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Activated Kras, but not Hras or Nras, may initiate tumors of endodermal origin via stem cell expansion

Margaret P Quinlan1, Steven E Quatela, Mark R Philips

  • 1Massachusetts General Hospital Cancer Center and Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA.

Molecular and Cellular Biology
|February 13, 2008
PubMed

Insights

Activating mutations in Kras genes drive cancer by promoting the proliferation of endodermal stem cells, unlike Hras or Nras. This expansion of susceptible stem cells explains Kras

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Stem Cell Biology

Background:

  • Human Ras genes (Hras, Nras, Kras) are closely related, widely expressed, and can drive oncogenesis.
  • Activating mutations in Kras are most common in human tumors, particularly those from endodermally derived tissues (lung, pancreas, colon).
  • This suggests Kras mutations initiate oncogenesis by affecting endodermal progenitor cells.

Purpose of the Study:

  • To investigate the distinct roles of activated Ras isoforms (HrasV12, KrasV12, NrasV12) in endodermal progenitor cell differentiation and proliferation.
  • To elucidate the structural basis for these differential effects and identify key Ras effectors involved.

Main Methods:

  • Utilized a retinoic acid (RA)-induced stem cell differentiation model to endoderm.
  • Introduced activated Ras isoforms (HrasV12, KrasV12, NrasV12) into endodermal progenitors.
  • Performed structure-function analysis of Ras isoforms and identified Ras effector requirements.

Main Results:

  • Activated HrasV12 promoted differentiation and growth arrest in endodermal progenitors.
  • Activated KrasV12 promoted proliferation and inhibited differentiation, maintaining stem cell characteristics.
  • NrasV12 had no significant effect on differentiation or proliferation.
  • Distinct effects of Ras isoforms are mediated by their C-terminal domains, involving compartmentalized signaling and specific effectors.

Conclusions:

  • Activated Ras isoforms exert significantly different effects on endodermal progenitor cells.
  • Mutant Kras may initiate tumorigenesis by expanding a susceptible stem/progenitor cell population.
  • This finding provides a potential explanation for the high frequency of Kras mutations in endodermal tumors.

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