Circulating platelets as liquid biopsy sources for cancer detection

Abstract

Nucleic acids and proteins are shed into the bloodstream by tumor cells and can be exploited as biomarkers for the detection of cancer. In addition, cancer detection biomarkers can also be nontumor-derived, having their origin in other organs and cell types. Hence, liquid biopsies provide a source of direct tumor cell-derived biomolecules and indirect nontumor-derived surrogate markers that circulate in body fluids or are taken up by circulating peripheral blood cells. The capacity of platelets to take up proteins and nucleic acids and alter their megakaryocyte-derived transcripts and proteins in response to external signals makes them one of the richest liquid biopsy biosources. Platelets are the second most abundant cell type in peripheral blood and are routinely isolated through well-established and fast methods in clinical diagnostics but their value as a source of cancer biomarkers is relatively recent. Platelets do not have a nucleus but have a functional spliceosome and protein translation machinery, to process RNA transcripts. Platelets emerge as important repositories of potential cancer biomarkers, including several types of RNAs (mRNA, miRNA, circRNA, lncRNA, and mitochondrial RNA) and proteins, and several preclinical studies have highlighted their potential as a liquid biopsy source for detecting various types and stages of cancer. Here, we address the usability of platelets as a liquid biopsy for the detection of cancer. We describe several studies that support the use of platelet biomarkers in cancer diagnostics and discuss what is still lacking for their implementation into the clinic.

Keywords: RNA; cancer; diagnostics; liquid biopsy; platelets.

Fig. 1

Platelets in circulation: biogenesis, interaction with CTCs, and crosstalk through EVs. Platelets originate from megakaryocytes and are released into the bloodstream (A). During their short lifespan in circulation, platelets are exposed to several interactions with other cells and the tumor microenvironment (TME). Other than the direct interaction of platelets with tumor cells, this crosstalk can occur also via extracellular vesicles (EVs). Both cancer cells and platelets release EVs, named, respectively, tumor‐derived EVs and platelet‐derived EVs (B). Circulating tumor cells (CTCs) may also activate and educate platelets. Platelets may also contribute to CTC survival, helping them escape from immune surveillance. Platelets also promote cell adhesion, arrest in vasculature and vascular permeability, facilitating the metastatic process (C).

Fig. 2

Composition, biomarkers, and omics analysis of platelets. Schematic representation of molecular components of platelets. Platelets are considered important repositories of diagnostic biomarkers, among them are the RNA biomarkers: mRNAs, miRNAs, circRNAs, lncRNAs, and other ncRNAs. Platelets do not have a nucleus but have a functional spliceosome and protein translation machinery, to process RNA transcripts. As most cells, platelets release extracellular vesicles (EVs). The platelet‐derived extracellular vesicles (PEVs) can have different designations, based on their biogenesis and size. Platelet microparticles (PMPs) are a type of PEVs and the most abundant population of EVs present in the blood, accounting for about 70% to 90% of all EVs. The PMPs are released via budding of the platelet membrane. Exosomes are also released by platelets, they are smaller and release out of the platelet upon fusion of an intermediate endocytic compartment, the multivesicular body (MVB), with the plasma membrane of the platelet. The PEVs carry components from the lumen of the platelet where they originated. Platelets have granules that release their content to the external upon activation. Dense granules contain phosphates, purines, and bioactive amines; alpha granules contain many soluble mediators that promote inflammation and coagulation. Platelets contain also a large set of membrane surface receptors that participate in the platelet activation process and act as adhesion molecules. The platelet receptors are integrins (β1, β2, and β3), leucine‐rich repeats receptors (GPIb‐IX‐V, TLR, and MMP); selectin s (P‐selectin, CLEC‐2, and CD72); tetraspanins (CD63, CD9, and CD53); transmembrane receptors (ADP and thrombin); prostaglandin receptors (thromboxane, PGI2, PGD2, and PGE2); lipid receptors (PAF and LPL‐R); immunoglobulin superfamily receptors (GPVI, CD32, CD23, JAM, PECAM‐1, CD31, and TLT‐1); tyrosine kinase receptors (c‐mpl, CD110, Leptin, Tie‐1, insulin, and PDGF); miscellaneous platelet membrane receptors (5‐HT2A, CD36, C1qR, LAMP‐1, CD107a; LAMP‐2, CD107b, and CD40L).