Emerging roles of platelets in cancer biology and their potential as therapeutic targets

Abstract

The main role of platelets is to control bleeding and repair vascular damage via thrombosis. They have also been implicated to promote tumor metastasis through platelet-tumor cell interactions. Platelet-tumor cell interactions promote tumor cell survival and dissemination in blood circulation. Tumor cells are known to induce platelet activation and alter platelet RNA profiles. Liquid biopsies based on tumor-educated platelet biomarkers can detect tumors and correlate with prognosis, personalized therapy, treatment monitoring, and recurrence prediction. Platelet-based strategies for cancer prevention and tumor-targeted therapy include developing drugs that target platelet receptors, interfere with the release of platelet particles, inhibit platelet-specific enzymes, and utilize platelet-derived "nano-platelets" as a targeted drug delivery platform for tumor therapy. This review elaborates on platelet-tumor cell interactions and the molecular mechanisms and discusses future research directions for platelet-based liquid biopsy techniques and platelet-targeted anti-tumor strategies.

Keywords: NETosis; immune escape; liquid biopsy; platelet activation; platelet aggregation activity; tumor metastasis; tumor treatment.

Figure 1

Platelet activation and function. Thrombin activates G protein-associated PARs on the platelet surface during platelet activation, triggering intracellular calcium flux and cAMP reduction. Other platelet activators include subendothelial matrix collagen, ADP, and TXA2 exposed during vascular injury. TXA2 binds to the G protein-coupled receptors P2Y and TBXA2 receptor, stimulating platelet degranulation and release of their contents. Platelets are important in hemostasis and thrombosis, inflammation, wound healing, immune responses, angiogenesis, and vessel stability. ADP, adenosine disphosphate; cAMP, cyclic adenosine monophosphate; PAR, protease-activated receptor; TXA2, thromboxane A2.

Figure 2

Platelet-tumor cell interactions in early steps of the metastatic cascade. After dissociating from the primary tumor, tumor cells enter the blood vessels and rapidly pass through the circulation into the vasculature of secondary organs. Platelets aggregate around CTCs or around stalled tumor cells to form a platelet protective barrier. Tumor cells promote platelet induction of NETs. Extravasation typically occurs within 1 to 3 days of the initial arrest, seeding into the stroma of the target tissue or organ and recruiting myeloid cells to the early metastatic niche. Tumor cells may remain dormant or start growing again to initiate metastases, with only a few cells completing the metastatic cascade and forming clinically relevant metastatic tumors. CTC, circulating tumor cell; NET, neutrophil extracellular trap.

Figure 3

CTCs interact with constituents of the blood circulation. (A) Cell adhesion molecules mediate adhesion and signal transduction between cells and between cells and the extracellular matrix to promote tumor metastasis. Integrins and selectins play important roles in this process. On the one hand, selectins can bind to leukocytes or endothelial cells to enable and maintain cell rolling. On the other hand, GPVI and podoplanin can be involved in platelet-mediated tumor metastasis. (B) Platelets promote recruit neutrophils to generate extracellular traps, and NETs interact with CTCs to form a protective barrier that facilitates CTC extravasation and the formation of metastatic niches. CTCs promote platelet-induced NETosis, associated with increased complications such as tumor-associated thrombosis, venous thromboembolism, and tumor metastasis. (C) Growth factors secreted by platelets (such as VEGF, PDGF, and FGF) bind to the corresponding receptors (such as integrins, Notch signaling receptors), which may regulate tumor angiogenesis and vascular integrity. CTC, circulating tumor cell; EGF, epidermal growth factor; GP, glycoprotein; NET, neutrophil extracellular trap; PDGF, platelet-derived growth factor; VEGF, vascular endothelial growth factor.

Figure 4

Escape of tumor cells from immune surveillance. (A) Platelets bind to tumor-derived HMGB1 via TLR4 and interact with podoplanin-expressing tumor cells via CLEC2 to stimulate their activation. (B) Activated platelets and fibrinogen can form a protective barrier against the mechanical forces of blood flow and also against NK cell attack. In addition to providing physical shielding, platelets can protect CTCs from circulating NK cell-mediated tumor lytic activity and can interfere with tumor cell recognition by NK cells. (C) TEPs as a noninvasive biomarker source for cancer detection and progression monitoring. The examination of TEPs mainly includes ultra-deep, massively parallel, and long-read sequencing of TEP transcripts and possible detection of epigenetic transcriptional signatures. Improving the sensitivity and accuracy of detection techniques and the specific selection of tumor-affected platelets can improve diagnostic accuracy and treatment prediction. CLEC-2, C-type lectin-like receptor-2; CTC, circulating tumor cell; HMGB1, high-mobility group box 1; NK cell, natural killer cell; TEPs, Tumor-educated platelets; TLR, toll-like receptor;.