Undercover Agents: Targeting Tumours with Modified Platelets

doi:10.1016/j.trecan.2017.01.006

Trends in Cancer

Volume 3, Issue 3, March 2017, Pages 235-246

https://doi.org/10.1016/j.trecan.2017.01.006 Get rights and content

Trends

Platelets and tumour cells closely interact throughout metastasis to promote disease progression.

Exposure to tumour cells can increase platelet production and stimulate platelet hyper-reactivity.

In the presence of malignancy, the RNA profile and ultrastructure of platelets change.

Novel technologies utilising platelets for potential cancer therapies are now being investigated.

Platelets have long been recognised to colocalise with tumour cells throughout haematogenous metastasis. Interactions between these cells contribute to tumour cell survival and motility through the vasculature into other tissues. Now, the research focus is shifting towards developing means to exploit this relationship to provide accurate diagnostics and therapies. Alterations to platelet count, RNA profile, and platelet ultrastructure are associated with the presence of certain malignancies, and may be used for cancer detection. Additionally, nanoparticle-based drug delivery systems are enhanced through the use of platelet membranes to specifically target cancer cells and camouflage the foreign particles from the immune system. This review discusses the development of platelets into highly powerful tools for cancer diagnostics and therapies.

Section snippets

Platelets and Malignancy: An Unavoidable Relationship

The relationship between platelets and tumour cells during haematogenous metastasis has been well studied. Mounting evidence points to tumour cell-induced platelet aggregation (TCIPA) as being a key step in aiding survival of circulating tumour cells, causing advanced disease 1, 2, 3, 4. Recently, interest in this topic has been growing and knowledge of the close interactions between these two cell types is now beginning to be exploited to aid development of targeted cancer therapies and more

Tumour-Cell-Induced Platelet Activation

Platelets and tumour cells share a relationship vital to tumour cell survival in the vasculature and subsequent haematogenous metastasis. A key process in this relationship is tumour cell-mediated activation, and subsequent aggregation, of platelets. Under normal haematological circumstances, platelets circulate in a resting state and activate in response to shear stress [21], signals from wounds in the endothelium, or nearby activated platelets [22]. However, there is now also a large body of

Platelets As Biomarkers of Cancer

As a result of the platelet activation and coagulable state induced by tumour cells, the incidence of VTE in cancer patients is high. First documented over 150 years ago [57], the hyper-reactive state of platelets induced by the cancer cells increases the risk of VTE 3–4-fold in cancer patients compared to healthy individuals, and is the second leading cause of death in cancer patients [45]. In several cancer types (for example lung, prostate, and breast) the presence of VTE is strongly

Platelets As Drug Delivery Systems

The colocalisation of platelets and tumour cells throughout haematogenous metastasis presents opportunities to manipulate this relationship for use in cancer therapies. Indeed, disruption of this relationship – through systemic depletion of platelets [4] or genetic deficiency of certain platelet adhesion molecules (e.g., P-selectin) [15] and secreted molecules (e.g., TGF-β1) [38] – elicits a significant reduction in metastatic foci in experimental models of metastasis. These methods are not

Concluding Remarks

The multifaceted interactions between tumour cells and platelets throughout the metastatic process afford numerous opportunities for the development of diagnostic tools and therapies that exploit this relationship. However, the full extent of the relationship between platelets and tumour cells is yet to be defined and questions pertaining to the possible roles of platelets in cancer progression outside of haematogenous metastasis remain unanswered (see Outstanding Questions). Cancer is a

Conflict of interest

The authors have no conflict of interest to declare.

Acknowledgements

This work was supported by grant funds received from the following: the Australian National Health and Medical Research Council Project and Program Grants (1079250, 1016647), an Independent Research Institutes Infrastructure Support Scheme Grant (9000220) and a Victorian State Government Operational Infrastructure Support Grant. E.C.J. is the recipient of a fellowship from the Galli Foundation. S.R.H. is the recipient of an Australian Postgraduate Award from the University of Melbourne. The

