Although once primarily recognized for its roles in hemostasis and thrombosis, the platelet has been increasingly recognized as a multipurpose cell. Indeed, circulating platelets have the ability to influence a wide range of seemingly unrelated pathophysiologic events. Here, we highlight some of the notable observations that link platelets to inflammation, reinforcing the platelet’s origin from a lower vertebrate cell type with both hemostatic and immunologic roles. In addition, we consider the relevance of platelets in cancer biology by focusing on the hallmarks of cancer and the ways platelets can influence multistep development of tumors. Beyond its traditional role in hemostasis and thrombosis, the platelet’s involvement in the interplay between hemostasis, thrombosis, inflammation, and cancer is likely complex, yet extremely important in each disease process. The existence of animal models of platelet dysfunction and currently used antiplatelet therapies provide a framework for understanding mechanistic insights into a wide range of pathophysiologic events. Thus, the basic scientist studying platelet function can think beyond the traditional hemostasis and thrombosis paradigms, while the practicing hematologist must appreciate platelet relevance in a wide range of disease processes.

Thrombosis, inflammation, and cancer are interrelated, and circulating blood platelets are one cellular element common to each process. Although the relevance of platelets in the pathophysiology of thrombosis is well established, their contributions to inflammatory pathways and cancer are less defined and appear to be complex and multifaceted. Indeed, the paradigms of hemostasis and thrombosis, where a temporal sequence of events starts with an unactivated platelet recognizing a surface or being stimulated by an agonist and leads to an activated platelet, have dynamic implications for platelet phenotype and function. Similar changes are likely to have dramatic consequences for the platelet’s influence on both inflammation and cancer, and this highlights the likely complexity of platelet involvement in each disease process.

In 1863, Rudolf Virchow hypothesized that cancer could arise from sites of chronic inflammation, hypothesizing these sites could sustain proliferation.1  In fact, cancer has often been referred to as a wound that never heals, hijacking the body’s natural ability to fight infection and produce a proproliferative environment to sustain healing and tissue remodeling. We now know that cell proliferation alone is not sufficient to lead to or support transformation, but the risk of cellular transformation can be enhanced by cell proliferation in an environment rich in inflammatory cells, growth factors, activated stroma, and factors that promote DNA damage. Indeed, today it is widely accepted that there is a causal relationship between inflammation, innate immunity, and cancer development. To this end, the platelet’s natural role in wound healing is poised to be hijacked by these pathophysiologic events.

In this review, we highlight examples where the platelet interfaces with the inflammatory process. Then, in consideration of Virchow’s hypothesis, we will examine the hallmarks of cancer from the perspective of the blood platelet. Indeed, there have been remarkable molecular insights into the platelet’s relevance in thrombosis, inflammation, and cancer. However, going forward, these pathologic events can no longer be considered functional silos because the broader consideration of multifactorial events and their consequences will likely shape future innovations.

It is presumed that platelets and leukocytes share a common ancestral cell, the thrombocyte, facilitating both hemostatic and immune roles in lower vertebrates, such as fish and birds.2  Therefore, it comes as no surprise that platelets so frequently pervade immunologic functions.3  Although not strictly appointed within the inflammatory pathway, the platelet can be viewed as an extension of the cellular immune system.4-8  Recent evidence places the platelet in the middle of diverse inflammatory processes that influence normal leukocyte biology and inflammatory signals (Figure 1).

Figure 1

Platelets and the inflammatory axis. Shown and discussed in the text are circulating platelet properties that influence the inflammatory axis. Long studied for roles in hemostasis and thrombosis, platelets interact with granulocytes, vessel walls, and pathogens, positioning them to modulate the inflammatory response via both anti-inflammatory and proinflammatory mechanisms. Future studies must consider the state of platelet activation and how this affects the inflammatory response. Antiplatelet therapies traditionally considered only for cardiovascular disease treatment also can be evaluated for their effects on inflammation.

Figure 1

Platelets and the inflammatory axis. Shown and discussed in the text are circulating platelet properties that influence the inflammatory axis. Long studied for roles in hemostasis and thrombosis, platelets interact with granulocytes, vessel walls, and pathogens, positioning them to modulate the inflammatory response via both anti-inflammatory and proinflammatory mechanisms. Future studies must consider the state of platelet activation and how this affects the inflammatory response. Antiplatelet therapies traditionally considered only for cardiovascular disease treatment also can be evaluated for their effects on inflammation.

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A number of key observations support the notion of the platelet as an immune cell. The platelet’s expression of Toll-like receptors (TLRs) indicates a capacity to directly engage microbial pathogens similar to leukocytes. Only a fraction of the platelet population is needed to maintain adequate hemostasis, suggesting that the excessive numbers allow platelets to act as major vascular surveyors of blood for recognizing foreign particles.9 

Emerging evidence indicates the relevance of platelets in development of cardiovascular disease. Chronic inflammation is a primary factor in events leading to atherosclerosis. It has been documented that platelets adhere to von Willebrand factor (VWF) bound to endothelial cells, and this interaction elicits tethering and rolling of leukocytes on the endothelial surface.10  Thus, platelets not only bring leukocytes to a site where inflammation potentially leads to atherosclerosis but also contain stores of proinflammatory mediators, such as thromboxanes and CD40 ligand.11,12  Proteins of the complement system have a reciprocal relationship with platelets: platelets activate the complement system, and proteins of the complement system activate platelets.13  In experimental models, hyperlipidemia induces platelet recruitment to the endothelial layer, and crucial molecular players are VWF, glycoprotein Ib-IX, and P-selectin,14,15  although the role of glycoprotein Ib-IX is not without some controversy.16  Here, we again find an emerging role for familiar players from the platelet paradigm of hemostasis and thrombosis.

