased percentage of tumor-infiltrating
lymphocytes (TILs) is associated with prolonged survival in patients with ovarian can-
cer [255,256].
Platelets may affect CD4
+
T cells directly through physical interaction [
257
] or indi-
rectly through the secretion of soluble mediators [
258
], extracellular vesicles, and mito-
chondria [
259
,
260
]. Activated platelets form complexes with CD4
+
T cells and mediate the
adhesion of lymphocytes to the endothelium under flow conditions, and to the ECM [
261
].
T cells cannot bind to fibronectin efficiently without the participation of platelets [
262
].
CD40–CD40L, P-selectin–PSGL-1, and ICAM-2–LFA-1 interactions are partly responsible
for the construction of platelet–CD4
+
T cell complexes and the rolling and firm adhesion of
T cells under flow [
262
]. CD4
+
T cells’ CD40L binds to platelets’ CD40 [
58
] and stimulates
CCL5 secretion [
263
]. The soluble CD40L (sCD40L) binds to CD40 on CD4
+
T cells, causing
CD4
+
T cells to undergo apoptosis following the suppressed expression of IL-2, Bcl-2, and
Bcl-xL [
264
]. Platelets, rather than T cells, are the predominant source of sCD40L in can-
cer [
59
]. Antiplatelet reagents might restore the antitumor immune response by reducing
sCD40L levels and preventing CD4+T cell apoptosis [59].
The interaction between platelet P-selectin and T cell PSGL-1 recruits T cells to the
activated endothelium at the site of inflammation or injury. Memory CD4
+
T cells form com-
plexes with platelets, which may exacerbate thrombo-inflammation [
265
]. In conjunction
with its role in mediating cell adhesion [
266
], the upregulation of PSGL-1 on effector T cells
may alter their function. PSGL-1 engagement can induce T cell exhaustion by inhibiting
ERK/Akt signaling and IL-2 secretion, and increasing PD-1 expression. In this context,
PSGL-1 ligation can reduce the antitumor effect of CD4+and CD8+T cells [267].
Platelets and CD4
+
T cells form complexes that can trigger immune-related adverse
events in cancer patients treated with chemotherapeutic agents or immune checkpoint
inhibitors. The elevated levels of PD-L1 in platelets can inhibit CD4
+
and CD8
+
T cells [
52
].
Moreover, platelet PD-L1 may increase the overall expression of PD-L1 in tumors after
platelet adhesion to cancer cells [
268
], suggesting that adding an antiplatelet agent can
improve the efficacy of anti-PD-L1 immunotherapy [
269
]. On the other hand, other studies
show that platelets induce the expression of PD-L1 in cancer cells [
14
,
270
], and reduc-
ing platelet counts via an antiplatelet agent treatment can minimize the effectiveness of
immunotherapy [
14
]. In addition, platelet-derived TGF-
β
reduces the efficacy of T cell
recruitment via bispecific antibody (BsAb)-based immunotherapy [
271
] in ovarian can-
cer [
272
]. Immune checkpoint inhibitors administered with VEGF inhibitors have been
shown to improve the efficacy of BsAbs in ovarian cancer [273].
3.3.2. Regulatory T Cells
Regulatory T cells (Tregs), which constitute 5% to 7% of CD4
+
T cells, induce immune
tolerance by cytokines such as TGF-
β
and IL-10, and receptors such as cytotoxic T lym-
phocyte antigen 4 (CTLA-4), CD39, and CD73 [
274
]. Consequently, Tregs exert protumor
effects by providing a permissive environment for tumor growth. In the early stages of
ovarian cancer, the Th17-related immune response is more dominant, whereas a persistent
shift toward Tregs is witnessed in the later stages [
275
]. Tregs are recruited and activated
by the hypoxic conditions in ovarian cancer TME [
276
] and are abundant in ascites. Their
Cancers 2023,15, 1282 14 of 37
presence has been linked to unfavorable clinical outcomes [
277
,
278
]. Meanwhile, high
CD8
+
T cell/Treg and CD4
+
T cell/Treg ratios are indicators of a better prognosis [
279
].
