Edited by: Leonardo Freire-de-Lima, Federal University of Rio de Janeiro, Brazil
Reviewed by: Alana L. Welm, The University of Utah, United States; Danielle Oliveira Nascimento, Universidade Federal Rural Do Rio De Janeiro, Brazil
This article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Accumulating evidence suggests that platelets play a key role in cancer metastatic dissemination through their multilevel interaction with tumor cells. Most crucial is the contribution of platelets to the formation and expansion of the early metastatic niche, a protective microenvironment that nurtures the first metastatic cells and is necessary for the establishment of overt metastatic disease. A multitude of mechanisms have been proposed toward this effect. The current review examines the implication of platelets in the three most well-studied mechanisms: (a) the initial preparation of the metastatic microenvironment by the formation of the extracellular matrix (ECM) and the recruitment of granulocytes, (b) the creation of the neovasculature (important for providing the developing tumor with oxygen and nutrients and clearing away the metabolic waste), and (c) the evasion of the immune response by the creation of an immune-suppressive environment around the developing metastases. Finally, the review provides current perspectives on the potential clinical relevance of platelets in cancer progression and their consequent role in cancer therapeutics.
Derived from the megakaryocytes, platelets are small fragments of circulating cytoplasm with a key role in primary hemostasis. Increasing evidence in recent years supports their critical role in cancer progression and particularly in metastatic dissemination through their multilevel interaction with tumor cells.
The formation of the micrometastatic niche is depended upon the arrival of circulating tumor cells (CTCs) to sites distant to the primary site. Preclinical evidence now suggests that platelets have a particular role in the formation of the “early metastatic niche” (
During their journey through the circulation, CTCs adhere to circulating platelets by adhesion molecules expressed on their surface, like the tissue factor and P-select in ligands (
After their extravasation and the loss of their protective coating, tumor cells are in the danger of undergoing apoptosis through a process called anoikis (detachment-induced apoptosis). This results from the lack of a protective surrounding environment, and isolated cancer cells are subject to this fate, unless they manage to discover a new home in the site where they metastasize (
The current review presents available evidence on the implication of platelets in the creation of the metastatic niche through the formation of the extracellular matrix, the building of the neovasculature and the establishment of the immune response. The future potential application of this knowledge in the clinical setting is also discussed here.
Although the various processes leading to the creation of the metastatic niche may be overlapping, they can be divided in three major phases: the initial preparation of the metastatic microenvironment by the formation of the extracellular matrix (ECM) and the recruitment of granulocytes; the creation of the neovasculature, which is important for providing the developing tumor with oxygen and nutrients, as well as for clearing away the metabolic waste; and, lastly, the evasion of the immune response by the creation of an immune-suppressive environment around the developing metastasis (
The role of platelets in the formation of the early metastatic niche.
There is increasing evidence to support the idea that platelets initiate the shaping of the metastatic microenvironment in the context of early metastatic niche. This has been shown in a lung cancer murine model, where tumor-aggregated platelets have guided the creation of metastatic sites by the production of CXCL-5 and CXCL-7 cytokines that attract granulocytes (
The early metastatic niche is formed mostly by ECM, by platelets and by the granulocytes that, as described above, are recruited on site by the activated platelets (
Conclusively, it appears that platelets can play a vital role in the very early formation of both the cellular and the acellular elements of the early metastatic microenvironment. The formation of a supportive structure consisting of ECM and host-derived cells is a prerequisite for the successful establishment of metastases.
The formation of new blood vessels from pre–existing ones in cancer is called neoangiogenesis (
The mechanisms through which platelets contribute in neoangiogenesis have been well-characterized (
Another hint for the importance of platelets in the process of neoangiogenesis is that platelets are activated within the tumor vasculature, subsequently secreting their VEGF-rich releasate in the tumor tissue (
Additionally, platelets have been shown to recruit endothelial progenitor cells (EPCs) from bone marrow and increase their angiogenic potential. EPCs are also involved in neoangiogenesis (
Finally, platelets seem to have a role in the formation of the lymphatic network of the tumor as well, since a-granules contain VEGF-C, the most important regulator of lymphangiogenesis (
As previously mentioned, platelets protect CTCs from NK-mediated lysis during their voyage through the circulation. Although that may appear as a mostly mechanical process, it has been shown that platelets need to undergo activation in order to shield tumor cells from lysis (
Platelets also interact with other immune cells, apart from NK, like macrophages and T-cells, and their effects on them may contribute in the creation of an immunosuppressive microenvironment. For example, the micrometastatic niche is rich in platelet-derived and tumor cell-derived TGF-β, which is suppressive for both CD4+ and CD8+ T-cell functions as well (
Moreover, platelets have been implicated in the activation of neutrophils and the creation of neutrophil extracellular traps (NETs), in a process called NETosis (
There exists enough evidence from preclinical studies and experimental models to support the pivotal role of platelets in the creation of the early metastatic niche (
On the contrary, when injecting thrombocytopenic mice with human-derived platelets, the rate and extent of metastatic spread increased substantially (
Furthermore, Kerr et al., also workingon mouse models, demonstrated that platelets facilitate communication between pre-metastatic tumor cells and their pre-metastatic niche in bone tissue (
Thrombocytosis of malignancy constitutes a well-known paraneoplastic syndrome, which is promoted by a multitude of cancer-related cytokines and growth factors, such as G-CSF, GM-CSF, IL-1, IL-6 and, more importantly, TPO (
Based on the experimental data, targeting platelets appears a promising approach against cancer itself. Most of the clinical trials have evaluated aspirin, perhaps the most well-studied antiplatelet drug, as an anticancer agent. In a 2012 meta-analysis of 5 randomized clinical trials (RCT), aspirin has been found to reduce the risk of metastasis and the risk of death by cancer in patients with adenocarcinoma, irrespective of the organ of origin (
Previous studies had shown that other platelet activation pathways could contribute to the establishment of the intravascular metastatic niche. In particular, Clopidogrel a P2Y12 receptor antagonist, and eptifibatide an αIIbβ3 integrin inhibitor, two drugs used in the clinical practice to reduce platelet aggregation, were found to be associated with reduction in experimental metastasis (
Finally, the creation of modified platelets that retained platelet binding functions but were incapable of functional activation and aggregation, termed “platelet decoys,” led to encouraging results in mouse models, where simultaneous injection of the platelet decoys with tumor cells inhibited metastatic tumor growth (
Although the role of platelets in cancer progression is not limited to the preparation and maintenance of the metastatic microenvironment, this specific function is of utmost importance since the few early clusters of metastasizing tumor cells are extremely vulnerable and subject to many dangers in their surrounding environment. Accumulated data from preclinical studies and experimental models support the hypothesis that platelets contribute in every stage of the formation of the pre-metastatic niche. It is also possible that antiplatelet drugs, especially aspirin, exhibit at least part of their anticancer properties by impairing the formation of a suitable microenvironment for the development of metastases.
Whilst ongoing preclinical work is expected to shed light on additional platelet activation pathways at different stages of metastatic progression, several clinical trials aiming to evaluate antiplatelet agents in the treatment and prevention of cancer progression are currently ongoing.
SG and AC developed the idea and drafted the manuscript. SG created the figure. RJ critically reviewed the manuscript and contributed new ideas. The final manuscript was edited by AC and approved by all authors.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
1Aspirin for Dukes C and HighRisk Dukes B Colorectal Cancers (ASCOLT).
2Finding the Best Dose of Aspirin to Prevent Lynch Syndrome Cancers (CaPP3 Israel).
3ADD-ASPIRIN Trial website.