When platelet TLRs detect microbial species, platelet activation is instigated, wherein the cell degranulates and releases a myriad of proinflammatory mediators.17,18  The release of granule content and surface shedding results in an estimated 300 proteins and biomolecules being released into the proximal vasculature.19  CD154, also known as CD40 ligand, is a potent secretory molecule that elicits lymphocyte activation, and it has been the feature of numerous studies implicating its relevance for potentiating the adaptive immune response.20  Platelets are the primary source of soluble CD154 released after agonist-driven platelet activation.21,22  Furthermore, platelets secrete antimicrobial proteins (thrombocidins), reactive oxygen species, and lytic enzymes in conjunction with other granule cargo to further augment clearance of the immune insult.6 

The ability of platelets to recognize and release a plethora of cytokines and chemokines in response to microbial invasion is merely one of the many facets of its arsenal to boost immunity. Platelets have exhibited an innate ability to engulf foreign particles such as human immunodeficiency virus bodies and Staphylococcus aureus cells into subcellular compartments.23,24  This internalization on activation localizes the microbes within the open canalicular system; although not entirely understood, this rudimentary ability does not appear to give rise to microbial degradation or any form of phagocytosis. Thus, the platelet acts as a storage cell for a plethora of bioactive molecules and lytic enzymes while maintaining a capacity to consume invaders, indicating that the platelet may in fact descend from an ancient granulocyte.25 

Alhough the platelet is capable of directly attacking microbial insults, it also aids primary immune cells in the clearance of pathogens. As described in the context of atherogenesis, platelets can adhere to an activated/inflamed endothelium due to the upregulation of endothelial adhesion molecules. Likewise, platelets also associate with leukocytes in the circulation and, by adhering to the endothelium, succeed in tethering white cells to the vascular wall.26  This function has a physiologic counterpart to atherosclerosis because increasing the ability of leukocytes to form an interface with the vasculature bolsters the ability of these cells to migrate within infected tissues.27  By enhancing the ability of leukocyte migration, platelets aid in the clearance of an infection by boosting the number of white cells recruited to the target site.

The interaction between platelets and Kupffer cells in the liver appears to contribute to clearance of both bacterial cells and platelets during infection.24,28,29  Interestingly, TLRs aren’t the only platelet receptors capable of interacting with microbes; surface membrane glycoproteins, such as integrin αIIbβ3, glycoprotein Ib-IX, and FcγRIIa, all have been implicated in forming an interface with bacterial cells.18,30-32  Bacterial adhesion via these platelet receptors leads to platelet activation and release of secondary mediators, including platelet factor 4, to create a positive feedback activation mechanism.33  Studies using glycoprotein Ib-IX–deficient mouse platelets have suggested that the platelet glycoprotein Ib–IX/VWF axis supports the platelet–Kupffer cell interaction.24 

The role of neutrophils in bacterial clearance has demonstrated these cells are capable of jettisoning nuclear content into the vasculature to ensnare migratory pathogens.34  The resultant web-like networks of chromatin, histones, and degradative enzymes known as neutrophil extracellular traps (NETs) capture circulating microbes and thus limit their ability to colonize alternate sites.35,36  Both in vitro and in vivo studies have illustrated that activated platelets adhering to neutrophils can initiate NET formation, or NETosis.37,38  Interestingly, experiments performed with the TLR4 agonist lipopolysaccharides (LPS), showed that, although capable of activating neutrophils, LPS alone is not potent enough to induce NET formation. However, when platelets are included, LPS administration is capable of eliciting NETosis, albeit this requires concentrations higher than those normally required to induce neutrophil activation.

Typically, formation of intravascular thrombi is regarded as a negative feature of platelet function; however, newer reports connect this feature to a physiologically relevant immune response. Microbial dissemination through the circulation increases the severity of infection. In the wake of microbial penetrance, a number of pathways initiate thrombogenesis in tandem with the inflammatory response.39  Controlled induction of thrombus formation within select vascular sites allows construction of a scaffolding network to ensnare microbial particles in a manner that parallels NETs. Although a thrombus is not traditionally considered a component of the immune response, evidence suggests that the clotting pathway activated in collaboration with inflammation is intended to serve a physiologic purpose. These “immunothrombi” are the result of several activating events converging on the players of hemostasis.

The very NETs that platelets help produce also have a reciprocal function. The negatively charged nucleobases of the NETs are capable of initiating the contact pathway of coagulation.40,41  The contact-dependent pathway raises circulating thrombin concentrations, which, in turn, increase platelet activation. Furthermore, NETs serve as a platform for the docking and activation of platelets.42  Direct engagement of microbes by platelets also contributes to platelet stimulation and thrombosis. An immunity-initiated thrombus not only serves as a dense network to trap migrating microbes but also acts as a foundation for tethering leukocytes, antimicrobial proteins, and lytic enzymes. By localizing the microbe with antimicrobial proponents, the immunothrombus serves as a focal point for microbial clearance.

Formation of additional platelet–leukocyte interfaces permits platelets to modulate the immune response. As previously mentioned, platelets can bolster the adaptive immune response by releasing CD154; moreover, they are capable of raising specific CD8+ T-cell clones by expressing antigen in the context of major histocompatibility complex I.43  Although more platelet endeavors within the immune cascade have yet to be uncovered, the current body of knowledge largely agrees with the notion of platelets as an extension of the immune system.

Platelet microparticles and inflammation

Platelet microparticles (membrane-bound fragments of platelet released on stimulation) have been linked to the chronic inflammation that produces rheumatoid arthritis.4,44  Specifically, in mouse models of rheumatoid arthritis, release of platelet microparticles elicits further inflammatory effector functions from synoviocytes to amplify synovitis in the disease. The microparticle release is mediated by platelet surface receptor glycoprotein VI, which complexes with the FcR-γ chain on the platelet surface. The best-characterized ligand of glycoprotein VI is collagen, and this binding presumably signals via immunoreceptor tyrosine-based activation motifs within the cytoplasmic tail of FcR-γ.45  The relevance of platelet microparticles in other inflammatory states has not yet been characterized.

Cancer is a disease by which multiple complex changes within the tumor cell of origin and within the microenvironment fuel a “perfect storm” for disease progression and dissemination. In 2000, Hanahan and Weinberg defined 6 hallmarks of cancer: (1) self-sufficiency in growth signals, (2) insensitivity to growth-inhibitory signals, (3) resisting cell death, (4) limitless replicative potential, (5) sustained angiogenesis, and (6) metastasis.46  In 2011, the list was updated with addition of other essential characteristics, such as cellular and microenvironment alterations necessary for malignant transformation, dysregulation of cell energetics, avoidance of immune destruction, genomic instability, and tumor-promoting inflammation.47  Indeed, many of these hallmarks resemble the inflamed state, placing the platelet within an interface that links thrombosis, inflammation, and cancer (Figure 2).48 

Figure 2

Platelets and the hallmarks of cancer. The original hallmarks of cancer included 6 biologic capabilities acquired during the complex development of tumors. Highlighted and discussed in the text are circulating platelet properties that contribute to some of the hallmarks. Thus, the platelet can be viewed as a normal cell contributing to the hallmark traits and influencing the TME. Antiplatelet therapies in the realm of cancer development and progression represent a future direction likely to impact patient prognosis and outcome.