Interestingly, a positive correlation between increased numbers of CD8
+
T cells and Tregs
in the TME has been observed in multiple patients with ovarian cancer, but this immune
profile has not influenced patients’ overall survival [280].
Treg-derived PSGL-1 is pivotal in regulating the immune response, since this glyco-
protein plays a part in hampering T cell–DC conjugation and subsequent T cell expansion
and activation [
281
]. In contrast, P-selectin is upregulated in CD4
+
non-Tregs and is critical
for Treg differentiation and activity because it functions in signaling cascades involving Syk
kinases and CCL5 [
263
,
282
,
283
]. P-selectin–PSGL-1 binding might potentiate the influence
of costimulatory components such as CD40L [
284
]. The engagement of CD40 with CD40L
is important for the development and survival of Tregs [
285
], and CD40–CD40L activates
Tregs and platelets in a positive feedback loop [
263
]. CD40 or CD40L deficiency reduces
the number of Tregs without affecting the total number of T cells [286].
Moreover, P-selectin plays an important role in recruiting Tregs to tumors and repress-
ing effector CD8
+
T cells [
16
]. IL-4 stimulates endothelial cells’ expression of P-selectin
and the recruitment of activated platelets expressing P-selectins to the TME, which causes
positive feedback in immunosuppression [287].
Platelet releasate stimulates Treg activity, which, in the short-term, increases and
subsequently inhibits Th1/Th17 responses. The mediators secreted by platelets (e.g., PF4
and TGF-
β
) and by platelet-activated Tregs downregulate Th1 polarization [
288
]. Platelet
deficiency leads to reduced Treg activation through several pathways related to TLR4
and TNF-
α
. The adherence of platelet-derived TNF-
α
to TNFR2 on Tregs activates these
cells [
74
]. In the tumor-associated ascites of patients with ovarian cancer, IL-6 stimulates
Tregs’ expression of TNFR2 [
289
]. IL-6 generated by platelets [
73
] supports the function of
Tregs in ascites, creating an immunosuppressive environment. TNFR antagonists might
restrict Treg expansion in the TME and hinder ovarian cancer cell proliferation [290].
TGF-
β
is required to generate Tregs, and platelets, as an important source of TGF-
β
,
are known to promote Treg activity. Platelet TGF-
β
modulates the expression of granzyme
B, IFN-
γ
, and IL-2 to promote Treg development [
291
]. Thus, platelet hyperactivity in
malignancies may create a favorable environment for Treg expansion [
292
]. Moreover,
platelet-derived growth factors, including IGF-1 [
62
] and PDGF [
293
], also foster Treg
proliferation. The inhibition of the TGF-
β
-directed network can mitigate an increased
number of Tregs and support cytotoxic T cell expansion while reducing tumor and ascites
volumes in patients with ovarian cancer [
294
]. Similarly, the blockade of IGF [
295
] and
PDGF [296] receptors might restore immunosurveillance for malignant ovarian cells.
PF4 suppresses the overall expansion of CD4
+
T cells and Th1 polarization while
promoting the proliferation of Tregs. The binding of PF4 to its receptor, CXCR3, escalates
mitochondrial transcription factor A (TFAM) expression, mitochondrial biogenesis, and
ATP and ROS generation. The increased concentrations of ATP and ROS increase T-bet
and Foxp3 expression, whichmodulates Th1 and Treg differentiation, respectively [
297
].
Moreover, thromboxane A2 (TxA2) secreted from platelets inhibits the activity of CD4
+
T
cells [
298
]. PF4 also heterodimerizes with other platelet-derived chemokines, including
CCL2, CCL5, CXCL7, SDF-1, and TxA2. The chemokine pairing aggravates chronic inflam-
mation in cancer; as a result, preventing chemokine pairing might provide a therapeutic
advantage [299,300].
