title: RB mutation and RAS overexpression induce resistance to NK cell-mediated cytotoxicity in glioma cells.
abstract: Several theories aim to explain the malignant transformation of cells, including the mutation of tumor suppressors and proto-oncogenes. Deletion of Rb (a tumor suppressor), overexpression of mutated Ras (a proto-oncogene), or both, are sufficient for in vitro gliomagenesis, and these genetic traits are associated with their proliferative capacity. An emerging hallmark of cancer is the ability of tumor cells to evade the immune system. Whether specific mutations are related with this, remains to be analyzed. To address this issue, three transformed glioma cell lines were obtained (Rb(-/-), Ras(V12), and Rb(-/-)/Ras(V12)) by in vitro retroviral transformation of astrocytes, as previously reported. In addition, Ras(V12) and Rb(-/-)/Ras(V12) transformed cells were injected into SCID mice and after tumor growth two stable glioma cell lines were derived. All these cells were characterized in terms of Rb and Ras gene expression, morphology, proliferative capacity, expression of MHC I, Rae1δ, and Rae1αβγδε, mult1, H60a, H60b, H60c, as ligands for NK cell receptors, and their susceptibility to NK cell-mediated cytotoxicity. Our results show that transformation of astrocytes (Rb loss, Ras overexpression, or both) induced phenotypical and functional changes associated with resistance to NK cell-mediated cytotoxicity. Moreover, the transfer of cell lines of transformed astrocytes into SCID mice increased resistance to NK cell-mediated cytotoxicity, thus suggesting that specific changes in a tumor suppressor (Rb) and a proto-oncogene (Ras) are enough to confer resistance to NK cell-mediated cytotoxicity in glioma cells and therefore provide some insight into the ability of tumor cells to evade immune responses.
authors.affiliation: Laboratorio de inmunorregulación, Escuela Nacional de Ciencias Biologicas, Instituto Politecnico Nacional, Mexico, DF Mexico ; Molecular Oncology Laboratory MOL, CIMUS; IDIS Departamento de Fisioloxia, Universidade de Santiago de Compostela, Av de Barcelona s/n 15782, Santiago de Compostela, Spain ; Neuroimmunology and Neuro-Oncology Unit, Instituto Nacional de Neurología y Neurocirugía, Insurgentes sur 3877, 14269 Mexico City, Mexico.
authors.forename: Mario
authors.initials: M
authors.lastname: Orozco-Morales
authors.affiliation: Laboratorio de inmunorregulación, Escuela Nacional de Ciencias Biologicas, Instituto Politecnico Nacional, Mexico, DF Mexico.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Sánchez-García
authors.affiliation: Molecular Oncology Laboratory MOL, CIMUS; IDIS Departamento de Fisioloxia, Universidade de Santiago de Compostela, Av de Barcelona s/n 15782, Santiago de Compostela, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Golán-Cancela
authors.affiliation: Neuroimmunology and Neuro-Oncology Unit, Instituto Nacional de Neurología y Neurocirugía, Insurgentes sur 3877, 14269 Mexico City, Mexico.
authors.forename: Norma
authors.initials: N
authors.lastname: Hernández-Pedro
authors.affiliation: Molecular Oncology Laboratory MOL, CIMUS; IDIS Departamento de Fisioloxia, Universidade de Santiago de Compostela, Av de Barcelona s/n 15782, Santiago de Compostela, Spain.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Costoya
authors.affiliation: Neurochemistry Unit, Instituto Nacional de Neurología y Neurocirugía, Mexico, DF Mexico.
authors.forename: Verónica Pérez
authors.initials: VP
authors.lastname: de la Cruz
authors.affiliation: Neuroradiosurgery, Instituto Nacional de Neurología y Neurocirugía, Mexico, DF Mexico.
authors.forename: Sergio
authors.initials: S
authors.lastname: Moreno-Jiménez
authors.affiliation: Neuroimmunology and Neuro-Oncology Unit, Instituto Nacional de Neurología y Neurocirugía, Insurgentes sur 3877, 14269 Mexico City, Mexico.
authors.forename: Julio
authors.initials: J
authors.lastname: Sotelo
authors.affiliation: Neuroimmunology and Neuro-Oncology Unit, Instituto Nacional de Neurología y Neurocirugía, Insurgentes sur 3877, 14269 Mexico City, Mexico.
authors.forename: Benjamín
authors.initials: B
authors.lastname: Pineda
keywords: Glioblastoma; Immune evasion; Natural Killer cells; Ras; Rb; Tumorigenesis