Higher metastatic efficiency of KRas G12V than KRas G13D in a colorectal cancer model
Por:
Alamo P., Gallardo A., Di Nicolantonio F., Pavón M.A., Casanova I., Trias M., Mangues M.A., Lopez-Pousa A., Villaverde A., Vázquez E., Bardelli A., Céspedes M.V., Mangues R.
Publicada:
1 ene 2015
Resumen:
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 ß5 integrin, vascular endothelial growth factor A (VEGFA), and Serpine-1 overexpression, whereas KRas G13D tumors showed integrin ß1 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. © FASEB.
Filiaciones:
Alamo P.:
Oncogenesis and Antitumor Drug Group, Biomedical Research Institute Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Biomedical Research Institute Sant Pau (IIB-SantPau), Hospital de la Santa Creu I Sant Pau, CIBER (CIBER-BBN), c/ Sant Antoni Maria Claret, 167, Barcelona, 08025, Spain
Gallardo A.:
Biomedical Research Institute Sant Pau (IIB-SantPau), Hospital de la Santa Creu I Sant Pau, CIBER (CIBER-BBN), c/ Sant Antoni Maria Claret, 167, Barcelona, 08025, Spain
Department of Pathology, Clínica Girona, Girona, Spain
Di Nicolantonio F.:
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
Pavón M.A.:
Oncogenesis and Antitumor Drug Group, Biomedical Research Institute Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Biomedical Research Institute Sant Pau (IIB-SantPau), Hospital de la Santa Creu I Sant Pau, CIBER (CIBER-BBN), c/ Sant Antoni Maria Claret, 167, Barcelona, 08025, Spain
Casanova I.:
Oncogenesis and Antitumor Drug Group, Biomedical Research Institute Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Biomedical Research Institute Sant Pau (IIB-SantPau), Hospital de la Santa Creu I Sant Pau, CIBER (CIBER-BBN), c/ Sant Antoni Maria Claret, 167, Barcelona, 08025, Spain
Trias M.:
Biomedical Research Institute Sant Pau (IIB-SantPau), Hospital de la Santa Creu I Sant Pau, CIBER (CIBER-BBN), c/ Sant Antoni Maria Claret, 167, Barcelona, 08025, Spain
Department of General and Digestive Surgery, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain
Mangues M.A.:
Department of Pharmacy, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Lopez-Pousa A.:
Biomedical Research Institute Sant Pau (IIB-SantPau), Hospital de la Santa Creu I Sant Pau, CIBER (CIBER-BBN), c/ Sant Antoni Maria Claret, 167, Barcelona, 08025, Spain
Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Villaverde A.:
Biomedical Research Institute Sant Pau (IIB-SantPau), Hospital de la Santa Creu I Sant Pau, CIBER (CIBER-BBN), c/ Sant Antoni Maria Claret, 167, Barcelona, 08025, Spain
Institut de Biotecnologia I de Biomedicina, Universitat Autònoma de Barcelona, Barcelona, Spain
Vázquez E.:
Biomedical Research Institute Sant Pau (IIB-SantPau), Hospital de la Santa Creu I Sant Pau, CIBER (CIBER-BBN), c/ Sant Antoni Maria Claret, 167, Barcelona, 08025, Spain
Institut de Biotecnologia I de Biomedicina, Universitat Autònoma de Barcelona, Barcelona, Spain
Bardelli A.:
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
FIRC Institute of Molecular Oncology, Milan, Italy
Céspedes M.V.:
Oncogenesis and Antitumor Drug Group, Biomedical Research Institute Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Biomedical Research Institute Sant Pau (IIB-SantPau), Hospital de la Santa Creu I Sant Pau, CIBER (CIBER-BBN), c/ Sant Antoni Maria Claret, 167, Barcelona, 08025, Spain
Mangues R.:
Oncogenesis and Antitumor Drug Group, Biomedical Research Institute Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Biomedical Research Institute Sant Pau (IIB-SantPau), Hospital de la Santa Creu I Sant Pau, CIBER (CIBER-BBN), c/ Sant Antoni Maria Claret, 167, Barcelona, 08025, Spain
All Open Access; Green
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