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Higher metastatic efficiency of KRas G12V than KRas G13D in a colorectal cancer model
Álamo, Patricia (Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina)
Gallardo Alcañiz, Alberto (Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina)
Di Nicolantonio, Federica (Università degli studi di Torino. Dipartimento di Oncologia)
Pavón Ribas, Miguel Ángel (Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina)
Casanova, Isolda (Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina)
Trias Folch, Manuel (Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina)
Mangues i Bafalluy, Ma. Antònia (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya). Servei de Cirurgia General i Digestiva)
Lopez-Pousa, Antonio (Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina)
Villaverde Corrales, Antonio (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Vázquez Gómez, Esther (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Bardelli, Alberto (Università degli studi di Torino. Dipartimento di Oncologia)
Céspedes, María Virtudes (Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina)
Mangues, Ramón (Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina)

Date: 2015
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.
Note: Número d'acord de subvenció ISCIII/FIS/PI12/01861
Note: Número d'acord de subvenció AGAUR/2009/SGR-1437
Rights: Tots els drets reservats.
Language: Anglès.
Document: article ; recerca ; submittedVersion
Subject: KRas mutants ; In vivo models aggressiveness ; Models in vivo d'agressivitat
Published in: The FASEB journal, Vol. 29 Issue 2 (Feb. 2015) , p. 464-476, ISSN 0892-6638

DOI: 10.1096/fj.14-262303


Pre-print
27 p, 8.4 MB

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Articles > Research articles
Articles > Published articles

 Record created 2015-06-18, last modified 2019-02-03



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