CXCR4 and SDF-1 are upregulated in ovarian cancer cells [
301
]. Platelets express
CXCR4 and SDF-1, and activated platelets generate SDF-1 [
302
,
303
]. Hypoxia increases
the expression of CXCR4 on Tregs and supports immunosuppression [
304
]. Blocking the
binding of SDF-1 to its receptor, CXCR4, increases the CD8
+
T cell/Treg ratio and reduces
the intraperitoneal metastasis of ovarian cancer cells [
305
]. Tregs with high immune
checkpoint expression support the immunoregulatory function of these cells in ovarian
cancer [
306
]. The Treg
hi
phenotype is distinguished by elevated expression levels of
forkhead box P3 (Foxp3), PD-1, 4-1BB, inducible T cell co-stimulator (ICOS), and CD25.
Cancers 2023,15, 1282 15 of 37
The infiltration of these Tregs into tumors is associated with intercepted antitumor immune
response [
306
]. Ovarian tumors display the Treg
hi
phenotype [
278
,
306
], which may explain
ovarian cancer patients’ unsatisfactory responses to immune checkpoint inhibitors. In
many cancers, PD-L1-containing platelet microparticles adhere to PD-1 on Tregs and
induce immune tolerance [
307
]. The simultaneous inhibition of the CXCR4—SDF-1 and
PD-1—PD-L1 pathways and the depletion of effector Tregs may enhance the antitumor
immune response and reduce mortality in ovarian cancer patients [242,308].
Platelet microparticles prevent Treg differentiation to proinflammatory T cells that gen-
erate IL-17 and IFN-
γ
[
309
]. This mechanism occurs when the P-selectin on microparticles
adheres to PSGL-1 on CCR6
+
HLA-DR
+
memory-like Tregs, which are the progenitors of
Th17-like cells and stabilizers of the inflammatory state [
309
,
310
]. The reduction in IFN-
γ
release after PF4–CXCR3 engagement [311] and in communication among Tregs upon the
binding of platelet microparticles [312] support this mechanism.
3.3.3. CD8+T Cells
CD8
+
T cells, also termed cytotoxic or cytolytic T lymphocytes (CTLs), play a cardinal
role in protecting the host from infections. Unlike acute infections, chronic inflammation
and cancer may involve CD8
+
T cells. CD8
+
T cells can become exhausted and develop
reduced functionality. Exhausted CD8
+
T cells are distinguished by their persistent over-
expression of immune checkpoints [
313
]. Functional cytotoxic TILs improve survival in
ovarian cancer patients [
314
], and the recruitment of CD8
+
T cells into the peritoneal cavity
is associated with better prognostic scores in these patients [315].
Platelets interact with CD8
+
T cells and decrease their cytolytic impact on cancer cells.
The abundance and size of platelet—T cell aggregates in cancer patients are increased
compared to healthy individuals. High levels of these aggregates are regarded as cancer
biomarkers [
316
]. Platelets in platelet—T cell aggregates express high levels of P-selectin,
and platelets may be more prone to adhering to PSGL-1 on CD8
+
T cells than on the surface
of CD4
+
T cells [
316
]. PSGL-1 is involved in the migration of T cells to the inflammation site
and secondary lymphoid tissues [
317
]. However, in chronic inflammation, PSGL-1 signaling
limits T cell survival and promotes CD8
+
T cell exhaustion because of the upregulation of
immune checkpoint molecules such as PD-1, B- and T-lymphocyte attenuator (BTLA), T
cell immunoglobulin mucin 3 (TIM-3), and lymphocyte activation gene 3 (LAG-3), and the
inhibition of immunostimulatory cytokines such as IL-2. The suppression of PSGL-1 may
prevent the exhaustion of cytotoxic T cells and reduce tumor growth [
267
]. However, this
effect may occur not through P-selectin—PSGL-1 ligation but through TCR signaling [
267
]
or the binding to other ligands [318].
