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- Title
Tumor-Promoting Circuits That Regulate a Cancer-Related Chemokine Cluster: Dominance of Inflammatory Mediators Over Oncogenic Alterations.
- Authors
Leibovich-Rivkin, Tal; Buganim, Yosef; Solomon, Hilla; Meshel, Tsipi; Rotter, Varda; Ben-Baruch, Adit
- 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 High Low chemokine cluster. The in vivo passage of Ras High/p53Low-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.
- Subjects
CHEMOKINES; INFLAMMATORY mediators; INTERLEUKINS; MONOCLONAL antibodies; NEOVASCULARIZATION inhibitors; RESEARCH funding; T-test (Statistics); TUMOR necrosis factors; TUMORS; WESTERN immunoblotting; DESCRIPTIVE statistics; IN vitro studies
- Publication
Cancers, 2012, Vol 4, Issue 1, p55
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers4010055