Review article
Patterns and functional implications of platelets upon tumor “education”

https://doi.org/10.1016/j.biocel.2017.07.018Get rights and content

Highlights

  • •

    Platelets play important roles in carcinogenesis, tumor metastasis and tumor therapy. Tumor cells “educate” or activate platelets in different manners.

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    Molecular and functional alterations of platelets upon tumor “education” need further elucidate.

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    The omics approaches in mapping profiles of platelets are perspective.

Abstract

While platelets are traditionally recognized to play a predominant role in hemostasis and thrombosis, increasing evidence verifies its involvement in malignancies. As a component of the tumor microenvironment, platelets influence carcinogenesis, tumor metastasis and chemotherapy efficiency. Platelets status is thus predictable as a hematological biomarker of cancer prognosis and a hot target for therapeutic intervention. On the other hand, the role of circulating tumor cells (CTCs) as an inducer of platelet activation and aggregation has been well acknowledged. The cross-talk between platelets and CTCs is reciprocal on that the CTCs activate platelets while platelets contribute to CTCs’ survival and dissemination. This review covers some of the current issues related to the loop between platelets and tumor aggression, including the manners of tumor cells in “educating” platelets and biofunctional alterations of platelets upon tumor “education”. We also highlight the potential clinical applications on the interplay between tumors and platelets. Further studies with well-designed prospective multicenter trials may contribute to clinical “liquid biopsy” diagnosis by evaluating the global changes of platelets.

Section snippets

Platelet physiology and bioactivity

Platelets are enucleated, disc-shaped cells with the diameter ranging 2.0–5.0 mm (White and Clawson, 1980), playing critical roles in hemostasis and thrombosis. Hemostasis is the most important physiological function of platelets, which halts bleeding after injury of blood vessels by the presence of platelet surface receptors, negatively charged cell surface, and interactions with coagulation factors (Bevers et al., 1983).

Beyond the roles in regulating hemostasis and coagulation, multiple

Platelets and cancer

It has been appreciated that, as a component of the tumor microenvironment, platelets can regulate carcinogenesis, tumor growth, tumor angiogenesis, tumor-related inflammation and tumor metastasis. Alteration of platelet numbers and functions has increasingly gained attention on cancer prevention, chemotherapy development and survival prolongation. For example, the platelet lymphocyte ratio (PLR) has been demonstrated to be invaluable in predicting cancer prognosis in the past decades (Nikolić

The ways of tumor cells “educating” platelets

The activation of platelets by tumor cells can be achieved by direct and indirect manners (Fig. 1). Direct manner indicates the straightforward contact between molecules on the membrane surface of platelets and circulating tumor cells (CTCs) (Falanga and Rickles, 1999). And here we refer “indirect” as the non-cellular contact between tumor cells and platelets.

The changes of platelets upon tumor “education”

The interactions between CTCs and platelets are reciprocal, with complicated network involved in this loop. The significant contribution of platelets to CTCs survival and tumor metastasis is nowadays well-acknowledged. However, the molecular and biochemical adaptions of platelets upon tumor “education” need to be further elucidated, which can hopefully give rise to novel therapies in cancer treatment. In the followed section, we will discuss the molecular and function changes of platelets in

Clinical applications of tumor-platelets axis

Studies on tumor-platelets axis would be helpful in tumor diagnosis, prognosis evaluation and novel anti-tumor therapy development. Due to the noninvasive advantages, “liquid biopsy” is becoming a hot topic on early diagnosis and following-up of malignancies, with platelets as one of the most studied plasma cell types. As discussed above, the tumor status can be implicated by many aspects of platelets including numerical changes, hypercoagulation activity and molecular changes. Even TCIPA is

Unanswered questions about tumor “educated” platelets

There are still several fundamental aspects to be addressed before fully illuminating tumor-platelets axis: How about the global RNA and protein changes in tumor “educated” platelets? Is the proteome and transcriptome data consistent since the platelets are anuclear? What’s the connections between multiple platelets proteins and their interplay roles in cancer? What’s the systematic platelets changes and functions in various anti-tumor therapy?

With discovery of the associations between

Conclusions

Circulating tumor cells can educate platelets by directly cell–cell interaction or indirectly via signaling molecules. Tumor cell education triggers various platelet signaling processes, such as mRNA splicing, protein expression, endocytosis and exocytosis, resulting in changes of gene and protein profiles in platelets. Investigating tumor-platelets axis is not only helpful for cancer diagnostics, but also invaluable on identifying novel drug targets.

Funding

This work was supported by the National Natural Science Foundation of China [NO. 81570078]; the Natural Science Foundation of Jiangsu Province [NO. BK20161386]; the Program of Nanjing Science and Technology of Nanjing Science and Technology Committee [No. 201605059]; and the Project of Invigorating Health Care through Science Technology and Education [Jiangsu Provincial Medical Youth Talent No. QNRC2016125].

Authors' contributions

Q. Z., P. Z. and J. Z. revised the manuscript.

T.L. and Y.S. reviewed and edited the manuscript.

All authors read and approved the final manuscript.

Acknowledgement

Thanking Bob Löwenberg for critically reading the manuscript.

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    These authors wrote the manuscript and contributed equally to this review.

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