Platelets Induce CD39 Expression in Tumor Cells to Facilitate Tumor Metastasis

Overview

Journal Br J Cancer

Specialty Oncology

Date 2024 Mar 9

PMID 38461171

Authors

Zhaochen Ning

Keyan Liu

Hui Zhang

Guanjun Dong

Xiaotong Wang

Huabao Xiong

Affiliations

Soon will be listed here.

Abstract

Background: Tumor 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.

Methods: RNA-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.

Results: RNA-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.

Conclusions: Our study shows that direct contact with platelets induces CD39 expression in tumor cells, leading to immune suppression and promotion of metastasis.

Citing Articles

CD39 Contributes to the Ability of Cell Invasion in Heterogeneity of Colorectal Cancer.

Li X, Shen Y, Lang J, Wu J, Qian Z, Shen G J Cell Mol Med. 2025; 29(5):e70486.

PMID: 40052646 PMC: 11886887. DOI: 10.1111/jcmm.70486.

Potential role of the CD39-CD73 ATP-adenosine pathway in platelet mediated dissemination of circulating tumour cells.

Ward M, OToole S, OLeary J Br J Cancer. 2024; 131(5):781-782.

PMID: 39128932 PMC: 11368966. DOI: 10.1038/s41416-024-02797-2.

References

Gu J, Ni X, Pan X, Lu H, Lu Y, Zhao J . Human CD39 regulatory T cells present stronger stability and function under inflammatory conditions. Cell Mol Immunol. 2016; 14(6):521-528. PMC: 5518817. DOI: 10.1038/cmi.2016.30. View

Flanagan M, Dabbs D, Brufsky A, Beriwal S, Bhargava R . Histopathologic variables predict Oncotype DX recurrence score. Mod Pathol. 2008; 21(10):1255-61. DOI: 10.1038/modpathol.2008.54. View

Li X, Moesta A, Xiao C, Nakamura K, Casey M, Zhang H . Targeting CD39 in Cancer Reveals an Extracellular ATP- and Inflammasome-Driven Tumor Immunity. Cancer Discov. 2019; 9(12):1754-1773. PMC: 6891207. DOI: 10.1158/2159-8290.CD-19-0541. View

Huong P, Nguyen L, Nguyen X, Lee S, Bach D . The Role of Platelets in the Tumor-Microenvironment and the Drug Resistance of Cancer Cells. Cancers (Basel). 2019; 11(2). PMC: 6406993. DOI: 10.3390/cancers11020240. View

Feng L, Sun X, Csizmadia E, Han L, Bian S, Murakami T . Vascular CD39/ENTPD1 directly promotes tumor cell growth by scavenging extracellular adenosine triphosphate. Neoplasia. 2011; 13(3):206-16. PMC: 3050864. DOI: 10.1593/neo.101332. View

Joyce J, Pollard J . Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009; 9(4):239-52. PMC: 3251309. DOI: 10.1038/nrc2618. View

Labelle M, Begum S, Hynes R . Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell. 2011; 20(5):576-90. PMC: 3487108. DOI: 10.1016/j.ccr.2011.09.009. View

Mandapathil M, Hilldorfer B, Szczepanski M, Czystowska M, Szajnik M, Ren J . Generation and accumulation of immunosuppressive adenosine by human CD4+CD25highFOXP3+ regulatory T cells. J Biol Chem. 2009; 285(10):7176-86. PMC: 2844167. DOI: 10.1074/jbc.M109.047423. View

Zhang H, Vijayan D, Li X, Robson S, Geetha N, Teng M . The role of NK cells and CD39 in the immunological control of tumor metastases. Oncoimmunology. 2019; 8(6):e1593809. PMC: 6492967. DOI: 10.1080/2162402X.2019.1593809. View

10.

Piranlioglu R, Lee E, Ouzounova M, Bollag R, Vinyard A, Arbab A . Primary tumor-induced immunity eradicates disseminated tumor cells in syngeneic mouse model. Nat Commun. 2019; 10(1):1430. PMC: 6441000. DOI: 10.1038/s41467-019-09015-1. View

11.

Placke T, Orgel M, Schaller M, Jung G, Rammensee H, Kopp H . Platelet-derived MHC class I confers a pseudonormal phenotype to cancer cells that subverts the antitumor reactivity of natural killer immune cells. Cancer Res. 2011; 72(2):440-8. DOI: 10.1158/0008-5472.CAN-11-1872. View

12.

Kunzli B, Bernlochner M, Rath S, Kaser S, Csizmadia E, Enjyoji K . Impact of CD39 and purinergic signalling on the growth and metastasis of colorectal cancer. Purinergic Signal. 2011; 7(2):231-41. PMC: 3146639. DOI: 10.1007/s11302-011-9228-9. View

13.

Plesner L . Ecto-ATPases: identities and functions. Int Rev Cytol. 1995; 158:141-214. DOI: 10.1016/s0074-7696(08)62487-0. View

14.

Guo S, Han F, Zhu W . CD39 - A bright target for cancer immunotherapy. Biomed Pharmacother. 2022; 151:113066. DOI: 10.1016/j.biopha.2022.113066. View

15.

Shi L, Feng M, Du S, Wei X, Song H, Yixin X . Adenosine Generated by Regulatory T Cells Induces CD8 T Cell Exhaustion in Gastric Cancer through A2aR Pathway. Biomed Res Int. 2020; 2019:4093214. PMC: 6942766. DOI: 10.1155/2019/4093214. View

16.

Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R . Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood. 2007; 110(4):1225-32. DOI: 10.1182/blood-2006-12-064527. View

17.

Ballerini P, Dovizio M, Bruno A, Tacconelli S, Patrignani P . P2Y Receptors in Tumorigenesis and Metastasis. Front Pharmacol. 2018; 9:66. PMC: 5801576. DOI: 10.3389/fphar.2018.00066. View

18.

Deaglio S, Dwyer K, Gao W, Friedman D, Usheva A, Erat A . Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med. 2007; 204(6):1257-65. PMC: 2118603. DOI: 10.1084/jem.20062512. View

19.

Huang B, Zhao J, Li H, He K, Chen Y, Chen S . Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res. 2005; 65(12):5009-14. DOI: 10.1158/0008-5472.CAN-05-0784. View

20.

Jackson S, Hoshi T, Wu Y, Sun X, Enjyoji K, Cszimadia E . Disordered purinergic signaling inhibits pathological angiogenesis in cd39/Entpd1-null mice. Am J Pathol. 2007; 171(4):1395-404. PMC: 1988887. DOI: 10.2353/ajpath.2007.070190. View