Exploring the platelet and cancer cell interaction in metastasis targeting

Abstract

Platelets are small anucleated cell fragments that ensure the stopping of bleeding. In blood metastasis of cancer, Platelets are essential. One of the most important aspects of cancer metastasis is the interaction between platelets and circulating tumor cells. Platelets are involved in cancer spread and constitute a hazardous collation with the cancer cells. There are various factors involved in hemostasis and thrombosis, which can be activated by several cancer-related stimuli, including extracellular matrix (ECM), adenosine diphosphate (ADP), and Toll-like receptors (TLRs). Furthermore, it has been previously published that platelets build up inside the main tumors, producing growth factors that encourage tumor growth and angiogenesis. Additionally, tumor cells can interact with platelets through aggregation, further protecting cancer cells. Platelets interact both functionally and physically with different types of tumor cells via integrin and other surface receptors. Platelet integrin's primary function is to maintain platelet adhesion and aggregation at vascular damage sites. Pharmacological treatments that target integrin have been shown to effectively inhibit experimental metastasis. This review paper summarized the recent advances and progress of mechanisms in platelet activation and its interaction with cancer cells in metastasis.

Full text

834
Journal of
Current Oncology and Medical Sciences
Vol. 4, No.2
https://journalofcoms.com
Corresponding Authors:
Muhammad Zubair
 Email: zubairbiochem1334@gmail.com
Receive: 2024.2.15, Accepted: 2024.4.18
eISSN:
2783-3127
Review
Free Access
Exploring the platelet and cancer cell interaction in metastasis targeting
Maria Riaz 1, Muhammad Zubair 1*, Muhammad Kaleem Iqbal 2, Syed Muhammad Ahmad Bukhari 1, Hafiz
Muhammad Sultan 1
1 Institute of Biological Sciences, Khwaja Fareed University of Engineering and Information Technology, Rahim Yar Khan,
Pakistan
2 Institute of Microbiology, University of Agriculture Faisalabad, Pakistan
Abstract
Platelets are small anucleated cell fragments that ensure the stopping of bleeding. In blood metastasis of cancer, Platelets
are essential. One of the most important aspects of cancer metastasis is the interaction between platelets and circulating
tumor cells. Platelets are involved in cancer spread and constitute a hazardous collation with the cancer cells. There are
various factors involved in hemostasis and thrombosis, which can be activated by several cancer-related stimuli,
including extracellular matrix (ECM), adenosine diphosphate (ADP), and Toll-like receptors (TLRs). Furthermore, it has
been previously published that platelets build up inside the main tumors, producing growth factors that encourage tumor
growth and angiogenesis. Additionally, tumor cells can interact with platelets through aggregation, further protecting
cancer cells. Platelets interact both functionally and physically with different types of tumor cells via integrin and other
surface receptors. Platelet integrin’s primary function is to maintain platelet adhesion and aggregation at vascular damage
sites. Pharmacological treatments that target integrin have been shown to effectively inhibit experimental metastasis.
This review paper summarized the recent advances and progress of mechanisms in platelet activation and its interaction
with cancer cells in metastasis.
Keywords: Platelets, Cancer cells, Tumor, CTCs, Immune cells

M. Riaz, et al. Journal of Current Oncology and Medical Sciences
Introduction
Platelets are small fragments that are derived from
megakaryocytes in bone marrow. Circulating in the
blood, platelets not only maintain hemostasis but also
play a vital role in cancer progression and metastasis
(1) The interaction between platelets and cancer cells
promotes cancer metastasis (2). One aspect of this
interaction includes Circulating Tumor Cells (CTCs)
(3). CTCs are cancer cells that separate from the
primary tumor and enter blood circulation (4). Platelets
bind to these CTCs and form a protective shield around
them (5). This protective shield protects the CTCs from
immune cell detection and helps in their dispersal to
distant tissues. The interaction between CTCs and
Cancer metastasis is observed in different types of
cancer including lung cancer, colon cancer, and breast
cancer. During cancer progression, a small number of
CTCs also invade nearby tissues by extravasation
process thus contributing to tumor angiogenesis (6).
