title: Microvesicle Cargo and Function Changes upon Induction of Cellular Transformation.
abstract: Extracellular vesicles (EVs), including exosomes and microvesicles (MVs), have emerged as a major form of intercellular communication, playing important roles in several physiological processes and diseases, including cancer. EVs generated by cancer cells contain a variety of proteins and RNA species that can be transferred between cancer cells as well as between cancer and non-transformed (normal) cells, thereby impacting a number of aspects of cancer progression. Here we show how oncogenic transformation influences the biogenesis and function of EVs using a mouse embryonic fibroblast (MEF) cell line that can be induced to express an oncogenic form of diffuse B cell lymphoma (Dbl). Although MEFs induced to express onco-Dbl generated a similar amount of MVs as uninduced control cells, we found that MVs isolated from onco-Dbl-transformed cells contain a unique signaling protein, the ubiquitously expressed non-receptor tyrosine kinase focal adhesion kinase. The addition of MVs isolated from MEFs expressing onco-Dbl to cultures of fibroblasts strongly promoted their survival and induced their ability to grow under anchorage-independent conditions, outcomes that could be reversed by knocking down focal adhesion kinase and depleting it from the MVs or by inhibiting its kinase activity using a specific inhibitor. We then showed the same to be true for MVs isolated from aggressive MDAMB231 breast cancer cells. Together, these findings demonstrate that the induction of oncogenic transformation gives rise to MVs, which uniquely contain a signaling protein kinase that helps propagate the transformed phenotype and thus may offer a specific diagnostic marker of malignant disease.
authors.affiliation: From the Departments of Molecular Medicine and.
authors.forename: Bridget T
authors.initials: BT
authors.lastname: Kreger
authors.affiliation: From the Departments of Molecular Medicine and.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Dougherty
authors.affiliation: From the Departments of Molecular Medicine and.
authors.forename: Kai Su
authors.initials: KS
authors.lastname: Greene
authors.affiliation: From the Departments of Molecular Medicine and Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853 rac1@cornell.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Cerione
authors.affiliation: From the Departments of Molecular Medicine and.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Antonyak
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D055252:Cell-Derived Microparticles / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000378:metabolism; D055354:Exosomes / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C057811:MCF2 protein, human; C512843:Mcf2 protein, mouse; D011518:Proto-Oncogene Proteins
keywords: PTK2 protein tyrosine kinase 2 (PTK2); cell signaling; exosome (vesicle); extracellular vesicles; focal adhesion kinase (FAK); intercellular communication; microparticles; microvesicles; transformation