Figure 2

Platelets and the hallmarks of cancer. The original hallmarks of cancer included 6 biologic capabilities acquired during the complex development of tumors. Highlighted and discussed in the text are circulating platelet properties that contribute to some of the hallmarks. Thus, the platelet can be viewed as a normal cell contributing to the hallmark traits and influencing the TME. Antiplatelet therapies in the realm of cancer development and progression represent a future direction likely to impact patient prognosis and outcome.

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More than 45 years ago, it was established that thrombocytopenic mice are protected against metastasis.49  Since then, extensive data have supported the relevance of platelets in the progression of cancer.48  An appreciation for the relationship between blood coagulation and cancer started in the 1860s, when French physician Armand Trousseau observed that increased incidence of venous thrombosis and/or blood hypercoagulability was associated with certain cancers (Trousseau’s syndrome).50  Later, Dr Trousseau observed a procoagulant state within his own blood that preceded his death from pancreatic cancer. In the 20th century, the molecular basis of Trousseau’s syndrome was established with a direct demonstration of tumor cell-induced platelet aggregation.51,52  Subsequent work corroborated these seminal findings in a number of experimental models, each implicating a wide range of platelet receptors.53-57  The pathophysiologic influence of circulating platelets on aspects of tumorigenesis is varied and substantial, suggesting platelet therapies typically reserved for cardiovascular disease may have profound implications in cancer.

Sustaining proliferative signals

Tumorigenesis is a multistep process requiring concerted changes in both tumor cells and the tumor microenvironment (TME). It has often been equated to a wound that doesn’t heal, with sustained tissue proliferation and remodeling and not balanced with reciprocal apoptosis. For initiation and progression of disease, tumor cells require constant growth signals or the ability to produce these growth signals themselves. Many tumor cells acquire activating mutations in growth-sustaining signaling cascades, but these signals also can be received from the TME. Janowska-Wieczorek et al58  showed that platelet-derived microparticles stimulate mitogen-activated protein kinases in lung carcinoma cell lines and increase cell proliferation. Further, incubating A549 lung carcinoma cells with the microparticles led to increased expression of matrix metalloproteinases (MMPs) and increased invasion through matrigel. Platelets and their releasates can activate the same pathways that are activated through oncogenic mutations.

Resisting cell death

Proliferation and apoptosis are carefully orchestrated during tissue remodeling and inflammation. Tissues and cells are endowed with intrinsic regulatory programs to control aberrant proliferation, inducing programs of cell death. These intrinsic programs prevent unregulated cell growth and allow proper healing. Tumor cells must develop or find mechanisms to circumvent these intrinsic programs to sustain their proliferative capacity, and they must coordinate extrinsic programs to safeguard their survival. Recent studies demonstrated that stromal cells can extrinsically assist neoplastic cells to evade apoptosis.59  Platelets induce MMP-9 expression and activation in colon and breast cancer cell lines, leading to increased remodeling of extracellular matrix, release of growth factors from the extracellular matrix, and relief of cell-cell contacts, all of which decrease apoptotic signals.59  Platelets and platelet lysates reduce apoptosis of leukemia cell lines and primary leukemic blasts induced by mitochondria-damaging agents.60  Contents of platelet microparticles inhibited intrinsic apoptosis through mitochondrial uncoupling, independent of autophagy.60  These are some of the first studies to extend the antiapoptotic role of platelets beyond solid tumors. The results highlight the need for future studies to investigate the platelet’s roles in both hematopoietic and solid tumor malignancies and in disrupting cellular energetics and metabolism related to apoptosis.

Resistance to chemotherapy and to molecularly targeted therapies is a major obstacle to the successful treatment and management of cancer. Tumor cells develop resistance-promoting responses, including altered expression of integrins, activation of oncogenic signaling by soluble factors such as cytokines and growth factors, and resistance to apoptotic signals. The growth factor-rich microenvironment created by platelet degranulation and activation supports proliferation and is antiapoptotic, with thrombocytosis increasing chemoresistance and thrombocytopenia improving chemotherapy efficacy in murine models. In a murine model of breast cancer, induction of thrombocytopenia by platelet-depleting antibodies increased the efficacy of paclitaxel therapy.61  This effect was mediated by increased delivery of the chemotherapeutic drug to the tumor site, likely through increased tumor vascular permeability and increased tumor-specific hemorrhaging, which was not observed in other organs.

In a cohort of patients with ovarian cancer that was enriched for those with recurrent disease, elevated platelet counts correlated with decreased overall survival and resistance to chemotherapy.62,63  The study further demonstrated that platelet transfusion resulted in significantly greater tumor weight in nude mice harboring A2780 tumors than in untreated mice; this effect was completely reversed by pretreating the platelets with aspirin before transfusion.63  Further, treating tumor-bearing mice with platelet-depleting antibodies alone decreased tumor weight, similar to the effects of treatment with docetaxel alone. Treatment with both platelet-depleting antibodies and docetaxel further reduced tumor weight.63  Infusion with platelets during docetaxel therapy suppressed the efficacy of chemotherapy with no reduction in tumor weight. In vivo reduction of platelet counts reduced tumor growth to a similar extent as chemotherapy, and platelet reinfusion significantly reduced the efficacy of chemotherapy. These studies raise important clinical questions about the necessity for platelet replacement in thrombocytopenic cancer patients, indicating the possibility that platelet infusion may “feed” the tumor and decrease chemotherapeutic efficacy. Future studies are needed to define the roles of platelets in tumor growth and to assess the potential adjuvant roles of platelets during therapeutic intervention.

Inducing angiogenesis

Tumor cells proliferate at alarming rates, necessitating neovascularization to support adequate blood supply for supplying necessary nutrients, removing waste, and oxygenating the tumor. Historically, tumor vascularization was thought to be primarily regulated by tumor-derived proangiogenic factors; however, it is now clear that the TME and stromal cells significantly contribute to the neovascularization that occurs during tumor progression and that this vascular network provides a highway for disseminating tumors to distant sites. Platelets have the ability to deliver multiple proangiogenic factors to the tumor, as well as the ability to stimulate expression of proangiogenic factors by the tumor cell.58  Platelets have long been identified as a major source of vascular endothelial growth factor (VEGF),64,65  platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF), each promoting tumor growth.66,67  Activation of platelets and release of platelet microparticles leads to the release of a variety of proangiogenic factors, including VEGF, PDGF, FGF, and MMPs. Relevant to this release is the reported increase in the stored platelet content of VEGF, platelet factor 4, and PDGF of patients with colorectal cancer.68  Increased levels of platelet microparticles are found in the plasma of patients with both solid tumors and hematologic malignancies.69  In those with gastric cancer, the highest circulating levels of platelet microparticles were found in individuals with stage IV disease and were significantly correlated with metastatic disease.70  In vitro and in vivo studies demonstrated that platelet microparticles can promote proliferation and survival of endothelial cells, as well as vascularization in both healthy and diseased states.71,72 