Platelets are disc-shaped blood cells, which consist of
three types of granules, Lysosomes, Dense granules,
and Alpha granules. Alpha granules are present in
abundant and store various factors such as ADP/ATP,
Fibrinogen, Extracellular Matrix (ECM), and
coagulation factors. Platelets release these growth
factors and molecules that stimulate angiogenesis,
which promotes the formation of new blood vessels
around tumors and provides them with essential
nutrients and oxygen to grow and spread. Cancer cells
also can activate platelets during Cancer metastasis.
Activated platelets and the release of various growth
factors enhance pro-thrombotic events. 25-30% of
thrombotic events are cancer-related (7). Cancer
patients encounter an increased occurrence of both
arterial and deep vein thrombosis. Activated platelets
also release clotting factors that lead to the formation
of blood clots within the blood vessel during cancer (8).
Platelets not only contribute to cancer metastasis but
can also be used to target cancer cells that are bound
with the platelets, to treat cancer (9). Platelets integrin's
primary role is to maintain platelets aggregation and
adhesion at the vascular damage site. Targeting integrin
has been shown to inhibit experimental metastasis. In
this review paper, we summarize the role of platelets in
different steps of cancer progression including cancer
metastasis, angiogenesis, and platelets-associated
thrombosis development during cancer and the
development of platelets-based target therapies to treat
cancer (10).
Interaction between cancer cells and platelets
The interaction between platelets and cancer cells
initiates when a particular molecule such as
chemokines is released by cancer cells (11). These
molecules will function as a signal that will attract
platelets to the tumor microenvironment (12). A type
of chemical gradient is generated by these molecules
that will direct platelets to the tumor site (13).
Interaction of cancer cells and platelets also occurs by
immediate receptor binding or by bridging of receptors
by Protein (14). For instance, one platelet receptor
engaged in Cancer progression is the CLEC-2 receptor
that in certain cancers binds with podoplanin.
Podoplanin that are present on tumor cells interact with
the CLEC-2 receptors and leads to the activation of
platelets that leads to tumor growth and metastasis.
However, platelets can also indirectly activated by
releasing several proteins and growth factors such as
VEGF and PDGF that stimulates tumor growth and
leads to cancer progression. Different integrins
involved in cancer and platelet interaction includes
αIIbβ3, αvβ3, α5β1, α6β1 and αvβ5 that bind
specifically to their ligand fibrinogen, vitronectin,
fibronectin, laminin and vitronectin respectively.
Although, the receptor αIIbβ3 integrin plays a
significant role in Cancer metastasis. It mediates the
interaction between Cancer Cells and platelets by
adhesive proteins (such as fibrinogen and von
Willebrand Factor). The receptor αIIbβ3 goes through
structural changes after activation by interaction with
platelet stimulants such as ADP, collagen, thrombin,
etc. (15). The receptor αIIbβ3 shows an increased
binding attraction to ligands (including fibrinogen and
WF) in its active form. By facilitating the cancer Cell
and Platelets aggregate's arrest in the endothelium, the
receptor alphaIIbbeta3 also supports the arrest of
cancer cells in vessels (16). Platelets and cancer cells
interaction is a very diverse process that leads to cancer
metastasis.
Progression of cancer by platelets surface receptors
Platelets surface receptors are a type of proteins that are
present on the membrane of platelets and promote the
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M. Riaz, et al. Journal of Current Oncology and Medical Sciences
interaction between the platelets and cancer cells.