TGF-
β
suppresses CD8
+
T cells and can promote cancer cell proliferation [
319
] and
metastasis [
320
]. The activation of latent TGF-
β
through the TGF-
β
/glycoprotein A repeti-
tions predominant (GARP) axis in the TME via platelets may inhibit the antitumor effect
of T cells [
321
]. The activation of platelets encourages tumor growth, at least partly, by
supporting the immunosuppressive TME and minimizing the adaptive immune response.
Therefore, the inhibition of platelets may increase the effects of immune checkpoint in-
hibitors [
322
]. In addition, bioengineered PD-1-expressing or antineoplastic agent-carrying
platelets may accumulate in tumors and block PD-L1 on cancer cells to help exhausted
CD8
+
T cells recover their functionality [
323
]. CD8
+
T Tregs, which are known to reduce the
expansion of CD4
+
T cells and follicular helper T cells, are enriched in ovarian tumors [
324
].
Indeed, CD8
+
CD25
+
Foxp3
+
CTLA-4
+
T cells have been detected in patients with ovarian
cancer and have increased in number as the tumor stage increases [
324
,
325
]. The increased
levels of TGF-
β
expand CD8
+
Tregs in the ovarian cancer TME, mainly through p38 MAPK.
The inhibition of TGF-
β
and the p38 signaling cascade can impede ovarian cancer progres-
sion [
326
]. In addition, various other mediators, including IFN-
γ
and IL-2, support the
regulatory functions of CD8
+
T cells [
324
]. In contrast, TGF-
β
upregulates CD103 (also
known as integrin
α
E
β
7 (ITGAE)) on CD8
+
T cells infiltrating the tumor and malignant
Cancers 2023,15, 1282 16 of 37
ascites, and by supporting the habitation of these cytotoxic T cells in the TME, they may
represent a prognostic advantage in patients with ovarian cancer [327].
Thrombin exerts its protumorigenic properties through platelet activation and the
subsequent release of various mediators involving VEGF and TGF-
β
[
198
,
328
]. These medi-
ators can further modify the immune response toward a tolerogenic state [
198
,
329
]. Specific
drugs, such as dabigatran etexilate, when given concurrently with potentially thrombogenic
antineoplastic agents, repress thrombin and thus benefit patients with ovarian cancer. This
treatment regimen may reduce the number of immunoregulatory myeloid cells and incite
CD8+cytotoxic T cell function in ascites [330].
Similarly, platelet-derived PF4 stimulates the differentiation of monocytes into myeloid-
derived suppressor cells (MDSCs), which suppresses the activity of CD8
+
T cells. This shift
can result in advanced metastatic disease and poor overall survival [
21
]. An antiplatelet
agent-based therapy regimen can promote the expansion of CD8
+
T cells, and the admin-
istration of antiplatelet agents with an anti-VEGF or anti-PD-1 antibody can resensitize
tumors to immune cells [331,332].
3.4. Interplay with B Cells
B cells are immune cells that produce antibodies during initial exposure to antigens
and memory cells and that mediate a subsequent antibody response after re-exposure to
the same antigens. Mature naïve B lymphocytes in the peripheral lymphoid structure
are exposed to antigens, selectively expand, hypermutate to generate antibodies that
better fit specific antigens, and differentiate into plasma cells or transform into memory
B cells [
333
]. Antibodies produced by B cells may recognize antigens on malignant cells
or other components of the TME, tag cancer cells for destruction, and lead to immune
cell- and antibody-mediated cytotoxicity [
334
]. On the other hand, cancer cells or their
extracellular vesicles modify the immune system, promote the generation of regulatory
B cells (Bregs) [
335
], and evade the antineoplastic impact of B cells [
336
]. Moreover,
circulating antigen–antibody complexes activate the complement system and platelets,
supporting angiogenesis and metastasis [
337
–
339
]. B cells may have prognostic significance
in ovarian cancer patients and have been shown to correlate with worse [
340
] or better [
341
]
clinical outcomes. High numbers of IL-10-positive Bregs have been detected in ascites of
ovarian cancer patients, and their numbers are correlated with the percentage of Tregs. The
recruitment of Bregs and Tregs is associated with advanced-stage and aggressive ovarian
cancer [335].