Activating invasion and metastasis and evading immune detection

Metastasis remains the biggest challenge to improving cancer prognoses and is the leading cause of cancer-associated mortality. Stromal cells provide the tumor cell with an ability to evade the immune system, recognize a premetastatic niche, and grow at a distant site; each highlights potential interplay among circulating tumor cells and all cells of the vasculature, including platelets. Data have suggested that a mechanism linking the platelet to metastasis is a platelet “cloak” that surrounds the tumor cell and protects it from immune surveillance.73  The ability of platelets to protect tumor cells in circulation from the normal immune response, or natural killer cells, is likely to significantly contribute to the metastatic process.73,74  Further, this platelet cloak protects tumor cells in circulation from extreme shear forces encountered in the vascular, preventing mechanical damage to the cells. The numerous receptors on the surfaces of platelets may help “dock” the cloaked tumor cells to the vascular endothelium and facilitate extravasation at a distant site. Releasates and direct interactions between platelets and tumor cells can contribute to sustaining growth and enhancing the ability of the tumor cells to migrate and colonize distant sites. Tumor cells can be primed by platelets while in circulation, or even in vitro, to induce a mesenchymal invasive phenotype and promote metastatic seeding in the lungs, mediated by transforming growth factor β signaling.59 

Platelets also play a role in osteolytic bone metastasis in breast cancer. Boucharaba et al75  reported that platelet-derived lysophosphatidic acid (LPA) can support and stimulate metastatic breast cancer cells. MDA-BO2 breast cancer cells facilitate platelet aggregation and release of LPA, which has a potent mitogenic effect upon MDA-BO2 cells. Further, LPA stimulates the release of interleukin-6 and interleukin-8 from MDA-BO2 cells, which is hypothesized to stimulate osteoclasts in the bone marrow, leading to bone destruction and further supporting metastatic growth. Additional work is needed to determine whether platelet release of LPA stimulates metastasis in other cancer models and to identify the role of LPA in stimulating tumor cell cytokine release to enhance metastatic potential at distant metastatic sites. These findings highlight the multifactorial signaling networks that platelets are able to stimulate in the primary TME and at distant sites.

Supporting cancer stem cells

Although not a hallmark of cancer, support of accessory cells, particularly cancer stem cells, is crucial to the support of tumorigenesis and colonization at distant sites. It has become well established that tumors are comprised of a heterogeneous mix of cells, including a subpopulation of cells with self-renewing capacity. Stromal cells, including platelets, are important in supporting this subpopulation within the tumor. Labelle et al59  found that platelets cocultured with Ep5 breast carcinoma cells for 24 hours induced a cancer stem cell gene signature in the Ep5 cells. They further demonstrated that platelets promoted both the transforming growth factor β and nuclear factor κB pathways, inducing an epithelial-to-mesenchymal transition in breast and colon carcinoma cell lines, promoting a metastatic phenotype. High platelet count is associated with increased mortality in a variety of cancers, including malignant mesothelioma; gynecological malignancies; and lung, renal, gastric, colorectal, and breast cancers.62,76-83  We should seek to discern the roles played by platelets in stimulating different cellular compartments within the tumor, which has the potential to expand therapeutic use of cardiovascular inhibitors in oncology.

Cancer prevention and aspirin

In the last 2 years, interest has been renewed in cancer prevention mediated by daily use of aspirin, a controversial topic spanning several decades.84  Extensive use of aspirin for its cardiovascular benefits and inhibition of platelet function has resulted in significant datasets that now can be used to examine other benefits of aspirin. Although the antimetastatic properties of aspirin were first described in the 1970s based on animal models of experimental metastasis,85  other studies reported no such effect.86  However, a recent retrospective analysis from large patient datasets supports the anticancer effect of aspirin.87-90  Thus, the topic has once again gained interest, and major questions surround the molecular basis of the benefit and the role played by of the platelet.91 

Aspirin directly inhibits cellular cyclooxygenase enzymes COX-1 and COX-2 and the production of prostaglandins. However, expression of COX-1 and/or COX-2 varies widely among cells. For example, endothelial cells and tumor cells express COX-2, but platelets express COX-1,92  which is the major contributor to aspirin’s side effect of bleeding. A significant gap in our understanding of aspirin’s anticancer effect lies in defining how much of the effect is dependent on platelets and how much is due to cyclooxygenase inhibition in other cell types. Virtually every step in the breast cancer metastatic process can be linked to normal platelet function.48  Determining the mechanism of action of aspirin in breast cancer and identifying the specific cells targeted by aspirin will allow development of therapeutic protocols that could mitigate the risks associated with prolonged aspirin therapy. The degree of aspirin’s protective action that depends on COX-1 vs COX-2 is unknown and was presented as one of the National Cancer Institute’s Provocative Questions for 2013.

Despite preclinical data and some positive clinical trials, the therapeutic strategy of antiplatelet drugs has not received significant attention from the cancer biology community. This may be due to the fact that antiplatelet drugs are not cytotoxic and therefore are ignored by the oncology community or to the mixed results of clinical trials that lead to the abandonment of these therapeutic strategies. However, this might also reflect a lack of communication and collaboration between the platelet and cancer biology fields. For too long, cancer biology has been tumor centric; however, with increased emphasis on the TME and the role of stromal cells in tumor initiation, progression, and metastasis, cancer biologists are reevaluating the roles of nontumor cells in carcinogenesis, including the roles of platelets. The widespread use of antiplatelet therapies emphasizes the importance for understanding mechanistic insights into the progression of cancer.

Inflammation is a process initiated by the host in response to injury. A multifactorial network of chemicals and cells is recruited to the site of injury to heal the tissue. Similarly, during tumorigenesis, many of these same processes are hijacked to promote cancer initiation and progression. In the ideal scenario, these mechanisms will act rapidly, and a normal state of homeostasis within the microenvironment will be attained. We attempted to present literature to highlight how these processes are used physiologically during the inflammatory process and when these same processes can become pathologic and support transformation and cancer progression. It is clear that additional studies are needed to bridge the fields of thrombosis and cancer and to elucidate mechanisms by which the platelet can promote and sustain tumorigenesis. Historically, thrombosis was viewed as an unfortunate consequence of malignancy, but emerging evidence strongly supports the fact that the platelet actively supports multiple stages of the tumorigenic process.

