title: Higher metastatic efficiency of KRas G12V than KRas G13D in a colorectal cancer model.
abstract: Although all KRas (protein that in humans is encoded by the KRas gene) point mutants are considered to have a similar prognostic capacity, their transformation and tumorigenic capacities vary widely. We compared the metastatic efficiency of KRas G12V (Kirsten rat sarcoma viral oncogene homolog with valine mutation at codon 12) and KRas G13D (Kirsten rat sarcoma viral oncogene homolog with aspartic mutation at codon 13) oncogenes in an orthotopic colorectal cancer (CRC) model. Following subcutaneous preconditioning, recombinant clones of the SW48 CRC cell line [Kras wild-type (Kras WT)] expressing the KRas G12V or KRas G13D allele were microinjected in the mouse cecum. The percentage of animals developing lymph node metastasis was higher in KRas G12V than in KRas G13D mice. Microscopic, macroscopic, and visible lymphatic foci were 1.5- to 3.0-fold larger in KRas G12V than in KRas G13D mice (P < 0.05). In the lung, only microfoci were developed in both groups. KRas G12V primary tumors had lower apoptosis (7.0 ± 1.2 vs. 7.4 ± 1.0 per field, P = 0.02), higher tumor budding at the invasion front (1.2 ± 0.2 vs. 0.6 ± 0.1, P = 0.04), and a higher percentage of C-X-C chemokine receptor type 4 (CXCR4)-overexpressing intravasated tumor emboli (49.8 ± 9.4% vs. 12.8 ± 4.4%, P < 0.001) than KRas G13D tumors. KRas G12V primary tumors showed Akt activation, and β5 integrin, vascular endothelial growth factor A (VEGFA), and Serpine-1 overexpression, whereas KRas G13D tumors showed integrin β1 and angiopoietin 2 (Angpt2) overexpression. The increased cell survival, invasion, intravasation, and specific molecular regulation observed in KRas G12V tumors is consistent with the higher aggressiveness observed in patients with CRC expressing this oncogene.
authors.affiliation: Oncogenesis and Antitumor Drug Group, Biomedical Research Institute Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina, Barcelona, Spain;
authors.forename: Patricia
authors.initials: P
authors.lastname: Alamo
authors.affiliation: CIBER de Bioingeniería, Biomateriales y Nanomedicina, Barcelona, Spain; Department of Pathology, Clínica Girona, Girona, Spain;
authors.forename: Alberto
authors.initials: A
authors.lastname: Gallardo
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy; Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia, Istituto Di Ricovero e Cura a Carattere Scientifico, Torino, Italy;
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.affiliation: Oncogenesis and Antitumor Drug Group, Biomedical Research Institute Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina, Barcelona, Spain;
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Pavón
authors.affiliation: Oncogenesis and Antitumor Drug Group, Biomedical Research Institute Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina, Barcelona, Spain;
authors.forename: Isolda
authors.initials: I
authors.lastname: Casanova
authors.affiliation: CIBER de Bioingeniería, Biomateriales y Nanomedicina, Barcelona, Spain; Departments of General and Digestive Surgery.
authors.forename: Manuel
authors.initials: M
authors.lastname: Trias
authors.affiliation: Pharmacy, and.
authors.forename: María Antonia
authors.initials: MA
authors.lastname: Mangues
authors.affiliation: CIBER de Bioingeniería, Biomateriales y Nanomedicina, Barcelona, Spain; Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain;
authors.forename: Antonio
authors.initials: A
authors.lastname: Lopez-Pousa
authors.affiliation: CIBER de Bioingeniería, Biomateriales y Nanomedicina, Barcelona, Spain; Institut de Biotecnologia i de Biomedicina, and.
authors.forename: Antonio
authors.initials: A
authors.lastname: Villaverde
authors.affiliation: CIBER de Bioingeniería, Biomateriales y Nanomedicina, Barcelona, Spain; Institut de Biotecnologia i de Biomedicina, and.
authors.forename: Esther
authors.initials: E
authors.lastname: Vázquez
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy; Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia, Istituto Di Ricovero e Cura a Carattere Scientifico, Torino, Italy; Department de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Barcelona, Spain; and FIRC Institute of Molecular Oncology, Milan, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.affiliation: Oncogenesis and Antitumor Drug Group, Biomedical Research Institute Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina, Barcelona, Spain;
authors.forename: María Virtudes
authors.initials: MV
authors.lastname: Céspedes
authors.affiliation: Oncogenesis and Antitumor Drug Group, Biomedical Research Institute Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina, Barcelona, Spain; rmangues@santpau.cat.
authors.forename: Ramón
authors.initials: R
authors.lastname: Mangues
mesh_terms: D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008207:Lymphatic Metastasis; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D042702:Angiopoietin-2; D019012:Integrin beta1; D016601:RNA-Binding Proteins; C532831:SERBP1 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: KRas mutants; in vivo models aggressiveness