The binding of CD40L to CD40 on resting B cells stimulates their differentiation to
plasma cells and memory B cells. Platelets and platelet microparticles express CD40L
and can trigger B cells’ production of antibodies, although not at the same level as the
T cell-dependent isotype-switched antibodies [
342
]. Through CD40L, platelets enable B
cell isotype conversion and enhance germinal center formation [
342
]. B cells stimulated
through CD40 and TLR9 restrict the differentiation of monocytes into mature dendritic cells
(DCs) and diminish DC-dependent T cell proliferation and function [
343
]. CD40–CD40L
contact is linked to the activation of Bregs and tumor growth via the suppression of IL-10
and TGF-
β
1 release [
344
]. In contrast, CD40L released from B cells binds platelet CD40 and
activates platelets, causing the expression of P-selectin, the secretion of
α
- and
γ
-granules,
the transformation of platelet morphology, and the upregulation of GPIIb/IIIa [58].
In addition to platelets and Tregs, peripheral B cells also express GARP, which releases
TGF-
β
and can induce immune tolerance [
345
]. TGF-
β
signaling stimulates the apoptosis
of B cells [
345
], suppresses immunoglobulin release, and impedes surface immunoglobulin
expression on activated B lymphocytes [
346
]. In addition, TGF-
β
promotes the class
switch to IgA during the differentiation of B cells into plasma cells [
347
]. Although IgA is
primarily associated with defense against pathogens on mucosal surfaces, IgG is involved
in adaptive and memory immune responses. Accordingly, the trend toward IgA instead
of IgG leads to a curtailed cytotoxic immune response in tissue [
348
]. Bregs’ production
of excess TGF-
β
can further propel the tolerogenic immune response by hastening the
Cancers 2023,15, 1282 17 of 37
differentiation of cytotoxic T cells into Tregs [
349
]. Thus, platelet-derived TGF-
β
may
contribute to immunosuppressive conditions in tumor progression.
PAF, an inflammatory phospholipid produced mainly by platelets, immune cells, and
endothelial cells [350], plays a role in B cell activation, expansion, and Ig production. PAF
receptor is upregulated on B cells by several cytokines, including IL-4 and TGF-
β
. The
binding of PAF to its receptors on B cells activates these cells [351].
The adhesion molecules on platelets that support the interaction between platelets
and immune cells are summarized in Figure 3.
Cancers 2023, 15, x FOR PEER REVIEW 18 of 38
Figure 3. The molecules that mediate the interaction between platelets and immune cells in the tu-
mor immune microenvironment (TIME). Activated platelets and immune cells in the TME com-
municate through various receptors and ligands or secreted modulatory factors, and these interac-
tions can be targeted for the therapy of ovarian cancer.
Table 2. The influence of various platelet-associated molecules on TME in cancer.
Hallmark Platelet Constituents Prognostic Role References
Pro-
tumorigenic
Endostatin, angiostatin, TSP-1, angi-
opoietin-1, VEGF, PDFG, HGF, FGF,
SDF-1, S1P, TGF-β, IL-6
Stimulation of angiogenesis [61,90]
Figure 3.
The molecules that mediate the interaction between platelets and immune cells in the tumor
immune microenvironment (TIME). Activated platelets and immune cells in the TME communicate
through various receptors and ligands or secreted modulatory factors, and these interactions can be
targeted for the therapy of ovarian cancer.
Cancers 2023,15, 1282 18 of 37
Table 2. The influence of various platelet-associated molecules on TME in cancer.
