Significant Downregulation of Platelet Gene Expression in Metastatic Lung Cancer

Abstract

IntroductionPlatelets arise as cytoplasmic fragments from megakaryocytes in the bone marrow. Thus they are anucleate, but retain megakaryocyte-derived cytoplasmic pre-mRNA, at least some of which is spliced into mRNA and translated into protein in response to external stimulation through surface receptor activation and outside-in signaling. [1][2][3] Previously unrecognized synthetic capabilities of platelets have recently emerged and the profi le of proteins released by activated platelets (the "secretome") has been well characterized. 4Prior studies have shown that the platelet transcriptome correlates well with platelet proteomic data, demonstrating that transcriptional analysis is relevant to the study of platelet biology, and can likely provide insights into platelet function and the mechanisms of platelet disorders. In one study, platelet proteomic data correlated well with the transcriptome, with 69% of secreted proteins detectable at the mRNA level.5 Using microarray analysis, Gnatenko et al reported that approximately 2,000 transcripts (13-17% of probed genes) are present in unstimulated platelets and concluded that evaluating the platelet transcriptome will be useful for identifying proteins that regulate normal and pathologic platelet functions. 6Platelets play a major role in the metastatic dissemination of tumor cells in vivo .7-10 Because of the leaky vasculature of angiogenic tumors, platelets are in contact with tumor cells and are therefore able to secrete multiple factors upon activation. 11Numerous tumor cell lines (e.g. MDA-MB-231 breast cancer cells) interact with platelets and stimulate platelet aggregation in vitro . 12Th e requirement of platelets for murine lung metastasis to occur has been long recognized and antibody-induced thrombocytopenia has been shown to markedly reduce the number and volume of metastasis associated with Lewis lung carcinoma, CT26 colon adenocarcinoma, and B16 amelanotic melanoma. 13Platelets facilitate metastasis through multiple mechanisms. [11][12][13][14][15] Tumor cell survival in the circulation is helped when they nest within platelet aggregates-this shields them from natural killer cell-mediated cell death and the eff ects of vascular shear stress. Platelets facilitate adhesion of blood-borne cancer cells to endothelium through selectins, along with transmigration at metastatic sites where they also enhance angiogenesis and release growth factors such as PDGF that have been shown to act as a mitogenic stimulus. While these observations are well accepted, the detailed mechanisms behind them remains uncertain. 16In this study, we sought to identify the relationship between platelet gene expression and lung cancer metastasis and surprisingly found near universal downregulated expression of the 200 genes with the most altered expression. Th ese genetic fi ndings further support the long-held view that platelet function is signifi cantly altered in the presence of cancer metastasis and that screening employing the tools outlined here may form the basis of an ef...

Regulation of the genetic code in megakaryocytes and platelets

“…Body mass index and circulating levels of C‐reactive protein and interleukin‐6 are also associated with changes in platelet gene expression , and there are many other published lines of evidence consistent with the supposition that human diseases are associated with changes in the genetic code of platelets . While an in‐depth discussion of these established and emerging findings is beyond the scope of the current brief review, the reader is encouraged to keep an eye on this rapidly evolving area of investigation.…”

“…These findings also support the hypothesis that in SLE patients, circulating IFNa production by plasmacytoid dendritic cells may alter the genetic code of megakaryocytes within the bone marrow niche, leading to the production of platelets enriched for IFN-regulated proteins. Body mass index and circulating levels of C-reactive protein and interleukin-6 are also associated with changes in platelet gene expression [40,41], and there are many other published lines of evidence consistent with the supposition that human diseases are associated with changes in the genetic code of platelets [30,[42][43][44][45]. While an indepth discussion of these established and emerging findings is beyond the scope of the current brief review, the reader is encouraged to keep an eye on this rapidly evolving area of investigation.…”

Blood platelets contain tumor-derived RNA biomarkers

“…26 It was recently shown that megakaryocytes selectively transport mRNAs into platelets, allowing only a subset of RNAs to be transferred into platelets, 27 and Calverly et al identified a subset of megakaryocyte/platelet-derived mRNAs that are differentially expressed in lung cancer metastasis. 28 However, any role of tumorderived RNA in platelet biology and cancer remains to be investigated, and it remains unclear to what extent the transferred tumor-derived RNA can be functionally translated into proteins, thereby manipulating platelet function, as previously shown to occur in endothelial cells after uptake of tumor-derived microvesicles. 12 A recent study demonstrated miR-28 to be deregulated in platelets of cancer patients.…”

Platelet RNA as a circulating biomarker trove for cancer diagnostics

“…Previous studies have identified diagnostic platelet RNA signatures for cardiovascular abnormalities , inflammatory conditions , sickle cell disease , essential thrombocytosis , and cancer . In 2010, Calverley et al .…”

“…In 2010, Calverley et al . used micro‐array analysis to profile the platelet mRNA of seven healthy individuals and five patients with metastatic lung cancer . The platelet samples of the patients with lung cancer were collected prior to any treatment, and 200 altered RNAs were discovered between the healthy individuals and the patients with lung cancer, of which 197 genes (99%) were decreased in platelets of patients with lung cancer.…”