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ELR+ CXC chemokines and oncogenic Ras-mediated tumorigenesis

Kevin M O'Hayer1, Donita C Brady, Christopher M Counter

  • 1Department of Pharmacology and Cancer Biology, DUMC, Durham, NC 27710, USA.

Carcinogenesis
|October 7, 2009
PubMed

Insights

Oncogenic Ras signaling promotes cancer by increasing secretion of ELR+ CXC chemokines. Blocking their receptor, CXCR2, reduced tumor growth, suggesting these chemokines are key drivers of Ras-driven tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Ras GTPase mutations are common in human cancers, driving tumorigenesis.
  • Oncogenic Ras signaling leads to the secretion of cytokines like VEGF, IL6, CXCL1, and CXCL8.
  • CXCL1 and CXCL8 are members of the ELR+ CXC chemokine family.

Purpose of the Study:

  • To investigate the role of the entire ELR+ CXC chemokine family in oncogenic Ras-mediated tumorigenesis.
  • To determine if oncogenic Ras induces the expression and secretion of these chemokines.
  • To assess the therapeutic potential of targeting the ELR+ CXC chemokine pathway.

Main Methods:

  • Studied oncogenic Ras-induced expression and secretion of ELR+ CXC chemokines in human cancer cells.
  • Analyzed chemokine levels in human tumor specimens.
  • Utilized genetic ablation of the mCXCR2 receptor in mouse models of oncogenic Ras-driven tumorigenesis.

Main Results:

  • Oncogenic Ras significantly induced the expression and secretion of the ELR+ CXC chemokine family.
  • Elevated levels of these chemokines were observed in tumor specimens.
  • Genetic ablation of mCXCR2 impaired oncogenic Ras-driven tumor growth in mice.

Conclusions:

  • Oncogenic Ras promotes tumorigenesis through the induction of ELR+ CXC chemokine secretion.
  • This chemokine signature may serve as a biomarker for Ras activation in cancer.
  • Targeting the ELR+ CXC chemokine pathway could be a therapeutic strategy for Ras-driven tumors.

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