Hallmark Platelet Constituents Prognostic Role References
Pro-
tumorigenic
Endostatin, angiostatin, TSP-1,
angiopoietin-1, VEGF, PDFG,
HGF, FGF, SDF-1, S1P,
TGF-β, IL-6
Stimulation of angiogenesis [61,90]
TGF-β, angiopoietin, PDGF,
CLEC-2, IL-6
Proliferation, differentiation, and
irregularity of pericytes [64,125,126,128,138]
Platelet microparticles Overexpression of MMPs on
endothelial cells [100]
P-selectin, GPIIb Transendothelial migration of
cancer cells [108,109]
VEGF, angiopoietin-1, PDGF,
IGF-1, CLEC-2
Stimulation of lymphangiogenesis
[61,111,113]
TGF-β, SDF-1, PDGF, CLEC-2
Stimulation and differentiation,
proliferation, and migration
of CAFs
[15,147–149]
TGF-β, G-CSF
Differentiation of neutrophils into
N2-like phenotype [173]
IL-8, G-CSF, GM-CSF, CXCL1,
CXCL2,
CXCL5, MIP-1α
Recruitment of neutrophils
into TME [192,197]
factor XII, P-selectin, GPIIb/IIIa
Platelet interaction with NETs and
subsequent platelet aggregation [202,204]
mtDNA, P-selectin NETosis [202,205]
P-selectin, TGF-β, COX-2, PGE2,
PF4, PAF, PDGF Activation of TAMs [220–222]
CCL2, CCL5, RANTES, SDF-1 Migration of TAMs into TME [238,241]
CD40, CCL5, TxA2 Apoptosis and inhibition of
CD4+T helper cells [264,298]
PF4, TGF-β, P-selectin Suppression of Th1 and Th17
differentiation [288,297,309,310]
P-selectin Stimulation of T cell exhaustion [267]
PD-L1, TGF-β
Inhibition of CD4+and
CD8+T cell
antitumor functions
[52,319–321,326]
CD40L, P-selectin, TNF-α, IL-6,
IGF-1, PDGF, SDF-1
Activation, proliferation, and
migration of Tregs
[16,62,73,74,263,285,293,
302,303]
PF4 Differentiation of monocytes
into MDSCs [21]
CD40L Expansion of Bregs [344]
Platelet microparticles Overexpression of MMPs [61,100]
CXCL5, CXCL7, TGF-β, TSP-1,
P2Y12, COX-1, TxA2
Formation of pre-metastatic
niches [352]
Cancers 2023,15, 1282 19 of 37
Table 2. Cont.
Hallmark Platelet Constituents Prognostic Role References
Anti-
tumorigenic
Endostatin, angiostatin, TSP-1 Inhibition of angiogenesis [56,61]
TRAIL, CCL2, MCP-1, IL-8 Activation of tumoricidal
macrophages [229]
Platelet microparticles Enhancement of the phagocytic
capacity of macrophages [228]
TGF-β, EGF
Upregulation of PD-1 in
cancer cells
and increase in the effectiveness
of immunotherapy
[14,270]
TGF-β, CD40L Activation and infiltration of
CD8+T cells into the tumor [327,353]
CD40L
Differentiation of resting B cells
into plasma cells and generation
of antibodies
[342]
OX40L Infiltration of immune cells
into TME [54]
CCL: chemokine (C-C motif) ligand; CD40L: CD40 ligand; CLEC-2: C-type lectin-like receptor 2; COX: cy-
clooxygenase; CXCL: chemokine (C-X-C motif) ligand; EGF: epidermal growth factor; FGF: fibroblast growth
factor; G-CSF: granulocyte colony-stimulating factor; GM-CSF: granulocyte-monocyte colony-stimulating factor;
HGF: hepatocyte growth factor; IGF-1: insulin-like growth factor 1; IL: interleukin; MCP-1: monocyte chemoat-
tractant protein 1; MIP-1
α
: migration inhibitory protein 1-alpha; mtDNA: mitochondrial DNA; PAF: platelet-
activating factor; PD-L1: programmed death ligand 1; PDGF: platelet-derived growth factor; PF4: platelet factor 4;
PGE2: prostaglandin E2; RANTES: regulated upon activation and normal T cell expressed and secreted;
S1P: sphingosine 1-phosphate; SDF-1: stromal-derived factor 1; TGF-
β
: transforming growth factor-beta;
TNF-
α
: tumor necrosis factor-alpha; TRAIL: TNF-related apoptosis-inducing ligand; TSP-1: thrombospondin 1;
TxA2: thromboxane A2; VEGF: vascular endothelial growth factor.
