Tumor educated platelet: the novel BioSource for cancer detection

Abstract

Platelets, involved in the whole process of tumorigenesis and development, constantly absorb and enrich tumor-specific substances in the circulation during their life span, thus called "Tumor Educated Platelets" (TEPs). The alterations of platelet mRNA profiles have been identified as tumor markers due to the regulatory mechanism of post-transcriptional splicing. Small nuclear RNAs (SnRNAs), the important spliceosome components in platelets, dominate platelet RNA splicing and regulate the splicing intensity of pre-mRNA. Endogenous variation at the snRNA levels leads to widespread differences in alternative splicing, thereby driving the development and progression of neoplastic diseases. This review systematically expounds the bidirectional tumor-platelets interactions, especially the tumor induced alternative splicing in TEP, and further explores whether molecules related to alternative splicing such as snRNAs can serve as novel biomarkers for cancer diagnostics.

Keywords: Small nuclear RNA; Tumor biomarker; Tumor educated platelet.

Fig. 1

The crosstalk between cancer and platelets. Tumor educates platelets: tumor can induce platelet activation, aggregation, and release of platelet-derived substances in circulation, and promote thrombocytosis via influencing megakaryopoiesis in bone marrow; Platelets support tumor growth and metastasis: platelets stimulate tumor angiogenesis and vascular remodeling, protect CTCs from shear forces and evade immune surveillance, and recruit stromal cells to facilitate the establishment of metastatic niches and promote the metastasis (MKP: megakaryocyte progenitor; MK: megakaryocyte; HSC: Hematopoietic stem cells)

Fig. 2

Structure basis of tumor-platelet interaction and molecular mechanisms of TCIPA. Direct surface receptor binding and extracellular protein-mediated receptor bridging are the structure basis of tumor-platelet interactions (left); The interactions trigger platelet activation and degranulation, in turn aggregation (TCIPA) dependent on GPIIb-IIIa and fibrin network (right)

Fig. 3

Mechanisms of cancer-associated thrombocytosis. Primary tumor cells secret TPO, or IL-6 which can accelerate TPO production in the liver. TPO can stimulate differentiation, proliferation and maturation of megakaryocytes in the bone marrow, as well as platelet production (TPO: thrombopoietin; IL-6: interleukin-6; MKP: megakaryocyte progenitor; MK: megakaryocyte)

Fig. 4

Platelets exploit a functional spliceosome for pre-mRNA splicing. Megakaryocytes sort distinctive RNA molecules into proplatelets during thrombopoiesis. Pre-mRNAs contain exons and introns and are processed by U snRNPs that make up the spliceosome. Platelet spliceosomes alternatively excise introns from pre-mRNA, yielding a mature message that is translated into protein