Platelets, immune cells and the coagulation cascade; friend or foe of the circulating tumour cell?

Abstract

Cancer cells that transit from primary tumours into the circulatory system are known as circulating tumour cells (CTCs). These cancer cells have unique phenotypic and genotypic characteristics which allow them to survive within the circulation, subsequently extravasate and metastasise. CTCs have emerged as a useful diagnostic tool using “liquid biopsies” to report on the metastatic potential of cancers. However, CTCs by their nature interact with components of the blood circulatory system on a constant basis, influencing both their physical and morphological characteristics as well as metastatic capabilities. These properties and the associated molecular profile may provide critical diagnostic and prognostic capabilities in the clinic. Platelets interact with CTCs within minutes of their dissemination and are crucial in the formation of the initial metastatic niche. Platelets and coagulation proteins also alter the fate of a CTC by influencing EMT, promoting pro-survival signalling and aiding in evading immune cell destruction. CTCs have the capacity to directly hijack immune cells and utilise them to aid in CTC metastatic seeding processes. The disruption of CTC clusters may also offer a strategy for the treatment of advance staged cancers. Therapeutic disruption of these heterotypical interactions as well as direct CTC targeting hold great promise, especially with the advent of new immunotherapies and personalised medicines. Understanding the molecular role that platelets, immune cells and the coagulation cascade play in CTC biology will allow us to identify and characterise the most clinically relevant CTCs from patients. This will subsequently advance the clinical utility of CTCs in cancer diagnosis/prognosis.

The induction of a mesenchymal phenotype by platelet cloaking of cancer cells is a universal phenomenon

“…Platelets are necessary components of the secondary metastatic niche [4] and platelet-cancer cell interactions aid survival of cancer cells via the inhibition of natural killer cell activity [12] , whilst providing protection from shear stress in the circulation [13] . Our recent review outlines in detail the molecular role that platelets, immune cells and the coagulation cascade play in CTC biology, impacting on EMT, pro-survival signalling and immune evasion [14] . Consequently, we believe that platelet cloaked CTCs have a higher propensity towards metastasis, and the protection conferred by platelets also assists their extravasation at the secondary metastatic site.…”

“Metabolic dysregulations of cancer cells with metastatic potential”

“…Coagulation proteins along with platelets have been shown to promote pro-survival signaling during metastasis [59]. The HMP cell lines displayed elevated levels of γ-carboxyglutamine, which is involved in coagulation cascade; the γ-carboxyglutamic acid residues play an important role in coagulation by governing the activation and binding of circulating blood-clotting enzymes to cell membrane surface [60].…”

Application of Microfluidic Systems for Breast Cancer Research

“…However, individual CTCs may undergo apoptosis under the influence of immune cytokines and fluid shear forces, and undergo anoikis upon loss of attachment to the extracellular matrix (ECM) and neighboring cells due to a lack of fibronectin mediation [83,84]. CTCs that aggregate through CD-44 cohesion have been shown to be more resilient, particularly when the aggregates include platelets and neutrophils which disguise them [85,86]. Heterogenous cell aggregates also lead to CTC proliferation through IL-1β and IL-6 crosstalk [87].…”