Cancer cell-derived microvesicles induce transformation by transferring tissue transglutaminase and fibronectin to recipient cells

Abstract

Tumor progression involves the ability of cancer cells to communicate with each other and with neighboring normal cells in their microenvironment. Microvesicles (MV) derived from human cancer cells have received a good deal of attention because of their ability to participate in the horizontal transfer of signaling proteins between cancer cells and to contribute to their invasive activity. Here we show that MV may play another important role in oncogenesis. In particular, we demonstrate that MV shed by two different human cancer cells, MDAMB231 breast carcinoma cells and U87 glioma cells, are capable of conferring onto normal fibroblasts and epithelial cells the transformed characteristics of cancer cells (e.g., anchorage-independent growth and enhanced survival capability) and that this effect requires the transfer of the protein cross-linking enzyme tissue transglutaminase (tTG). We further demonstrate that tTG is not sufficient to transform fibroblasts but rather that it must collaborate with another protein to mediate the transforming actions of the cancer cell-derived MV. Proteomic analyses of the MV derived from MDAMB231 and U87 cells indicated that both these vesicle preparations contained the tTG-binding partner and cross-inking substrate fibronectin (FN). Moreover, we found that tTG cross-links FN in MV from cancer cells and that the ensuing MV-mediated transfers of cross-linked FN and tTG to recipient fibroblasts function cooperatively to activate mitogenic signaling activities and to induce their transformation. These findings highlight a role for MV in the induction of cellular transformation and identify tTG and FN as essential participants in this process.

Silencing of human papillomavirus (HPV) E6/E7 oncogene expression affects both the contents and the amounts of extracellular microvesicles released from HPV‐positive cancer cells

“…Exosomes are thus believed to have the potential to serve as shuttles for intercellular communication. 8,31 This may be highly relevant for carcinogenesis, and reported effects for tumor cell-derived exosomes range from inhibition of antitumor immune response 9,45 to the horizontal transfer of oncogenic factors, 11,15,50,51 induction of angiogenesis 11,48 and promotion of premetastatic niche formation. 52 Although these observations are potentially extremely important, one must be aware that most studies performed thus far used concentrated exosome preparations, and it is not clear how these experimental …”

Microvesicles secreted from human multiple myeloma cells promote angiogenesis

“…Although these classical events have been commonly thought of as the predominant modes of cell-to-cell communication, a novel type of vesicle secretion has recently received a great deal of attention [8,9,15,33] . Though the secretion of exosomes by myeloma [21,34] , there have been no previous studies about MM-MVs.…”

“…MVs can reach the local target cells but can also travel over long dis tances [12,13] . A large number of studies have reported that tumor cellderived MVs (TMVs) reflect the special potential of tumor cells for the expansion of the tumor, independently from cell to cell contact [14,15] . Recently, a growing body of evidence suggests that TMVs contain a selective enrichment of a discrete set of cellular molecules that can be transferred into the target cells [16][17][18][19] .…”

Glycosylated extracellular vesicles released by glioblastoma cells are decorated by CCL18 allowing for cellular uptake via chemokine receptor CCR8

“…GBM is the most common primary malignant tumour of the central nervous system in adults and known to release large amounts of EVs [10,35,36]. Affected patients have an extremely poor prognosis with a median survival of only 15 months following treatment [37].…”