title: Immune-dependent and independent antitumor activity of GM-CSF aberrantly expressed by mouse and human colorectal tumors.
abstract: Granulocyte-macrophage colony-stimulating factor (GM-CSF/CSF2) is a cytokine produced in the hematologic compartment that may enhance antitumor immune responses, mainly by activation of dendritic cells. Here, we show that more than one-third of human colorectal tumors exhibit aberrant DNA demethylation of the GM-CSF promoter and overexpress the cytokine. Mouse engraftment experiments with autologous and homologous colon tumors engineered to repress the ectopic secretion of GM-CSF revealed the tumor-secreted GM-CSF to have an immune-associated antitumor effect. Unexpectedly, an immune-independent antitumor effect was observed that depended on the ectopic expression of GM-CSF receptor subunits by tumors. Cancer cells expressing GM-CSF and its receptor did not develop into tumors when autografted into immunocompetent mice. Similarly, 100% of the patients with human colon tumors that overexpressed GM-CSF and its receptor subunits survived at least 5 years after diagnosis. These data suggest that expression of GM-CSF and its receptor subunits by colon tumors may be a useful marker for prognosis as well as for patient stratification in cancer immunotherapy.
authors.affiliation: Cancer Epigenetics Laboratory, HUCA, Institute of Oncology of Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain
authors.forename: Rocio G
authors.initials: RG
authors.lastname: Urdinguio
authors.forename: Agustin F
authors.initials: AF
authors.lastname: Fernandez
authors.forename: Angela
authors.initials: A
authors.lastname: Moncada-Pazos
authors.forename: Covadonga
authors.initials: C
authors.lastname: Huidobro
authors.forename: Ramon M
authors.initials: RM
authors.lastname: Rodriguez
authors.forename: Cecilia
authors.initials: C
authors.lastname: Ferrero
authors.forename: Pablo
authors.initials: P
authors.lastname: Martinez-Camblor
authors.forename: Alvaro J
authors.initials: AJ
authors.lastname: Obaya
authors.forename: Teresa
authors.initials: T
authors.lastname: Bernal
authors.forename: Adolfo
authors.initials: A
authors.lastname: Parra-Blanco
authors.forename: Luis
authors.initials: L
authors.lastname: Rodrigo
authors.forename: Maria
authors.initials: M
authors.lastname: Santacana
authors.forename: Xavier
authors.initials: X
authors.lastname: Matias-Guiu
authors.forename: Beatriz
authors.initials: B
authors.lastname: Soldevilla
authors.forename: Gemma
authors.initials: G
authors.lastname: Dominguez
authors.forename: Felix
authors.initials: F
authors.lastname: Bonilla
authors.forename: Santiago
authors.initials: S
authors.lastname: Cal
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopez-Otin
authors.forename: Mario F
authors.initials: MF
authors.lastname: Fraga
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019175:DNA Methylation; D004797:Enzyme-Linked Immunosorbent Assay; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D011379:Prognosis; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D046888:Tissue Array Analysis; D014162:Transfection
chemical_list: D014408:Biomarkers, Tumor; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor