title: Intercellular transfer of transferrin receptor by a contact-, Rab8-dependent mechanism involving tunneling nanotubes.
abstract: Intercellular communication between cancer cells, especially between cancer and stromal cells, plays an important role in disease progression. We examined the intercellular transfer of organelles and proteins in vitro and in vivo and the role of tunneling nanotubes (TNTs) in this process. TNTs are membrane bridges that facilitate intercellular transfer of organelles of unclear origin. Using 3-dimensional quantitative and qualitative confocal microscopy, we showed that TNTs contain green fluorescent protein (GFP)-early endosome antigen (EEA) 1, GFP Rab5, GFP Rab11, GFP Rab8, transferrin (Tf), and Tf receptor (Tf-R) fused to mCherry (Tf-RmCherry). Tf-RmCherry was transferred between cancer cells by a contact-dependent but secretion-independent mechanism. Live cell imaging showed TNT formation preceding the transfer of Tf-RmCherry and involving the function of the small guanosine triphosphatase (GTPase) Rab8, which colocalized with Tf-RmCherry in the TNTs and was cotransferred to acceptor cells. Tf-RmCherry was transferred from cancer cells to fibroblasts, a noteworthy finding that suggests that this process occurs between tumor and stromal cells in vivo. We strengthened this hypothesis in a xenograft model of breast cancer using enhanced (e)GFP-expressing mice. Tf-RmCherry transferred from tumor to stromal cells and this process correlated with an increased opposite transfer of eGFP from stromal to tumor cells, together pointing toward complex intercellular communication at the tumor site.
authors.affiliation: *Department of Biomedicine, Biomaterials, Department of Clinical Dentistry, and K. G. Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway; Department of Pathology and Department of Clinical Medicine, Haukeland University Hospital, Bergen, Norway; and NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg a.p.burtey@ibv.uio.no.
authors.forename: Anne
authors.initials: A
authors.lastname: Burtey
authors.affiliation: *Department of Biomedicine, Biomaterials, Department of Clinical Dentistry, and K. G. Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway; Department of Pathology and Department of Clinical Medicine, Haukeland University Hospital, Bergen, Norway; and NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg.
authors.forename: Marek
authors.initials: M
authors.lastname: Wagner
authors.affiliation: *Department of Biomedicine, Biomaterials, Department of Clinical Dentistry, and K. G. Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway; Department of Pathology and Department of Clinical Medicine, Haukeland University Hospital, Bergen, Norway; and NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg.
authors.forename: Erlend
authors.initials: E
authors.lastname: Hodneland
authors.affiliation: *Department of Biomedicine, Biomaterials, Department of Clinical Dentistry, and K. G. Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway; Department of Pathology and Department of Clinical Medicine, Haukeland University Hospital, Bergen, Norway; and NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg.
authors.forename: Kai Ove
authors.initials: KO
authors.lastname: Skaftnesmo
authors.affiliation: *Department of Biomedicine, Biomaterials, Department of Clinical Dentistry, and K. G. Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway; Department of Pathology and Department of Clinical Medicine, Haukeland University Hospital, Bergen, Norway; and NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg.
authors.forename: Julia
authors.initials: J
authors.lastname: Schoelermann
authors.affiliation: *Department of Biomedicine, Biomaterials, Department of Clinical Dentistry, and K. G. Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway; Department of Pathology and Department of Clinical Medicine, Haukeland University Hospital, Bergen, Norway; and NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg.
authors.forename: Ivan Rios
authors.initials: IR
authors.lastname: Mondragon
authors.affiliation: *Department of Biomedicine, Biomaterials, Department of Clinical Dentistry, and K. G. Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway; Department of Pathology and Department of Clinical Medicine, Haukeland University Hospital, Bergen, Norway; and NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg.
authors.forename: Heidi
authors.initials: H
authors.lastname: Espedal
authors.affiliation: *Department of Biomedicine, Biomaterials, Department of Clinical Dentistry, and K. G. Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway; Department of Pathology and Department of Clinical Medicine, Haukeland University Hospital, Bergen, Norway; and NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg.
authors.forename: Anna
authors.initials: A
authors.lastname: Golebiewska
authors.affiliation: *Department of Biomedicine, Biomaterials, Department of Clinical Dentistry, and K. G. Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway; Department of Pathology and Department of Clinical Medicine, Haukeland University Hospital, Bergen, Norway; and NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg.
authors.forename: Simone P
authors.initials: SP
authors.lastname: Niclou
authors.affiliation: *Department of Biomedicine, Biomaterials, Department of Clinical Dentistry, and K. G. Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway; Department of Pathology and Department of Clinical Medicine, Haukeland University Hospital, Bergen, Norway; and NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg.
authors.forename: Rolf
authors.initials: R
authors.lastname: Bjerkvig
authors.affiliation: *Department of Biomedicine, Biomaterials, Department of Clinical Dentistry, and K. G. Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway; Department of Pathology and Department of Clinical Medicine, Haukeland University Hospital, Bergen, Norway; and NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg.
authors.forename: Tanja
authors.initials: T
authors.lastname: Kögel
authors.affiliation: *Department of Biomedicine, Biomaterials, Department of Clinical Dentistry, and K. G. Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway; Department of Pathology and Department of Clinical Medicine, Haukeland University Hospital, Bergen, Norway; and NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg.
authors.forename: Hans-Hermann
authors.initials: HH
authors.lastname: Gerdes
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D064593:Heterografts; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D021381:Protein Transport / Q000235:genetics; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; D011990:Receptors, Transferrin; D049452:Green Fluorescent Proteins; C082377:RAB8A protein, human; D020691:rab GTP-Binding Proteins
keywords: cell–cell communication; endosomes; organelle exchange; tumor microenvironment