Tumor-promoting circuits that regulate a cancer-related chemokine cluster: Dominance of inflammatory mediators over oncogenic alterations

Tal Leibovich-Rivkin, Yosef Buganim, Hilla Solomon, Tsipi Meshel, Varda Rotter, Adit Ben-Baruch*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Here, we investigated the relative contribution of genetic/signaling components versus microenvironmental factors to the malignancy phenotype. In this system, we took advantage of non-transformed fibroblasts that carried defined oncogenic modifications in Ras and/or p53. These cells were exposed to microenvironmental pressures, and the expression of a cancer-related chemokine cluster was used as readout for the malignancy potential (CCL2, CCL5, CXCL8, CXCL10). In cells kept in-culture, synergism between Ras hyper-activation and p53 dysfunction was required to up-regulate the expression of the chemokine cluster. The in vivo passage of Ras High/p53 Low-modified cells has led to tumor formation, accompanied by potentiation of chemokine release, implicating a powerful role for the tumor microenvironment in up-regulating the chemokine cluster. Indeed, we found that inflammatory mediators which are prevalent in tumor sites, such as TNFα and IL-1β, had a predominant impact on the release of the chemokines, which was substantially higher than that obtained by the oncogenic modifications alone, possibly acting through the transcription factors AP-1 and NF-κB. Together, our results propose that in the unbiased model system that we were using, inflammatory mediators of the tumor milieu have dominating roles over oncogenic modifications in dictating the expression of a pro-malignancy chemokine readout.

Original languageAmerican English
Pages (from-to)55-76
Number of pages22
JournalCancers
Volume4
Issue number1
DOIs
StatePublished - Mar 2012
Externally publishedYes

Keywords

  • Cluster of cancer-related chemokines
  • IL-1β
  • Inflammatory cytokines
  • P53 dysfunction
  • Ras hyper-activation
  • TNFα

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