Abstract
Metastasis requires that cancer cells survive in the circulation, colonize distant organs, and grow. Despite platelets being central contributors to hemostasis, leukocyte trafficking during inflammation, and vessel stability maintenance, there is significant evidence to support their essential role in supporting metastasis through different mechanisms. In addition to their direct interaction with cancer cells, thus forming heteroaggregates such as leukocytes, platelets release molecules that are necessary to promote a disseminating phenotype in cancer cells via the induction of an epithelial–mesenchymal-like transition. Therefore, agents that affect platelet activation can potentially restrain these prometastatic mechanisms. Although the primary adhesion of platelets to cancer cells is mainly independent of G protein-mediated signaling, soluble mediators released from platelets, such as ADP, thromboxane (TX) A2, and prostaglandin (PG) E2, act through G protein-coupled receptors (GPCRs) to cause the activation of more additional platelets and drive metastatic signaling pathways in cancer cells. In this review, we examine the contribution of the GPCRs of platelets and cancer cells in the development of cancer metastasis. Finally, the possible use of agents affecting GPCR signaling pathways as antimetastatic agents is discussed.
Highlights
Thrombosis is commonly detected in cancer patients and is associated with the progression to a metastatic stage
An experimental model of hematogenous metastases, where immunodeficient NOD-scid IL2Rγnull (NSG) mice were injected via the tail vein with colon adenocarcinoma HT29 cells showed that tumor cell exposure to platelets in vitro caused a significant increase in the development of metastases (E); it was associated with enhanced platelet activation in vivo, as assessed by the urinary levels of TX-M, which is a major enzymatic metabolite of TXA2, a potent stimulus for platelet activation, mainly derived from platelets (F)
The prevention of cardiovascular disease is obtained via drugs affecting the amplification pathways of platelet aggregation, i.e., aspirin at low doses, which mainly targets the platelet COX-1 and inhibits TXA2, and P2Y12 antagonists, which block the action of ADP [154]
Summary
Thrombosis is commonly detected in cancer patients and is associated with the progression to a metastatic stage. Platelets can protect tumor cells from immune elimination within the circulatory system, promote tumor cell arrest within the vasculature, and affect tumor cell survival, thereby supporting the spreading of the tumor to distant organs [3] Both the pharmacological inhibition of platelet function and platelet crosstalk with cancer cells have the potential to prevent cancer metastasis development [4,5,6,7]. Khalil et al [12] clarified the role of Gbg–p110b interaction in the tumor cell–macrophage crosstalk and invadopodia function involved in the metastatic process They suggested that the disruption of p110β–Gβγ binding could constitute a novel therapeutic pharmacological approach to treating metastasis [12]. The possible use of agents affecting GPCR signaling pathways as antimetastatic agents is discussed
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