Various platelets surface receptors include GPIbα,
GPVI, P-selectin and GPIb-IX-V. Among them GPVI
and GPIb-IX-V are platelets surface receptors that
participate in maintaining hemostasis, also imply the
interaction among cancer cells and platelets (17). They
also contribute a vital role in encouraging the
Extravasation and the arrest of Circulating Tumor Cells
(CTCs) which are facilitated ultimately by the
progression of metastasis by adhesion proteins. GPVI
is a vital receptor for fibrin and collagen so; it facilitates
the adhesion of platelets at the Injury site. In vivo
experiments performed on lung carcinoma and
melanoma that lack GPVI receptor in mice, show a
45% visible decrease in tumor (18). The experiment
performed on mice with cancer with defective GPIb-IX
shows a 14% decrease in metastatic foci. Although
these receptors on platelets are involved in cancer
metastasis only, they are not involved in Primary tumor
growth. The activation of the platelets and adhesion of
platelet-cancer cells is also facilitated by the interplay
among platelet and integrin. Integrin behave as a
receptor that interplay with the ligands that are present
on the surface of both CTCs and platelets and thus
contributes to their adhesions. On the other hand,
selectin can also contribute to the adhesion between
CTCs and platelets by promoting the interplay among
CTCs and platelets. When platelets are activated they
express P-selectin upon them, that binds to its ligand
present on the CTCs and thus contribute to the adhesion
between CTCs and platelets. The range of interaction
among cancer Cells and Platelets does not depend upon
a single receptor-receptor pairing (19).
Platelets role in tumor angiogenesis
After attaining a specific size, tumor cells have to
initiate angiogenesis, in which the tumor receives
additional growth factors and nutrients that are
necessary for tumor cells to differentiate and spread
into different parts of the body. During Tumor
angiogenesis, new blood vessels at the growing tumor
site are formed by the lining up of epithelial cells that
are attracted by various growth factors that are released
in the tumor microenvironment by platelets and lead to
the formation of new capillaries and arteries (20).
Platelet α-granules are the main site for storing various
factors that maintain angiogenesis and hemostasis at
the same time in the tumor microenvironment. When
platelets are activated, they release α-granules that
contain various growth factors that initiate
angiogenesis, such as Vascular Endothelial Growth
Factor (VEGF) and Pro-angiogenic factors; epithelial
cells and some anti-angiogenic factors such as
endostatin and thrombospondin-1 are also released.
The complex interaction among pro-angiogenic and
anti-angiogenic leads to the formation of pro-
angiogenic and anti-angiogenic microenvironment
respectively. This interplay contributes to both the
angiogenesis of tumor for progression of cancer as well
as understanding of these anti-angiogenic factors can
be used to inhibit cancer. Based on stimuli that
platelets receive from the external environment
platelets can particularly secrete various factors to
initiate or prevent the development of blood vessels in
the developing tumor microenvironment (21). For
example, ADP-induced platelets can secrete VEGF but
cannot release end statin; meanwhile, thromboxane
induces platelets to secrete endostatin rather than
VEGF (22). ADP secretes VEGF in tumor
microenvironment that is a pro-angiogenic factor and it
is released to promote tumor progression.
Thromboxane releases endostatin in tumor
microenvironment that is an anti-angiogenic factor and
it is released to limit tumor vascularization.
Figure 1. Demonstrates that various growth factors and
receptors released by platelets induce angiogenesis.
Platelets-induced release of Angiogenic factors
Platelets are also activated by various cancer cells,
these activation initiates the secretion of several
substances such as Angiogenic factors (23). These are
the substances that encourage the formation of new
blood vessels (24). Currently, it has also been
developed that Stimulated Emission Depletion (STED)
imaging can also be used to demonstrate platelets-
induced release of various growth factors that initiate
Platelets
Surface
Receptors
VEGF
PDGF
Pro-
Inflammatory
molecules
Tumor
Angiogenesis
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M. Riaz, et al. Journal of Current Oncology and Medical Sciences
angiogenesis more accurately. Depending upon the
external stimuli, platelets can increase or suppress the
angiogenesis of tumors by particular secretion of pro or
anti-angiogenic factors (25). Factors like inflammation,
hypoxia and shear stress act as external stimuli and
contribute to the release of pro-angiogenic and anti-
angiogenic factors. For example, if inflammatory
signal is released by external environment, it will
promote the release of cytokines and growth factors
which lead to the release of VEGF that in result
encourage angiogenesis. Although factors like nutrient
availability and pH can also contribute to the secretion
of pro-angiogenic and anti-angiogenic factors.
