Higher metastatic efficiency of KRas G12V than KRas G13D in a colorectal cancer model

Patricia Alamo, Alberto Gallardo, Federica Di Nicolantonio, Miguel Angel Pavón, Isolda Casanova, Manuel Trias, María Antonia Mangues, Antonio Lopez-Pousa, Antonio Villaverde, Esther Vázquez, Alberto Bardelli, María Virtudes Céspedes, Ramón Mangues

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)464-476
Number of pages13
JournalFASEB Journal
Volume29
Issue number2
DOIs
Publication statusPublished - Feb 1 2015

Fingerprint

Tumors
Colorectal Neoplasms
Oncogenes
Neoplasms
Integrins
Codon
Sarcoma
Rats
Neoplastic Cell Transformation
Cells
Angiopoietin-2
CXC Chemokines
Mutation
Cecum
Chemokine Receptors
Valine
Embolism
Vascular Endothelial Growth Factor A
Cell Survival
Animals

Keywords

  • In vivo models aggressiveness
  • KRas mutants

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Alamo, P., Gallardo, A., Di Nicolantonio, F., Pavón, M. A., Casanova, I., Trias, M., ... Mangues, R. (2015). Higher metastatic efficiency of KRas G12V than KRas G13D in a colorectal cancer model. FASEB Journal, 29(2), 464-476. https://doi.org/10.1096/fj.14-262303

Higher metastatic efficiency of KRas G12V than KRas G13D in a colorectal cancer model. / Alamo, Patricia; Gallardo, Alberto; Di Nicolantonio, Federica; Pavón, Miguel Angel; Casanova, Isolda; Trias, Manuel; Mangues, María Antonia; Lopez-Pousa, Antonio; Villaverde, Antonio; Vázquez, Esther; Bardelli, Alberto; Céspedes, María Virtudes; Mangues, Ramón.

In: FASEB Journal, Vol. 29, No. 2, 01.02.2015, p. 464-476.

Research output: Contribution to journalArticle

Alamo, P, Gallardo, A, Di Nicolantonio, F, Pavón, MA, Casanova, I, Trias, M, Mangues, MA, Lopez-Pousa, A, Villaverde, A, Vázquez, E, Bardelli, A, Céspedes, MV & Mangues, R 2015, 'Higher metastatic efficiency of KRas G12V than KRas G13D in a colorectal cancer model', FASEB Journal, vol. 29, no. 2, pp. 464-476. https://doi.org/10.1096/fj.14-262303
Alamo, Patricia ; Gallardo, Alberto ; Di Nicolantonio, Federica ; Pavón, Miguel Angel ; Casanova, Isolda ; Trias, Manuel ; Mangues, María Antonia ; Lopez-Pousa, Antonio ; Villaverde, Antonio ; Vázquez, Esther ; Bardelli, Alberto ; Céspedes, María Virtudes ; Mangues, Ramón. / Higher metastatic efficiency of KRas G12V than KRas G13D in a colorectal cancer model. In: FASEB Journal. 2015 ; Vol. 29, No. 2. pp. 464-476.
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