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Platelets have been shown to enhance the survival of lymphoma cell lines. However, it remains unclear whether they play a role in lymphoma. Here, we investigated the potential role of platelets and/or megakaryocytes in the progression of Eμ-myc lymphoma. Eμ-myc tumor cells were transplanted into recipient wild-type (WT) control, Mpl^−/−, or Tpo^Tg mice, which exhibited normal, low, and high platelet and megakaryocyte counts, respectively. Tpo^Tg mice that underwent transplantation exhibited enhanced lymphoma progression with increased white blood cell (WBC) counts, spleen and lymph node weights, and enhanced liver infiltration when compared with WT mice. Conversely, tumor-bearing Mpl^−/− mice had reduced WBC counts, lymph node weights, and less liver infiltration than WT mice. Using an Mpl-deficient thrombocytopenic immunocompromised mouse model, our results were confirmed using the human non-Hodgkin lymphoma GRANTA cell line. Although we found that platelets and platelet-released molecules supported Eμ-myc tumor cell survival in vitro, pharmacological inhibition of platelet function or anticoagulation in WT mice transplanted with Eμ-myc did not improve disease outcome. Furthermore, transient platelet depletion or sustained Bcl-x_L–dependent thrombocytopenia did not alter lymphoma progression. Cytokine analysis of the bone marrow fluid microenvironment revealed increased levels of the proinflammatory molecule interleukin 1 in Tpo^Tg mice, whereas these levels were lower in Mpl^−/− mice. Moreover, RNA sequencing of blood-resident Eμ-myc lymphoma cells from Tpo^Tg and WT mice after tumor transplantation revealed the upregulation of hallmark gene sets associated with an inflammatory response in Tpo^Tg mice. We propose that the proinflammatory microenvironment in Tpo^Tg mice promotes lymphoma progression.
Targeting nanoparticles to malignant tumors
2022, Biochimica et Biophysica Acta - Reviews on Cancer
Citation Excerpt :
Other biological membranes may also be suitable to perform this task. Recent advances with membranes from platelets, neutrophils, natural killer cells, macrophages, stem cells, and even cancer cells warrant further studies [366–370]. As the lifespan of platelets, red blood cells, and stem cells differ profoundly, it will be interesting to determine how individual membrane coats affect NP elimination.
Nanomaterials are at the forefront of health research and development. Among different nanomaterials, nanoparticles are especially promising for cancer theranostics. However, despite great potential, the clinical translation of nano-based applications continues to face obstacles. A major hurdle to the localized eradication of tumors is the efficient targeting of nanomaterials to the desired tissues and cells. In particular, nanoparticle properties and the route of administration impact the efficacy of precision nanomedicine. This review focuses on nanoparticles that have been produced for the detection and treatment of cancer. Common and tissue-specific barriers that limit the accumulation of nanoparticles in malignant tumors are discussed. The in-depth discussion focuses on the physicochemical properties of nanoparticles and the surface modifications that achieve efficient accumulation at tumor sites. Furthermore, limitations of current strategies and open questions are presented. The review concludes with an outlook on future directions and the trajectories that will drive the field forward to advance nano-oncology in the clinic.
Recent advances in platelet engineering for anti-cancer therapies
2022, Particuology
Citation Excerpt :
In particular, novel technologies using platelets for potential cancer therapies are now being widely investigated (Hu, Fang et al., 2015). Platelets, produced by megakaryocytes, represent one type of versatile vehicle for drug delivery due to their relatively small size, lack of nucleus, and intimate role in mitigating injury to blood vessels and maintaining hemostasis through aggregation, or clumping to clot blood at the site of injuries (Hyslop & Josefsson, 2017; Yeung et al., 2018; Gaertner & Massberg, 2019). In addition, since Armand Trousseau first established the relationship between platelets and cancer metastasis, platelets have been shown to contribute central functions in cancer progression and metastasis, especially through recognition and interaction with circulating tumor cells (CTCs) in blood (Varki, 2007; Ortiz-otero et al., 2018).
Platelets contribute a major role in hemostasis by clumping and coagulation at the site of blood vessel injuries. In light of recent findings of a close relationship between platelets and immunological response, as well as interactions between platelets and cancer cells, novel engineering strategies have emerged for the integration of platelets or platelet membrane (PM) with anti-cancer therapeutics. In this review, we discuss several recent innovations that use platelets or their membranes to circumvent host immune responses and target tumor cells with high specificity to deliver a range of pharmacological, photothermal, or immunologic agents for eradication of recalcitrant tumor cells. More specifically, we compare the relative advantages of using whole platelets versus single or hybrid PM to coat nanoparticle cargoes. These cargoes range from well-established anti-tumor apoptosis-inducing agents, to relatively new photothermal agents that can induce a feedback cascade in which they induce vascular damage to the tumor which recruits more platelet- or membrane-encapsulated agents to induce further damage. We also discuss the use of engineered platelets to produce programmed cell death-inducing platelet derived microparticles. This review provides an overview and future directions for this promising platelet-based biomimetic approach to anti-cancer therapy.
Targeting transgenic proteins to alpha granules for platelet-directed gene therapy
2022, Molecular Therapy Nucleic Acids
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This unique physiology makes platelets attractive cell therapy targets. Researchers have studied the use of platelets and of platelet membrane-coated nanoparticles as drug delivery tools (e.g., to target tumors or cardiovascular disease).1–4 Platelet-directed gene therapy has been explored for the delivery of coagulation factors to treat hemophilia.5
Platelets are anucleate blood cells that are shed from megakaryocytes (MKs) into the bloodstream to maintain hemostasis and promote wound healing after vascular injury. To carry out their functions, platelets become activated and release bioactive substances from their secretory granules. As alpha granules (αGs) in resting platelets store proteins and release them only after activation, the packaging of proteins into αGs is an attractive strategy to deliver therapeutic proteins. Here, we propose an adjustable model for targeting transgenic proteins to platelet αGs using third-generation self-inactivating lentiviral vectors. The vectors express from the murine platelet factor 4 promoter (mPf4P), restricting transgene expression to the MK lineage. For the delivery and retention of expressed proteins in αGs, proteins are fused to short peptide sorting signals derived from the human cytokine RANTES or from the transmembrane protein P-selectin. We demonstrate effective targeting of GFP to αGs of murine and human in vitro-differentiated MKs and murine platelets in vivo. Furthermore, interferon-α (IFNα), as a potentially therapeutic cytokine, was successfully delivered to and stored in murine platelets in vivo, was released after activation, and inhibited virus replication in vitro. Our vectors create possibilities for numerous applications in cell therapy utilizing platelets as carriers of therapeutic proteins.
Platelets in chronic liver disease, from bench to bedside
2019, JHEP Reports
Citation Excerpt :
In turn, cancer cells can influence platelet activation and shape by releasing growth factors that bind to specific receptors on their surface (tumour “education”). Moreover, the tight communication between platelets and tumour cells, as well as their physical interactions, indicate a possible role for platelets as promising vectors for targeted drug delivery.35 Therefore, platelets take part in an intricate interplay with innate and adaptive immune responses, perpetuating inflammatory and malignant processes via various mechanisms (summarised in Fig. 2).
In the last decade, numerous studies revealed physiologic and pathophysiologic roles of platelets beyond haemostasis, a process to prevent and stop bleeding. These include the activation of the immune system and the promotion of inflammation, infection and cancer. Hence, the emerging view on the role of platelets has shifted – platelets are now seen as alert “sentinels” of the immune compartment, rather than passive bystanders. Herein, we review well-established and newly discovered features of platelets that define their natural role in maintaining blood haemostasis, but also their functional relationship with other cells of the immune system. We focus on recent studies underlining functional involvement of platelets in chronic liver diseases and cancer, as well as the effects of anti-platelet therapy in these contexts. Finally, we illustrate the potential of platelets as possible diagnostic and therapeutic tools in liver disease based on recently developed methodologies.
An Overview of the Latest Applications of Platelet-Derived Microparticles and Nanoparticles in Medical Technology 2010-2020
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Trends in Cancer