Platelets selectively intake and store VEGF in the α-
granule that is released by a tumor in the tumor
microenvironment. However, tumors can also activate
the secretion of VEGF by platelet, thus maintaining the
level of VEGF in the tumor microenvironment that
significantly initiates angiogenesis in the tumor
microenvironment (26). Various other angiogenic
factors are also released by platelets including
Fibroblast Growth Factor (FGF) and Platelets Derived
Growth Factors (PDGF) (27). FGF promotes the
migration of epithelial cells role and PDGF regulates
the growth of muscle cells both of them are essential
for the formation of new blood vessels in tumor
angiogenesis. The Pro-angiogenic environment is
established by these angiogenic factors that will
encourage cancer progression (28).
Platelets encourage circulating tumor cells dispersal
Platelets not only assist the growth of the primary
tumor; however, but they also play an important role in
metastatic progression. They attach to the surface of
Circulating Tumor Cells and act as a shield (29). This
shield of platelets serves as a camouflage for CTCs, due
to which CTCs are very less visible to immune cells.
Platelets also make a cloak that surrounds CTCs,
deterring various immune cells from identifying them
as a foreign particle. This interplay prevents the CTCs
from immune system detection and recognition.
Platelets aid these CTCs when they encourage
vasculature, which in turn assists the CTCs in the
bloodstream and dissemination of CTCs to different
tissues. CTCs arrest could be passive or active. During
Passive arrest CTCs move in the bloodstream till they
attach to the platelets without any active contribution
by CTCs. Passive arrest includes the blockage of CTCs
due to the formation of platelets, fibrinogen, and tumor
cells in small blood vessels (30). On the other hand,
active arrest includes the process in which platelets
actively identify and binds to CTCs and contributes to
the development of aggregate that promotes tumor cells
survival. Active process refers to the transfer of tumor
cells from the primary tumor into the bloodstream.
Platelets also act as a framework by covering the upper
layer of circulating tumor cells that aid CTCs to move
freely in the bloodstream. Thus, platelets are core
regulators of tumor cells. When Platelets are activated
by tumors they provide various growth factors to the
CTCs. Label et al. indicated that the secretion of TGF-
β (Transforming Growth Factor) by platelets and
cancer cell-platelets interaction initiates metastasis by
stimulating various signaling pathways (31). When
these pathways are activated, they trigger Epithelial
Mesenchyme Transition (EMT), which is the process
in which tumor cells having epithelial phenotype lose
their various features. EMT maintains the transfer of
primary tumor cells into the bloodstream, which leads
to the dissemination of tumor cells to distant tissues
(32). Different detection methods that are used to detect
CTCs include PCR, immunocytochemistry, flow
cytometry and several approaches based on
microfluidics.
Platelets-induced cancer cell reconfiguration
EMT (Epithelial-Mesenchymal Transition) is a vital
developmental program that also takes place in cancer
metastasis (33). Epithelial cancer cells create a Key
Mesenchymal cell layer via the Epithelial-
Mesenchymal Transition and alter their shape as they
drop connection with the basement membrane. The
activity of Epithelial Mesenchymal Transition can be
invertible and epithelial cells can be converted into
mesenchymal cells and vice versa. Epithelial
Mesenchymal Transition is also assisted by
components of the Extracellular Matrix, cells obtained
from the microenvironment of tumor and immune cells
(34). Several factors also participate in controlling
Epithelial-Mesenchymal Transition including
Transcription Factors, Hepatocyte Growth Factors, and
Transforming Growth factors (TGF). TGF discharged
by alpha granules of activated platelets transforms
Tumor cells into pro-metastatic EMT (35).
