Brain tumor microvesicles: insights into intercellular communication in the nervous system

Abstract

Brain tumors are heterogeneous tumors composed of differentiated tumor cells that resemble various neural cells and a small number of multipotent cancer stem cells. These tumors modify normal cells in their environment to promote tumor growth, invasion and metastases by various ways. Recent publications show that glioblastoma cells release microvesicles that contain a select subset of cellular proteins and RNAs. These microvesicles are avidly taken up by normal cells in cell culture and can change the translational profile of these cells through delivery of tumor-derived mRNAs, which are translated into functional proteins. In addition to mRNA and proteins, microvesicles have been shown to contain microRNAs, non-coding RNAs and DNA. This commentary explores the recent advances in this novel intercellular communication route and discusses the potential physiological role of microvesicles in brain tumorigenesis.

Fig. 1

Monitoring MVs. a Scanning transmission electron micrograph of primary human GBM cell (bar 10 μm) (Skog et al. 2008), b Nanosight microscope (Nanosight Ltd.), c Serum MVs diluted 1/5000 and visualized using the Nanosight Tracking Analysis, d Histogram showing distribution of MV diameter in serum sample

Fig. 2

MV-mediated intercellular communication. Components of donor cells are incorporated into MVs which contain proteins (e.g., signaling proteins, transcriptional regulators, RT, and transmembrane proteins), RNAs (i.e., mRNAs, miRNAs, and ncRNAs), and DNA (i.e., cDNA and genomic DNA). MVs can be taken up by recipient cells through endocytosis and release their contents after fusing with the endosomal membrane, or fusion at the plasma membrane. 1 Transmembrane proteins can be transferred to the plasma membrane and trigger signaling. 2 Transcriptional regulators can potentially be transferred into the nucleus and regulate promoter activity. 3 mRNAs/miRNAs can be transferred and influence the translational profile. 4 Donor cell-derived cDNAs, e.g., c-Myc can be delivered directly within MVs. 5 or generated from reverse-transcribed mRNAs in the cell of origin, within MVs or possibly in the recipient cell. 6 Retrotransposon and other DNA elements from MVs may integrate into the recipient cell genome. In one scenario, the donor cell is a tumor cell and the recipient cells are normal cells in the microenvironment. These MV delivery events have the potential to change the phenotype of normal cells to make them more supportive of tumor growth (figure modified from Dr. Charles Lai; produced using Servier Medical Art, http://www.servier.com)

Fig. 3

Multicellular organisms have high levels of non-coding DNA sequences. The ratio of ncDNA to total genomic DNA (ncDNA/tgDNA) increases with the biological complexity of organisms. prokaryotes, unicellular eukaryotes, the multicellular fungus Neurospora crassa, plants, non-chordate invertebrates (nematodes, insects), Ciona intestinalis (urochordate), vertebrates. (Reproduced with permission from Taft and Mattick 2003)