Although the platelet remains a long-term therapeutic target for preventing cardiovascular disease, how such treatment impacts other disease processes is relevant also to understanding molecular pathogenesis and to guiding patient treatment. Retrospective analyses of large populations taking daily aspirin have revealed an aspirin-dependent preventive effect for some cancers. Thus, new questions are emerging about the platelet-dependent mechanisms in cancer, which may also be relevant to chronic inflammation. Understanding the relevance and overlap of platelet function in each of these disease processes is likely to be informative on the risks and benefits of antiplatelet therapies and also should provide the practicing clinician with knowledge to facilitate active dialogue with patients on the risks and benefits of individual therapies.

Being associated with inflammatory events and cancer progression places the platelet within a myriad of complex pathophysiologic events.93  However, the well-defined paradigm of the platelet’s roles in hemostasis and thrombosis is likely to provide key insights into platelet responses in these intricately related disease processes. The goal would be to use the plethora of animal models and antiplatelet agents already available to further define platelet-mediated overlap among diseases not strictly associated with hemostasis and thrombosis. Future challenges will be to translate mechanistic findings from animal models to the course of human disease.

Caution will be needed as we move forward because some have recently reported marked differences between the mouse and human inflammatory responses.94  However, that study remains controversial, with others concluding that mouse models are representative of human inflammatory diseases.95  Indeed, many paradigms have translated well between species. In the case of platelets, the majority of thrombotic mechanisms are similar in mice and humans.96  Armed with decades of important platelet-dependent insights, the future is bright for broadening an appreciation of the platelet’s influence on many hematologic disorders.

The editorial assistance of Peggy Brenner, ELS, is acknowledged.

This work was supported by National Institutes of Health, Heart, Lung and Blood Institute grants HL50545 and AR61991 (to J.W.) and an American Heart Association predoctoral fellowship (to A.C.).

Contribution: A.C. and J.W. wrote and edited the inflammation portion; and A.T.F. and J.W. wrote and edited the cancer portion.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Jerry Ware, Slot 505, 4301 West Markham St, Little Rock, AR 72205; e-mail: [email protected].

1
Balkwill
 
F
Mantovani
 
A
Inflammation and cancer: back to Virchow?
Lancet
2001
, vol. 
357
 
9255
(pg. 
539
-
545
)
2
Levin
 
J
Michelson
 
AD
The evolution of mammalian platelets.
Platelets
2013
New York
Elsevier
(pg. 
3
-
25
)
3
Morrell
 
CN
Aggrey
 
AA
Chapman
 
LM
Modjeski
 
KL
Emerging roles for platelets as immune and inflammatory cells.
Blood
2014
, vol. 
123
 
18
(pg. 
2759
-
2767
)
4
Weyrich
 
AS
Zimmerman
 
GA
Platelets: signaling cells in the immune continuum.
Trends Immunol
2004
, vol. 
25
 
9
(pg. 
489
-
495
)
5
von Hundelshausen
 
P
Weber
 
C
Platelets as immune cells: bridging inflammation and cardiovascular disease.
Circ Res
2007
, vol. 
100
 
1
(pg. 
27
-
40
)
6
Semple
 
JW
Italiano
 
JE
Freedman
 
J
Platelets and the immune continuum.
Nat Rev Immunol
2011
, vol. 
11
 
4
(pg. 
264
-
274
)
7
Huang
 
HS
Chang
 
HH
Platelets in inflammation and immune modulations: functions beyond hemostasis.
Arch Immunol Ther Exp (Warsz)
2012
, vol. 
60
 
6
(pg. 
443
-
451
)
8
Jenne
 
CN
Urrutia
 
R
Kubes
 
P
Platelets: bridging hemostasis, inflammation, and immunity.
Int J Lab Hematol
2013
, vol. 
35
 
3
(pg. 
254
-
261
)
9
Clemetson
 
KJ
Platelets and pathogens.
Cell Mol Life Sci
2010
, vol. 
67
 
4
(pg. 
495
-
498
)
10
Bernardo
 
A
Ball
 
C
Nolasco
 
L
Choi
 
H
Moake
 
JL
Dong
 
JF
Platelets adhered to endothelial cell-bound ultra-large von Willebrand factor strings support leukocyte tethering and rolling under high shear stress.
J Thromb Haemost
2005
, vol. 
3
 
3
(pg. 
562
-
570
)
11
Phipps
 
RP
Atherosclerosis: the emerging role of inflammation and the CD40-CD40 ligand system.
Proc Natl Acad Sci USA
2000
, vol. 
97
 
13
(pg. 
6930
-
6932
)
12
Nijm
 
J
Wikby
 
A
Tompa
 
A
Olsson
 
AG
Jonasson
 
L
Circulating levels of proinflammatory cytokines and neutrophil-platelet aggregates in patients with coronary artery disease.
Am J Cardiol
2005
, vol. 
95
 
4
(pg. 
452
-
456
)
13
Del Conde
 
I
Crúz
 
MA
Zhang
 
H
López
 
JA
Afshar-Kharghan
 
V
Platelet activation leads to activation and propagation of the complement system.
J Exp Med
2005
, vol. 
201
 
6
(pg. 
871
-
879
)
14
Theilmeier
 
G
Michiels
 
C
Spaepen
 
E
, et al. 
Endothelial von Willebrand factor recruits platelets to atherosclerosis-prone sites in response to hypercholesterolemia.
Blood
2002
, vol. 
99
 
12
(pg. 
4486
-
4493
)
15
Koltsova
 
EK
Sundd
 
P
Zarpellon
 
A
, et al. 
Genetic deletion of platelet glycoprotein Ib alpha but not its extracellular domain protects from atherosclerosis.
Thromb Haemost
2014
, vol. 
112
 
6
(pg. 
1252
-
1263
)
16
Strassel
 
C
Hechler
 
B
Bull
 
A
Gachet
 
C
Lanza
 
F
Studies of mice lacking the GPIb-V-IX complex question the role of this receptor in atherosclerosis.
J Thromb Haemost
2009
, vol. 
7
 
11
(pg. 
1935
-
1938
)
17
Stark
 
RJ
Aghakasiri
 
N
Rumbaut
 
RE
Platelet-derived Toll-like receptor 4 (Tlr-4) is sufficient to promote microvascular thrombosis in endotoxemia.
PLoS One
2012
, vol. 
7
 
7
pg. 
e41254
 
18
Kerrigan
 
SW
Cox
 
D
Platelet-bacterial interactions.
Cell Mol Life Sci
2010
, vol. 
67
 
4
(pg. 
513
-
523
)
19
Cox
 
D
Kerrigan
 
SW
Watson
 
SP
Platelets and the innate immune system: mechanisms of bacterial-induced platelet activation.
J Thromb Haemost
2011
, vol. 
9
 