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M. Riaz, et al. Journal of Current Oncology and Medical Sciences
TGF is activated by the interplay among platelet-cancer
cells and platelets are referred as a main source for
TGF-β. TGF derived from platelets in cancer cells,
leading to the enhanced cancer metastasis and
Epithelial-Mesenchymal Transition phenotype in vivo.
Altogether, these findings show a direct linkage
between EMT development and TGF released from
platelets (36). However, TGF-β also activates Smad
signaling pathway that promotes EMT. Interaction of
TGF-β with tumor cells receptor leads to the activation
of various Smad proteins that form complexes and
move in to the nucleus where they promote the
expression of certain genes that leads to the Epithelial
Mesenchymal Transition. ECM components that are
released by tumor microenvironment or tumor are
recommended for being involved in Epithelial-
Mesenchymal Transition. Cathepsin belongs to a group
of protease enzymes that are released by various tumor
cells. Cathepsin is primarily restrained in lysosomal
vesicles and released as soluble enzymes that split
ECM components near cancer cells. Cathepsin also
triggers platelet aggregation and assists interplay of
Epithelial-Mesenchymal Transition-Cancer Cells (5).
Figure 2. Schematic representation of activated platelets
interaction with cancer cells as well as initiate EMT and both
of them induce cancer metastasis.
Thrombosis in cancer and tumor-induced platelet
activation
Patients who suffer from cancer often face blood-
clotting problems in the various blood vessels that
include both arteries and veins. The development of
thrombosis in cancer patients is another major reason
for mortality. Thrombosis elevates the possibilities of
cancer metastasis and progression that have been
observed in lung and breast cancers and it is associated
with poor survival (37). There are more chances of the
development of thrombotic complications in cancer
patients in contrast to patients without cancer.
Meanwhile, the accurate procedure for the
development of thrombosis in cancer is not completely
understood. However, more than one-fourth of the
patients who suffer from cancer have been diagnosed
to have relatively high levels of platelets in their blood
(38).
Platelets that are activated by tumor cells can lead to
the development of thrombosis (39). Tumor cell-
induced platelets activation and aggregation (TCIPA)
is detected in fibro-blastoma. The main controller of
this pathway is cancer cell Resident Podoplanin
(PDPN). High expression of Podoplanin increases the
chances of thrombosis development during cancer.
Podoplanin expression in epithelial cells can also
increase the risk of thrombotic complications. (40).
When platelets are indirectly activated by cancer cells
they trigger the epithelial cells to secrete various
proteins and growth factors that provide an area for
platelets attachment and development of thrombosis
(41). In cancer patients development of Neutrophil
extracellular trap (NET) is mostly identified that as
contributing to the elevated level of histone protein and
other nucleosomes in the bloodstream (42). NET leads
to the development of tumor-induced thrombosis and
dysfunction of various organs (43). In pancreatic
cancer, NET is regarded as the main contributor to the
development of cancer. Elevated concentrations of TF
were observed in these patients (44). These findings
show that platelets lead to thrombotic complications
among cancer patients (45).
Figure 3. Diagrammatic representation of the interaction
between platelets and cancer cells that induce angiogenesis,
Cancer
Metastasis
Prevent
immune attack
EMT
Primary
Tumor Cells
Blood
Circulation
Extravasation
Activated
platelets
Interact with
Cancer Cells
Initiate
Angiogenesis
Protects from
Immune Cells
Aid in CTCs
Dispersal
Thrombosis
838

M. Riaz, et al. Journal of Current Oncology and Medical Sciences
protection from immune cells, CTCs dispersal, and
thrombosis in tumor microenvironment.
