title: Barriers to horizontal cell transformation by extracellular vesicles containing oncogenic H-ras.
abstract: Extracellular vesicles (EVs) enable the exit of regulatory, mutant and oncogenic macromolecules (proteins, RNA and DNA) from their parental tumor cells and uptake of this material by unrelated cellular populations. Among the resulting biological effects of interest is the notion that cancer-derived EVs may mediate horizontal transformation of normal cells through transfer of mutant genes, including mutant ras. Here, we report that H-ras-mediated transformation of intestinal epithelial cells (IEC-18) results in the emission of exosome-like EVs containing genomic DNA, HRAS oncoprotein and transcript. However, EV-mediated horizontal transformation of non-transformed cells (epithelial, astrocytic, fibroblastic and endothelial) is transient, limited or absent due to barrier mechanisms that curtail the uptake, retention and function of oncogenic H-ras in recipient cells. Thus, epithelial cells and astrocytes are resistant to EV uptake, unless they undergo malignant transformation. In contrast, primary and immortalized fibroblasts are susceptible to the EV uptake, retention of H-ras DNA and phenotypic transformation, but these effects are transient and fail to produce a permanent tumorigenic conversion of these cells in vitro and in vivo, even after several months of observation. Increased exposure to EVs isolated from H-ras-transformed cancer cells, but not to those from their indolent counterparts, triggers demise of recipient fibroblasts. Uptake of H-ras-containing EVs stimulates but fails to transform primary endothelial cells. Thus, we suggest that intercellular transfer of oncogenes exerts regulatory rather than transforming influence on recipient cells, while cancer cells may often act as preferential EV recipients.
authors.affiliation: Research Institute of the McGill University Health Centre, Glen Site, McGill University, QC, H4A 3J1 Canada.
authors.forename: Tae Hoon
authors.initials: TH
authors.lastname: Lee
authors.affiliation: Research Institute of the McGill University Health Centre, Glen Site, McGill University, QC, H4A 3J1 Canada.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Chennakrishnaiah
authors.affiliation: Research Institute of the McGill University Health Centre, Glen Site, McGill University, QC, H4A 3J1 Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Meehan
authors.affiliation: Research Institute of the McGill University Health Centre, Glen Site, McGill University, QC, H4A 3J1 Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: Montermini
authors.affiliation: Research Institute of the McGill University Health Centre, Glen Site, McGill University, QC, H4A 3J1 Canada.
authors.forename: Delphine
authors.initials: D
authors.lastname: Garnier
authors.affiliation: Research Institute of the McGill University Health Centre, Glen Site, McGill University, QC, H4A 3J1 Canada.
authors.forename: Esterina
authors.initials: E
authors.lastname: D'Asti
authors.affiliation: Research Institute of the McGill University Health Centre, Glen Site, McGill University, QC, H4A 3J1 Canada.
authors.forename: Wenyang
authors.initials: W
authors.lastname: Hou
authors.affiliation: Research Institute of the McGill University Health Centre, Glen Site, McGill University, QC, H4A 3J1 Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Magnus
authors.affiliation: Research Institute of the McGill University Health Centre, Glen Site, McGill University, QC, H4A 3J1 Canada.
authors.forename: Tenzin
authors.initials: T
authors.lastname: Gayden
authors.affiliation: Research Institute of the McGill University Health Centre, Glen Site, McGill University, QC, H4A 3J1 Canada.
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.affiliation: Research Institute of the McGill University Health Centre, Glen Site, McGill University, QC, H4A 3J1 Canada.
authors.forename: Kolja
authors.initials: K
authors.lastname: Eppert
authors.affiliation: Research Institute of the McGill University Health Centre, Glen Site, McGill University, QC, H4A 3J1 Canada.
authors.forename: Loydie
authors.initials: L
authors.lastname: Majewska
authors.affiliation: Research Institute of the McGill University Health Centre, Glen Site, McGill University, QC, H4A 3J1 Canada.
authors.forename: Janusz
authors.initials: J
authors.lastname: Rak
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000502:physiology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D000067128:Extracellular Vesicles / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D064593:Heterografts; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*
chemical_list: C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: exosomes; extracellular vesicles; horizontal transformation; oncogenes; ras