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Interactions of platelets with circulating tumor cells contribute to cancer metastasis.

ABSTRACT: Recent studies have suggested that platelets have a crucial role in enhancing the survival of circulating tumor cells in the bloodstream and aggravating cancer metastasis. The main function of platelets is to bind to the sites of the damaged vessels to stop bleeding. However, in cancer patients, activated platelets adhere to circulating tumor cells and exacerbate metastatic spreading. Several hypotheses have been proposed about the platelet-cancer cell interactions, but the underlying mechanisms of these interactions are not completely understood yet. In this work, we quantitatively investigated the interactions between circulating tumor cells, red blood cells, platelets, plasma flow and microvessel walls via computational modelling at the cellular scale. Our highly detailed computational model allowed us to understand and quantitatively explain the role of platelets in deformation, adhesion and survival of tumor cells in their active arrest to the endothelium.

SUBMITTER: Anvari S

PROVIDER: S-EPMC8322323 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Interactions of platelets with circulating tumor cells contribute to cancer metastasis.

Anvari Sina S Osei Ernest E Maftoon Nima N

Scientific reports 20210729 1

Recent studies have suggested that platelets have a crucial role in enhancing the survival of circulating tumor cells in the bloodstream and aggravating cancer metastasis. The main function of platelets is to bind to the sites of the damaged vessels to stop bleeding. However, in cancer patients, activated platelets adhere to circulating tumor cells and exacerbate metastatic spreading. Several hypotheses have been proposed about the platelet-cancer cell interactions, but the underlying mechanisms ...[more]

PMID: 34326373

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Project description:BackgroundTumor cells continue to evolve the metastatic potential in response to signals provided by the external microenvironment during metastasis. Platelets closely interact with tumor cells during hematogenous metastasis and facilitate tumor development. However, the molecular mechanisms underlying this process are not fully understood.MethodsRNA-sequencing was performed to screen differentially expressed genes mediated by platelets. The effects of platelet and CD39 on tumor metastasis were determined by experimental metastasis models with WT, NCG and CD39-/- mice.ResultsRNA-sequencing results showed that platelets significantly up-regulated CD39 expression in tumor cells. CD39 is a novel immune checkpoint molecule and a key driver of immunosuppression. Our data provided evidence that the expression of CD39 was enhanced by platelets in a platelet-tumor cell contact dependent manner. Although the role of CD39 expressed by immune cells is well established, the effect of CD39 expressed by tumor cells on tumor cell behavior, anti-tumor immunity and tumor metastasis is unclear. We found that CD39 promoted tumor cell invasion, but had no effect on proliferation and migration. Notably, we showed that the ability of platelets to prime tumor cells for metastasis depends on CD39 in the experimental tumor metastasis model. CD39 silencing resulted in fewer experimental metastasis formation, and this anti-metastasis effect was significantly reduced in platelet-depleted mice. Furthermore, overexpression of CD39 in tumor cells promoted metastasis. In order to eliminate the effect of CD39 expressed in cells other than tumor cells, we detected tumor metastasis in CD39-/- mice and obtained similar results. Moreover, overexpression of CD39 in tumor cells inhibited antitumor immunity. Finally, the data from human samples also supported our findings.ConclusionsOur study shows that direct contact with platelets induces CD39 expression in tumor cells, leading to immune suppression and promotion of metastasis.

Project description:BackgroundImmune checkpoint inhibition is effective in several cancers. Expression of programmed death-ligand 1 (PD-L1) on circulating tumor or immune effector cells could provide insights into selection of patients for immune checkpoint inhibition.MethodsWhole blood was collected at serial timepoints from metastatic breast cancer patients and healthy donors for circulating tumor cell (CTC) and platelet PD-L1 analysis with a phycoerythrin-labeled anti-human PD-L1 monoclonal antibody (Biolegend clone 29E.2A3) using the CellSearch® assay. CTC PD-L1 was considered positive if detected on at least 1% of the cells; platelet PD-L1 was considered positive if ≥100 platelets per CellSearch frame expressed PD-L1.ResultsA total of 207 specimens from 124 metastatic breast cancer patients were collected. 52/124 (42%) samples at timepoint-1 (at or close to time of progressive disease) had ≥5 CTC/7.5ml whole blood. Of those, 21 (40%) had positive CTC PD-L1. In addition, platelet PD-L1 expression was observed in 35/124 (28%) at timepoint-1. Platelet PD-L1 was not detected in more than 70 specimens from 12 healthy donors. Platelet PD-L1 was associated with ≥5 CTC/7.5ml whole blood (p = 0.0002), less likely in patients with higher red blood cell counts (OR = 0.72, p<0.001) and a history of smoking tobacco (OR = 0.76, p<0.001). Platelet PD-L1 staining was not associated with tumor marker status, recent procedures or treatments, platelet-affecting drugs, or CTC PD-L1 expression.ConclusionPD-L1 expression was found in metastatic breast cancer patients on both CTC and platelets in an independent fashion. Inter-patient platelet PD-L1 expression was highly heterogeneous suggesting that it is a biological event associated with cancer in some but not all patients. Taken together, our data suggest that CTC and platelet PD-L1 expression could play a role in predicting which patients should receive immune checkpoint inhibition and as a pharmacodynamics biomarker during treatment.

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Interactions of platelets with circulating tumor cells contribute to cancer metastasis.

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Interactions of platelets with circulating tumor cells contribute to cancer metastasis.

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