Effect of platelets on anti-tumor immunity
Platelets perform very diverse roles in anti-tumor
immunity activity (46). Among all cancers, only a
small number of cancer cells form metastatic foci.
Natural Killer (NK) cells are the immune cells that can
remove cancer cells from blood circulation. Platelets
are the only blood cells that interact with the cancer
cells and form a protective shield around them that
prevents them from immune cell detection and
recognition (47). Platelets also protect tumor cells from
anti-tumor immunity by the release of various
molecules that are immunosuppressive in their action
(48). These immunosuppressive molecules include
Transforming Growth Factor Beta (TGF-β) which can
suppress the anti-tumor activity of various immune
cells including NK cells as well as T cells (49). TGF-β
inhibits NK cells and T cells activity by inhibiting their
proliferation and suppressing of cytotoxicity that leads
to the immune tolerance and cancer progression.
Platelets also can suppress the activity of dendritic cells
that are crucial for regulating various immune
responses against tumor cells (50). Platelets suppress
the activity of dendritic cells through various
mechanisms such as by direct physical interaction with
dendritic cells that suppress their maturation and by
releasing various immunosuppressive molecules such
as TGF-β and PGE2 that inhibit the function of
dendritic cells and their capability to activate T cells.
Platelets not only play an important role in tumor
angiogenesis but they also maintain the integrity of the
tumor, thus preventing hemorrhage of the tumor (51).
By regulating the integrity of the tumor, platelets
decrease the effect of the immune system on the tumor.
To survive in circulation Circulating Tumor Cells
(CTCs) need to protect themselves from immune
system recognition and killing mechanism (52).
Platelets protect tumor cells from NK cells
Natural Killer cells play an important role in Antitumor
immunity activity (53). Platelets that are activated
along with fibrinogen shield the tumor cells and protect
them from Natural killer cells by the formation of a
barrier that protects the tumor cells from NK cells (54).
This protective shield makes it more difficult for NK
cells to affect tumor cells. Moreover, various immuno-
suppressive molecules released by platelets also
diminish the activity of NK cells (55). A decrease in
the level of Natural killer cells will enhance metastasis
of cancer. It has been shown that the platelets induce
metastasis of the tumor within 1 hour after the tumor
has entered the blood circulation meanwhile Natural
killer cells employ their antitumor immunity activity
one and sixth hour after tumor extravasation. In
comparison to any other blood cells, platelets can keep
a large quantity of Transforming Growth Factor and
secrete it into the microenvironment of the tumor
during metastasis and progression of cancer. It is
demonstrated that the release of this growth factor by
platelets can lead to the down-regulation of Natural
Killer cells, thus inhibiting their antitumor immunity
(56). As platelets also promote tumor angiogenesis it is
difficult for NK cells to eradicate tumor cells (57).
Drugs against tumor microenvironment
Different types of receptors and cytokines present in
the tumor microenvironment take part in cancer
metastasis (31). Many elements that contribute to
tumor metastasis assemble in the tumor
microenvironment making cancer treatment more
difficult. The cancer resulting from cancer-platelets
interaction explains the fact that platelet is the main
factor that promote cancer by promoting angiogenesis,
CTCs dispersal and protection from immune system.
Thus, targeting platelets will be the best strategy to
overcome the cancer progression resulting from
cancer-platelet interaction. For the molecules that are
over-activated in cancer, various drugs have come into
being to target them (58). When it is revealed that the
platelets in cancer contribute to the suppression of the
immune system, an attempt to make a drug that will
induce immune responses in cancer was started (59).
The best strategy to inhibit cancer metastasis that is
initiated by cancer-platelet interaction is to use drugs
that suppress the amount of platelets in tumor site as
well as use of chemotherapeutics that will use to treat
cancer. The microenvironment of the tumor helps us to
understand how tumors gain resistance against any
antitumor drug. This concept is referred to as “de novo
mechanisms” that show how a change in the
microenvironment of a tumor can give tumor cells a
new pathway to overcome the effect of antitumor drugs
(60).