4. Discussion and Perspectives
The involvement of platelets in cancer progression through the modulation of tu-
mor growth, angiogenesis, metastasis, and chemoresistance has been recognized for
decades [
354
]. Tumor cells activate platelets, and platelets alter cancer cells and the TME
and their interaction [
64
]. As a result, improving our understanding of platelets’ role in
cancer would have a diagnostic, prognostic, and therapeutic impact.
Ovarian cancer is one of the many types of cancer in which platelets interact with
immune and nonimmune cellular components of the TME, including endothelial cells,
pericytes, CAFs, neutrophils, macrophages, and T and B lymphocytes. The adhesion
molecules on the platelets mediate the platelets’ binding to endothelial cells and extravasa-
tion [
355
–
357
]. The proangiogenic factors released by activated platelets, including VEGF
and angiopoietin-1, facilitate neovascularization, lymphangiogenesis [
61
], and remodeling
of the ECM [
100
], required for tumor growth and metastasis. The binding of platelet
CLEC-2 to podoplanin on pericytes [
125
] and the release of platelet-derived mediators,
such as TGF-
β
and PDGF, promote pericyte accumulation and interaction with endothe-
lial cells [
64
]. Thus, platelets, through pericytes, contribute to vessel density [
127
] and
integrity [
128
,
129
]. Platelets [
147
,
148
], platelet microparticles [
24
], and platelet-derived
mitochondria [
24
] contribute to the transformation of fibroblasts to CAFs, which promotes
the peritoneal dissemination of ovarian cancer cells [
160
] and the formation of malignant
ascites [358].
Platelets communicate with immune cells and induce a tolerogenic state [
359
]. Platelets
bind neutrophils [
181
–
183
,
188
,
189
] and facilitate neutrophil recruitment to the TME. Cy-
tokines and chemokines released from platelets promote neutrophil migration to the
TME [
360
]. Neutrophils activate platelets and promote thrombosis by releasing prothrom-
botic mediators and generating NETs [
360
,
361
]. Platelet–macrophage interaction favors
Cancers 2023,15, 1282 20 of 37
immunosuppressive macrophage polarization [
222
,
362
]. Activated monocytes, in turn,
promote coagulation and thrombosis [
230
]. Platelets promote the exhaustion of CD4
+
T
helper and CD8
+
cytotoxic T cells [
321
] in conjunction with Tregs and Bregs [
363
]. More-
over, platelets promote the expression of immune checkpoint molecules on ovarian cancer
cells, which further supports cancer progression [
14
] and can affect patients’ responses to
immunotherapies [307,364].
Thrombocytosis is responsible for the approximately 8-fold elevated risk of ovarian
cancer occurrence and 5-fold mortality rate in ovarian cancer patients [
28
]. An elevated
platelet count is significantly associated with poor progression-free and overall survival
of patients with localized and advanced cancer stages [
365
]. Moreover, ovarian cancer
patients with high platelet numbers respond less to chemotherapy and demonstrate shorter
treatment-free intervals caused by increased resistance [
366
,
367
]. This makes platelet
count an important parameter for the preoperative assessment of pelvic mass [
368
] and in
evaluating the response to therapy in ovarian cancer patients [369].