6
(pg. 
1097
-
1107
)
20
Elgueta
 
R
Benson
 
MJ
de Vries
 
VC
Wasiuk
 
A
Guo
 
Y
Noelle
 
RJ
Molecular mechanism and function of CD40/CD40L engagement in the immune system.
Immunol Rev
2009
, vol. 
229
 
1
(pg. 
152
-
172
)
21
Danese
 
S
Katz
 
JA
Saibeni
 
S
, et al. 
Activated platelets are the source of elevated levels of soluble CD40 ligand in the circulation of inflammatory bowel disease patients.
Gut
2003
, vol. 
52
 
10
(pg. 
1435
-
1441
)
22
Yacoub
 
D
Hachem
 
A
Théorêt
 
JF
Gillis
 
MA
Mourad
 
W
Merhi
 
Y
Enhanced levels of soluble CD40 ligand exacerbate platelet aggregation and thrombus formation through a CD40-dependent tumor necrosis factor receptor-associated factor-2/Rac1/p38 mitogen-activated protein kinase signaling pathway.
Arterioscler Thromb Vasc Biol
2010
, vol. 
30
 
12
(pg. 
2424
-
2433
)
23
Youssefian
 
T
Drouin
 
A
Massé
 
JM
Guichard
 
J
Cramer
 
EM
Host defense role of platelets: engulfment of HIV and Staphylococcus aureus occurs in a specific subcellular compartment and is enhanced by platelet activation.
Blood
2002
, vol. 
99
 
11
(pg. 
4021
-
4029
)
24
Wong
 
CH
Jenne
 
CN
Petri
 
B
Chrobok
 
NL
Kubes
 
P
Nucleation of platelets with blood-borne pathogens on Kupffer cells precedes other innate immunity and contributes to bacterial clearance.
Nat Immunol
2013
, vol. 
14
 
8
(pg. 
785
-
792
)
25
Yeaman
 
MR
Platelets in defense against bacterial pathogens.
Cell Mol Life Sci
2010
, vol. 
67
 
4
(pg. 
525
-
544
)
26
Devi
 
S
Kuligowski
 
MP
Kwan
 
RY
, et al. 
Platelet recruitment to the inflamed glomerulus occurs via an alphaIIbbeta3/GPVI-dependent pathway.
Am J Pathol
2010
, vol. 
177
 
3
(pg. 
1131
-
1142
)
27
Kuckleburg
 
CJ
Yates
 
CM
Kalia
 
N
, et al. 
Endothelial cell-borne platelet bridges selectively recruit monocytes in human and mouse models of vascular inflammation.
Cardiovasc Res
2011
, vol. 
91
 
1
(pg. 
134
-
141
)
28
Grewal
 
PK
Uchiyama
 
S
Ditto
 
D
, et al. 
The Ashwell receptor mitigates the lethal coagulopathy of sepsis.
Nat Med
2008
, vol. 
14
 
6
(pg. 
648
-
655
)
29
Grozovsky
 
R
Hoffmeister
 
KM
Falet
 
H
Novel clearance mechanisms of platelets.
Curr Opin Hematol
2010
, vol. 
17
 
6
(pg. 
585
-
589
)
30
Byrne
 
MF
Kerrigan
 
SW
Corcoran
 
PA
, et al. 
Helicobacter pylori binds von Willebrand factor and interacts with GPIb to induce platelet aggregation.
Gastroenterology
2003
, vol. 
124
 
7
(pg. 
1846
-
1854
)
31
Brennan
 
MP
Loughman
 
A
Devocelle
 
M
, et al. 
Elucidating the role of Staphylococcus epidermidis serine-aspartate repeat protein G in platelet activation.
J Thromb Haemost
2009
, vol. 
7
 
8
(pg. 
1364
-
1372
)
32
Tilley
 
DO
Arman
 
M
Smolenski
 
A
, et al. 
Glycoprotein Ibα and FcγRIIa play key roles in platelet activation by the colonizing bacterium, Streptococcus oralis.
J Thromb Haemost
2013
, vol. 
11
 
5
(pg. 
941
-
950
)
33
Arman
 
M
Krauel
 
K
Tilley
 
DO
, et al. 
Amplification of bacteria-induced platelet activation is triggered by FcγRIIA, integrin αIIbβ3, and platelet factor 4.
Blood
2014
, vol. 
123
 
20
(pg. 
3166
-
3174
)
34
Zawrotniak
 
M
Rapala-Kozik
 
M
Neutrophil extracellular traps (NETs) - formation and implications.
Acta Biochim Pol
2013
, vol. 
60
 
3
(pg. 
277
-
284
)
35
Brinkmann
 
V
Reichard
 
U
Goosmann
 
C
, et al. 
Neutrophil extracellular traps kill bacteria.
Science
2004
, vol. 
303
 
5663
(pg. 
1532
-
1535
)
36
McDonald
 
B
Urrutia
 
R
Yipp
 
BG
Jenne
 
CN
Kubes
 
P
Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis.
Cell Host Microbe
2012
, vol. 
12
 
3
(pg. 
324
-
333
)
37
Ma
 
AC
Kubes
 
P
Platelets, neutrophils, and neutrophil extracellular traps (NETs) in sepsis.
J Thromb Haemost
2008
, vol. 
6
 
3
(pg. 
415
-
420
)
38
Caudrillier
 
A
Kessenbrock
 
K
Gilliss
 
BM
, et al. 
Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury.
J Clin Invest
2012
, vol. 
122
 
7
(pg. 
2661
-
2671
)
39
O’Brien
 
M
The reciprocal relationship between inflammation and coagulation.
Top Companion Anim Med
2012
, vol. 
27
 
2
(pg. 
46
-
52
)
40
von Brühl
 
ML
Stark
 
K
Steinhart
 
A
, et al. 
Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo.
J Exp Med
2012
, vol. 
209
 
4
(pg. 
819
-
835
)
41
Massberg
 
S
Grahl
 
L
von Bruehl
 
ML
, et al. 
Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases.
Nat Med
2010
, vol. 
16
 
8
(pg. 
887
-
896
)
42
Fuchs
 
TA
Brill
 
A
Duerschmied
 
D
, et al. 
Extracellular DNA traps promote thrombosis.
Proc Natl Acad Sci USA
2010
, vol. 
107
 
36
(pg. 
15880
-
15885
)
43
Chapman
 
LM
Aggrey
 
AA
Field
 
DJ
, et al. 
Platelets present antigen in the context of MHC class I.
J Immunol
2012
, vol. 
189
 