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M. Riaz, et al. Journal of Current Oncology and Medical Sciences
Table 1. Some platelets targeting drugs that can be used
along chemotherapeutics in different types of cancers.
Cancer Cell
type
Platelets
targeting
Drugs
Chemotherapeutics
Human lungs
cells
Aspirin
Doxorubicin
hydrochloride (Dox)
Breast cancer
cells
Trastuzumab
Monomethyl
auristatin E
(MMAE)
Human
leukemia
Hydroxyurea
Epidoxorubicin
imaging
Agent CY5
Carboxyfluorescein
di-ester
Human
lymphoma
cells
Rituximab
Doxorubicin (Dox)
Human
colonic
carcinoma
Oxaliplatin,
Bevacizumab
Tumor necrosis
factor -
Related apoptosis-
inducing
Ligand (TRAIL)
Human triple
negative
Breast cancer
cells
Aspirin
TRAIL
Platelet is a main target to overcome cancer
metastasis
Platelets and cancer cell interaction plays a major role
in promoting CTCs dispersal to distant tissues,
angiogenesis, suppression of anti-tumor immunity
activity, and eventually cancer metastasis, so platelets
are a main target to overcome cancer metastasis (61).
Metastasis of cancer is the major cause of death in
cancer patients. Clinical studies have shown that tumor
cells that are surrounded by platelets are less affected
by chemotherapy. Furthermore, platelets also
encourage Epithelial-Mesenchymal Transition in
tumor cells that have chemoresistance (62). These
studies show that to overcome cancer metastasis
effectively and completely targeting platelets will be
the best strategy. Inhibition of platelets in the clinical
model shows that it inhibits the metastasis of cancer. It
is also demonstrated that attachment of the platelets
with the cancer cells, prevents them from immune
system recognition and attack, thus enhancing cancer
metastasis (63). After studying the vital role of platelets
in cancer metastasis, it was demonstrated that targeting
platelets will be the best strategy to treat platelets-
induced cancer (64). Various drugs that can suppress
platelets can be used. These drugs can be transferred
directly to the tumor microenvironment. Although
many drugs that can target platelets also have tumor
suppressive activity (65).
Platelet suppression by Aspirin and Integrin as a
therapeutic target in cancer metastasis
Aspirin is a common drug that is used to overcome
fever and pain. Aspirin also can suppress platelets,
therefore it is used by patients with cardiac and
thrombotic complications (66). Platelets-induced
cancer metastasis can also be reduced by the use of
aspirin. It has also been shown in clinical experiments
the growth and development of cancer is reduced by
aspirin. Aspirin function by suppressing the formation
of various chemicals such as prostaglandins that
contributes to aggregation and activation of platelets.
By suppressing the amount of these chemicals, aspirin
assist in preventing platelets to adhere together and
form clots. Tamoxifen is another drug that is used in
breast cancer as an antiestrogen (67). It is demonstrated
that tamoxifen suppresses metastasis of cancer that is
induced by platelets. Tamoxifen inhibit platelet
activation by altering the secretion of various
angiogenic factors by platelets and by suppressing the
expression of various adhesion molecules on the
surface of platelets. Different types of integrins are
expressed by platelets, such as α6β1which facilitate the
binding with collagen. Direct interplay among platelets
and collagen is regulated by GPVI and α6β1 integrin.
