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Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context

Carmen Guerra1, Nieves Mijimolle, Alma Dhawahir

  • 1Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain.

Cancer Cell
|September 6, 2003
PubMed

Insights

Introducing an oncogenic K-ras allele in mouse cells created immortal cell lines. However, in vivo, K-ras oncogene expression primarily induced lung tumors, highlighting the importance of cellular context in neoplastic growth.

Area of Science:

  • Molecular Biology
  • Oncology
  • Genetics

Background:

  • K-ras is a proto-oncogene frequently mutated in human cancers.
  • Understanding the in vivo oncogenic potential of K-ras requires precise genetic models.
  • Cellular context is critical in determining the outcome of oncogene activation.

Purpose of the Study:

  • To develop a conditional mouse model for K-ras(V12) oncogene expression.
  • To investigate the in vitro and in vivo consequences of endogenous K-ras(V12) activation.
  • To determine the role of cellular context in K-ras-driven tumorigenesis.

Main Methods:

  • Targeted K-ras allele in mouse embryonic stem (ES) cells to express K-Ras(V12) oncoprotein.
  • Utilized a bicistronic transcript with a beta-geo marker.
  • Employed Cre recombinase for conditional activation of the oncogenic allele.
  • Analyzed primary mouse embryonic fibroblasts (MEFs) and K-ras(V12) expressing mice.

Main Results:

  • K-ras(V12) expression in MEFs resulted in immortalization, bypassing proliferative senescence.
  • Systemic K-ras(V12) expression in mice did not cause widespread proliferation or abnormalities up to eight months.
  • A subset of lung bronchiolo-alveolar cells expressing K-ras(V12) underwent malignant transformation, forming adenomas and adenocarcinomas.

Conclusions:

  • Endogenous K-ras oncogene activation can lead to immortalization in vitro.
  • In vivo, K-ras oncogene-induced neoplastic growth is context-dependent, primarily affecting specific cell types like lung epithelia.
  • Cellular environment significantly influences the manifestation of K-ras-driven cancer.

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