2
(pg. 
916
-
923
)
44
Boilard
 
E
Nigrovic
 
PA
Larabee
 
K
, et al. 
Platelets amplify inflammation in arthritis via collagen-dependent microparticle production.
Science
2010
, vol. 
327
 
5965
(pg. 
580
-
583
)
45
Watson
 
SP
Herbert
 
JM
Pollitt
 
AY
GPVI and CLEC-2 in hemostasis and vascular integrity.
J Thromb Haemost
2010
, vol. 
8
 
7
(pg. 
1456
-
1467
)
46
Hanahan
 
D
Weinberg
 
RA
The hallmarks of cancer.
Cell
2000
, vol. 
100
 
1
(pg. 
57
-
70
)
47
Hanahan
 
D
Weinberg
 
RA
Hallmarks of cancer: the next generation.
Cell
2011
, vol. 
144
 
5
(pg. 
646
-
674
)
48
Gay
 
LJ
Felding-Habermann
 
B
Contribution of platelets to tumour metastasis.
Nat Rev Cancer
2011
, vol. 
11
 
2
(pg. 
123
-
134
)
49
Gasic
 
GJ
Gasic
 
TB
Stewart
 
CC
Antimetastatic effects associated with platelet reduction.
Proc Natl Acad Sci USA
1968
, vol. 
61
 
1
(pg. 
46
-
52
)
50
Varki
 
A
Trousseau’s syndrome: multiple definitions and multiple mechanisms.
Blood
2007
, vol. 
110
 
6
(pg. 
1723
-
1729
)
51
Gasic
 
GJ
Gasic
 
TB
Galanti
 
N
Johnson
 
T
Murphy
 
S
Platelet-tumor-cell interactions in mice. The role of platelets in the spread of malignant disease.
Int J Cancer
1973
, vol. 
11
 
3
(pg. 
704
-
718
)
52
Karpatkin
 
S
Pearlstein
 
E
Ambrogio
 
C
Coller
 
BS
Role of adhesive proteins in platelet tumor interaction in vitro and metastasis formation in vivo.
J Clin Invest
1988
, vol. 
81
 
4
(pg. 
1012
-
1019
)
53
Kim
 
YJ
Borsig
 
L
Varki
 
NM
Varki
 
A
P-selectin deficiency attenuates tumor growth and metastasis.
Proc Natl Acad Sci USA
1998
, vol. 
95
 
16
(pg. 
9325
-
9330
)
54
Bakewell
 
SJ
Nestor
 
P
Prasad
 
S
, et al. 
Platelet and osteoclast β3 integrins are critical for bone metastasis.
Proc Natl Acad Sci USA
2003
, vol. 
100
 
24
(pg. 
14205
-
14210
)
55
Palumbo
 
JS
Degen
 
JL
Mechanisms linking tumor cell-associated procoagulant function to tumor metastasis.
Thromb Res
2007
, vol. 
120
 
Suppl 2
(pg. 
S22
-
S28
)
56
Labelle
 
M
Hynes
 
RO
The initial hours of metastasis: the importance of cooperative host-tumor cell interactions during hematogenous dissemination.
Cancer Discov
2012
, vol. 
2
 
12
(pg. 
1091
-
1099
)
57
Jain
 
S
Harris
 
J
Ware
 
J
Platelets: linking hemostasis and cancer.
Arterioscler Thromb Vasc Biol
2010
, vol. 
30
 
12
(pg. 
2362
-
2367
)
58
Janowska-Wieczorek
 
A
Wysoczynski
 
M
Kijowski
 
J
, et al. 
Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer.
Int J Cancer
2005
, vol. 
113
 
5
(pg. 
752
-
760
)
59
Labelle
 
M
Begum
 
S
Hynes
 
RO
Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis.
Cancer Cell
2011
, vol. 
20
 
5
(pg. 
576
-
590
)
60
Velez
 
J
Enciso
 
LJ
Suarez
 
M
, et al. 
Platelets promote mitochondrial uncoupling and resistance to apoptosis in leukemia cells: a novel paradigm for the bone marrow microenvironment.
Cancer Microenviron
2014
, vol. 
7
 
1-2
(pg. 
79
-
90
)
61
Demers
 
M
Ho-Tin-Noé
 
B
Schatzberg
 
D
Yang
 
JJ
Wagner
 
DD
Increased efficacy of breast cancer chemotherapy in thrombocytopenic mice.
Cancer Res
2011
, vol. 
71
 
5
(pg. 
1540
-
1549
)
62
Stone
 
RL
Nick
 
AM
McNeish
 
IA
, et al. 
Paraneoplastic thrombocytosis in ovarian cancer.
N Engl J Med
2012
, vol. 
366
 
7
(pg. 
610
-
618
)
63
Bottsford-Miller
 
J
Choi
 
HJ
Dalton
 
HJ
, et al. 
Differential platelet levels affect response to taxane-based therapy in ovarian cancer.
Clin Cancer Res
2015
, vol. 
21
 
3
(pg. 
602
-
610
)
64
Verheul
 
HM
Hoekman
 
K
Luykx-de Bakker
 
S
, et al. 
Platelet: transporter of vascular endothelial growth factor.
Clin Cancer Res
1997
, vol. 
3
 
12 Pt 1
(pg. 
2187
-
2190
)
65
Pinedo
 
HM
Verheul
 
HM
D’Amato
 
RJ
Folkman
 
J
Involvement of platelets in tumour angiogenesis?
Lancet
1998
, vol. 
352
 
9142
(pg. 
1775
-
1777
)
66
Cross
 
MJ
Claesson-Welsh
 
L
FGF and VEGF function in angiogenesis: signalling pathways, biological responses and therapeutic inhibition.
Trends Pharmacol Sci
2001
, vol. 
22
 
4
(pg. 
201
-
207
)
67
Ferrara
 
N
Gerber
 
HP
LeCouter
 
J
The biology of VEGF and its receptors.
Nat Med
2003
, vol. 
9
 
6
(pg. 
669
-
676
)
68
Peterson
 
JE
Zurakowski
 
D
Italiano
 
JE
, et al. 
VEGF, PF4 and PDGF are elevated in platelets of colorectal cancer patients.
Angiogenesis
2012
, vol. 
15
 
2
(pg. 
265
-
273
)
69
Mezouar
 
S
Mege
 
D
Darbousset
 
R
, et al. 
Involvement of platelet-derived microparticles in tumor progression and thrombosis.
Semin Oncol
2014
, vol. 
41
 