Studies have shown that the interplay among platelets
and cancer cells that contribute to cancer metastasis is
terminated by blocking α6β1 integrin (68). The
blocking function of integrin with the help of
antibodies will suppress the interaction between cancer
cells and platelets. Suppression of the function of
integrin by antibodies does not affect hemostasis and
number of platelets in mice. This antibody does not
have any effect on cancer metastasis when introduced
into platelet α6β1 deficient mice. Integrin α6β1 is also
found in endothelial cells and pericytes, where they
impart tumorigenic effect to the microenvironment of a
tumor. Inhibiting integrin α6β1 will suppress the
different types of integrin-facilitated cancer metastasis,
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M. Riaz, et al. Journal of Current Oncology and Medical Sciences
thus inhibiting the function of this integrin is one of the
best strategies against cancer (69). There are several
integrin inhibitors involved in suppressing cancer
metastasis in vivo models such as Cilengitide,
Volociximab and ATN-161. Cilengitide is an integrin
inhibitor that targets αvβ5 and αvβ3 and is a promising
strategy in inhibiting clinical models by inhibiting the
ability of the primary tumor cells to spread at distant
tissues. Volociximab is a type of anti-angiogenic agent
that inhibits the α5β1 integrin. In clinical models it
inhibits metastasis by preventing the development of
angiogenesis. ATN-161 is an integrin inhibitor that also
inhibits α5β1. In clinical models it inhibit metastasis by
effecting growth of tumors, angiogenesis and dispersal
of CTCs to distant tissues.
Platelets-dependent drug delivery to target primary
tumor and platelets carriers for cancer therapy
Platelets also can take chemotherapeutics to tumor cells
at two sites, in the microenvironment of the tumor and
blood circulation (70). For a long period, platelets were
used as blood clotting agents in blood circulations.
There are various ways to treat cancer but one of the
best ways is to treat cancer by using platelets as a
carrier for the transfer of chemotherapeutics (71).
Many factors make the platelets a potential carrier to
deliver the drug in the tumor microenvironment (72).
Its example is Doxorubicin, which is filled with
platelets by the using general incubation method. This
platelets-loaded Dox has been shown to inhibit the
growth of cancer in clinical models (73). The platelets-
based carrier has also been shown to inhibit tumors in
mouse models (74). Entirely it is demonstrated that the
use of platelets as a carrier can expertly transfer
chemotherapeutics to the tumor microenvironment and
inhibit platelets-induced cancer (9). Additionally, Yap
et al. show that there is no side effect of using platelets-
based carrier on various functions of the organs. There
is also research on using platelets as a carries to transfer
antibodies to be used as immunotherapeutic in which
antibodies are loaded into the membrane of platelets
(75). In clinical models, antibody-loaded platelets have
been shown to inhibit the growth of tumors (76).
Conclusion
Interaction between Platelets and cancer cells plays a
very important part in cancer metastasis and
progression. Platelets release various growth factors
that help CTCs to grow and spread into the different
parts of the body and form aggregates with them that
protect them from the immune system. Cancer cell-
induced activation of platelets increases the risk of
developing thrombosis. Platelets also protect cancer
cells from antitumor immunity activity by forming a
protective layer around tumor cells that acts as a shield
and prevents them from immune cell detection and
killing mechanisms. Thus, targeting interaction
between platelets and cancer cells is the best strategy to
overcome cancer metastasis as well as cancer-induced
thrombotic complications. Treating strategies include
specifically targeting primary tumors, CTCs, and
circulating malignancies. Among targeting strategies
one of the best strategies is to use platelets as a carrier
to deliver chemotherapeutics to tumor
microenvironment. Meanwhile, delivery of the
chemotherapeutics using platelets gives us an excellent
potential to treat platelets-induced cancer but there are
still many challenges that need to be controlled.
Acknowledgment
We would like to thank the Khawaja Fareed University
of Engineering and Information Technology Institute
of Biological Sciences students who participated in the
data collection and were not listed in the author list.
Author contribution
MR, MZ, and SMAB design the study. MR, MZ, and
HMS wrote the first draft of the manuscript. MKI
wrote a section of the manuscript. All the authors
contributed to the article and approved the submitted
version
Conflict of interest
The authors report no conflict of interest.
Funding
There is no funding agency involved in this research.
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