title: Tumor-promoting circuits that regulate a cancer-related chemokine cluster: dominance of inflammatory mediators over oncogenic alterations.
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 RasHigh/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 TNFa 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-kB. 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.
authors.affiliation: Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel. aditbb@tauex.tau.ac.il.
authors.forename: Tal
authors.initials: T
authors.lastname: Leibovich-Rivkin
authors.forename: Yosef
authors.initials: Y
authors.lastname: Buganim
authors.forename: Hilla
authors.initials: H
authors.lastname: Solomon
authors.forename: Tsipi
authors.initials: T
authors.lastname: Meshel
authors.forename: Varda
authors.initials: V
authors.lastname: Rotter
authors.forename: Adit
authors.initials: A
authors.lastname: Ben-Baruch