3
(pg. 
346
-
358
)
70
Kim
 
HK
Song
 
KS
Park
 
YS
, et al. 
Elevated levels of circulating platelet microparticles, VEGF, IL-6 and RANTES in patients with gastric cancer: possible role of a metastasis predictor.
Eur J Cancer
2003
, vol. 
39
 
2
(pg. 
184
-
191
)
71
Kim
 
HK
Song
 
KS
Chung
 
JH
Lee
 
KR
Lee
 
SN
Platelet microparticles induce angiogenesis in vitro.
Br J Haematol
2004
, vol. 
124
 
3
(pg. 
376
-
384
)
72
Varon
 
D
Shai
 
E
Role of platelet-derived microparticles in angiogenesis and tumor progression.
Discov Med
2009
, vol. 
8
 
43
(pg. 
237
-
241
)
73
Palumbo
 
JS
Talmage
 
KE
Massari
 
JV
, et al. 
Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells.
Blood
2005
, vol. 
105
 
1
(pg. 
178
-
185
)
74
Nieswandt
 
B
Hafner
 
M
Echtenacher
 
B
Männel
 
DN
Lysis of tumor cells by natural killer cells in mice is impeded by platelets.
Cancer Res
1999
, vol. 
59
 
6
(pg. 
1295
-
1300
)
75
Boucharaba
 
A
Serre
 
CM
Grès
 
S
, et al. 
Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer.
J Clin Invest
2004
, vol. 
114
 
12
(pg. 
1714
-
1725
)
76
Costantini
 
V
Zacharski
 
LR
Moritz
 
TE
Edwards
 
RL
The platelet count in carcinoma of the lung and colon.
Thromb Haemost
1990
, vol. 
64
 
4
(pg. 
501
-
505
)
77
Ikeda
 
M
Furukawa
 
H
Imamura
 
H
, et al. 
Poor prognosis associated with thrombocytosis in patients with gastric cancer.
Ann Surg Oncol
2002
, vol. 
9
 
3
(pg. 
287
-
291
)
78
Kerpsack
 
JT
Finan
 
MA
Thrombocytosis as a predictor of malignancy in women with a pelvic mass.
J Reprod Med
2000
, vol. 
45
 
11
(pg. 
929
-
932
)
79
Menczer
 
J
Schejter
 
E
Geva
 
D
Ginath
 
S
Zakut
 
H
Ovarian carcinoma associated thrombocytosis. Correlation with prognostic factors and with survival.
Eur J Gynaecol Oncol
1998
, vol. 
19
 
1
(pg. 
82
-
84
)
80
O’Keefe
 
SC
Marshall
 
FF
Issa
 
MM
Harmon
 
MP
Petros
 
JA
Thrombocytosis is associated with a significant increase in the cancer specific death rate after radical nephrectomy.
J Urol
2002
, vol. 
168
 
4 Pt 1
(pg. 
1378
-
1380
)
81
Pedersen
 
LM
Milman
 
N
Prognostic significance of thrombocytosis in patients with primary lung cancer.
Eur Respir J
1996
, vol. 
9
 
9
(pg. 
1826
-
1830
)
82
Taucher
 
S
Salat
 
A
Gnant
 
M
, et al. 
Austrian Breast and Colorectal Cancer Study Group
Impact of pretreatment thrombocytosis on survival in primary breast cancer.
Thromb Haemost
2003
, vol. 
89
 
6
(pg. 
1098
-
1106
)
83
Zeimet
 
AG
Marth
 
C
Müller-Holzner
 
E
Daxenbichler
 
G
Dapunt
 
O
Significance of thrombocytosis in patients with epithelial ovarian cancer.
Am J Obstet Gynecol
1994
, vol. 
170
 
2
(pg. 
549
-
554
)
84
Kaiser
 
J
Will an aspirin a day keep cancer away?
Science
2012
, vol. 
337
 
6101
(pg. 
1471
-
1473
)
85
Kolenich
 
JJ
Mansour
 
EG
Flynn
 
A
Haematological effects of aspirin.
Lancet
1972
, vol. 
2
 
7779
pg. 
714
 
86
Wood
 
S
Hilgard
 
P
Aspirin and tumour metastasis.
Lancet
1972
, vol. 
2
 
7792
(pg. 
1416
-
1417
)
87
Rothwell
 
PM
Fowkes
 
FG
Belch
 
JF
Ogawa
 
H
Warlow
 
CP
Meade
 
TW
Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials.
Lancet
2011
, vol. 
377
 
9759
(pg. 
31
-
41
)
88
Rothwell
 
PM
Wilson
 
M
Price
 
JF
Belch
 
JF
Meade
 
TW
Mehta
 
Z
Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials.
Lancet
2012
, vol. 
379
 
9826
(pg. 
1591
-
1601
)
89
Rothwell
 
PM
Price
 
JF
Fowkes
 
FG
, et al. 
Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials.
Lancet
2012
, vol. 
379
 
9826
(pg. 
1602
-
1612
)
90
Bowers
 
LW
Maximo
 
IX
Brenner
 
AJ
, et al. 
NSAID use reduces breast cancer recurrence in overweight and obese women: role of prostaglandin-aromatase interactions.
Cancer Res
2014
, vol. 
74
 
16
(pg. 
4446
-
4457
)
91
Kaiser
 
J
Wondering how the wonder drug works.
Science
2012
, vol. 
337
 
6101
pg. 
1472
 
92
Catella-Lawson
 
F
Reilly
 
MP
Kapoor
 
SC
, et al. 
Cyclooxygenase inhibitors and the antiplatelet effects of aspirin.
N Engl J Med
2001
, vol. 
345
 
25
(pg. 
1809
-
1817
)
93
Mueller
 
K
Inflammation. Inflammation’s yin-yang. Introduction.
Science
2013
, vol. 
339
 
6116
pg. 
155
 
94
Seok
 
J
Warren
 
HS
Cuenca
 
AG
, et al. 
Inflammation and Host Response to Injury, Large Scale Collaborative Research Program
Genomic responses in mouse models poorly mimic human inflammatory diseases.
Proc Natl Acad Sci USA
2013
, vol. 
110
 
9
(pg. 
3507
-
3512
)
95
Takao
 
K
Miyakawa
 
T
Genomic responses in mouse models greatly mimic human inflammatory diseases.
Proc Natl Acad Sci USA
2015
, vol. 
112
 
4
(pg. 
1167
-
1172
)
96
Ware
 
J
Dysfunctional platelet membrane receptors: from humans to mice.
Thromb Haemost
2004
, vol. 
92
 
3
(pg. 
478
-
485
)
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