ReviewUndercover Agents: Targeting Tumours with Modified Platelets

Trends

Section snippets

Platelets and Malignancy: An Unavoidable Relationship

Tumour-Cell-Induced Platelet Activation

Platelets As Biomarkers of Cancer

Platelets As Drug Delivery Systems

Concluding Remarks

Conflict of interest

Acknowledgements

J. Thromb. Haemost.

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Thromb. Res.

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Cancer Cell

Cancer Cell

Blood

Blood

Thromb. Res.

Cell Rep.

Eur. J. Cancer Clin. Oncol.

Blood

Blood

Blood

Biomaterials

J. Control Release

Contribution of platelets to tumour metastasis

Nat. Rev. Cancer

Paraneoplastic thrombocytosis in ovarian cancer

N. Engl. J. Med.

Prognostic significance of thrombocytosis in patients with primary lung cancer

Eur. Respir. J.

Pretreatment thrombocytosis as a prognostic factor in metastatic breast cancer

Int. J. Breast Cancer

Prognostic role of elevated platelet count in patients with lung cancer: a systematic review and meta-analysis

Int. J. Clin. Exp. Med.

Thrombocytosis associated with malignant disease

Arch. Intern. Med.

Cancer-associated venous thromboembolism: burden, mechanisms, and management

Thromb. Haemost.

Trousseau’s syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: clinical, pathophysiologic, and therapeutic features

Medicine (Baltimore)

Antimetastatic effects associated with platelet reduction

Proc. Natl. Acad. Sci. U. S. A.

P-selectin deficiency attenuates tumor growth and metastasis

Proc. Natl. Acad. Sci. U. S. A

The ability of different forms of heparins to suppress P-selectin function in vitro correlates to their inhibitory capacity on bloodborne metastasis in vivo

Thromb. Haemost.

Anticancer platelet-mimicking nanovehicles

Adv. Mater.

Selective targeting of bioengineered platelets to prostate cancer vasculature: new paradigm for therapeutic modalities

J. Cell Mol. Med.

Shear-induced platelet activation and platelet microparticle formation at blood flow conditions as in arteries with a severe stenosis

Arterioscler. Thromb. Vasc. Biol.

Platelet activation by extracellular matrix proteins in haemostasis and thrombosis

Curr. Pharm. Des.

Mechanisms of platelet activation by cultured human cancer cells and cells freshly isolated from tumor tissues

Invasion Metastasis

Review
Undercover Agents: Targeting Tumours with Modified Platelets