Antiplatelet reagents that have been extensively studied in cardiovascular disease [
370
,
371
]
can beconsidered for potential therapeutic goals in cancers, including ovarian cancer. Agents
that hinder platelet functions, including aspirin, ADP receptor antagonists (e.g., ticagrelor
and clopidogrel), thrombin receptor-targeting molecules, inhibitors of GP Ib-IX, P-selectin,
and CLEC-2, can be used as complementary therapeutics in ovarian cancer. Although they
have arole in preventing cancer progression [
372
–
374
], long-term usage of antiplatelet agents
such as aspirin, clopidogrel, and ticagrelor is associated with increased bleeding risk [
375
,
376
].
The blockade of CLEC-2 can be a beneficial alternative for patients with elevated bleeding
susceptibility, since this approach a lower tendency to cause hemorrhage due to its inhibition
of platelet activation without substantially affecting aggregation [
227
,
377
]. Including agents
that target EGFR, PDGFR, and FGFR in anti-VEGF therapy can also improve the efficacy of
cancer treatment by rewiring multiple cellular pathways and minimizing drug resistance in
ovarian and other cancers [
89
,
378
,
379
]. Apart from suppressing the viability, progression, and
dissemination of tumor cells, platelet-targeting compounds interfere with platelet-induced
angiogenesis, thrombosis, ascites formation, and immunosuppression. Multiple clinical trials
have assessed the impact of antiplatelet agents, alone or with chemotherapeutic drugs, on
preventing or treating ovarian cancer. Significantly, platelet counts or platelet-derived molecules
can beused as diagnostic, prognostic, or predictive biomarkers [380].
Of note, thrombocytopenia, a side-effect of cancer treatment, is a common phe-
nomenon in cancer patients [
381
]. Platelet transfusion and platelet-stimulating agent treat-
ment are clinically exploited applications to recover the platelet counts of cancer patients
with immune thrombocytopenia and those who have undergone chemotherapy or radio-
therapy. On the other hand, thrombocytosis supports tumor growth and chemoresistance
by enhancing platelet-directed alterations in cancer cells and TME components [
30
,
382
].
Therefore, extra caution must be taken during the treatment of thrombocytopenia to avoid
promoting cancer progression.
5. Conclusions
Paraneoplastic thrombocytosis in ovarian cancer is due to IL-6 originating from can-
cer cells and consequent thrombopoietin released from the liver. Thrombocytosis and
activated platelets can be detected in advanced diseases, and might be associated with
cancer-induced venous thrombosis and reduced overall survival. Besides cancer cells,
platelets interact with other components of the TME. Antiplatelet strategies might interfere
with neoangiogenesis, lymphangiogenesis, ECM remodeling, and the immunosuppressive
profile of the TME. In addition, antiplatelet agents may reduce the formation of malignant
ascites and premetastatic niches. Future studies must examine platelet—TME interaction
and plan specific treatments for ovarian and other cancers.
Cancers 2023,15, 1282 21 of 37
Author Contributions:
Conceptualization, M.S.C.; initial draft preparation, S.O. and M.S.C.; draft
review and editing, S.O. and M.S.C.; visualization, S.O. and M.S.C.; supervision, M.S.C.; project
administration, M.S.C. All authors have read and agreed to the published version of the manuscript.
Funding:
This work was supported by an Early Career Investigator Grant from the Ovarian Cancer
Research Alliance (ECIG-P-2018–600065); the Ovarian Cancer Research Fund in honor of Liza Chance
from the Foundation for Women’s Cancer; and the National Institutes of Health (P50 CA217685)
(all to M.S.C.).
Acknowledgments:
The authors thank Vahid Afshar-Kharghan, Section of Benign Hematology,
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center) for his
critical reading and valuable comments on the manuscript. Figures were created using Biorender.com.
Conflicts of Interest: The authors declare no conflict of interest.
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