Tumor-Promoting Circuits That Regulate a Cancer-Related Chemokine Cluster: Dominance of Inflammatory Mediators Over Oncogenic Alterations

Cancers

Tal Leibovich-Rivkin²  Yosef Buganim¹  Hilla Solomon¹  Tsipi Meshel²  Varda Rotter¹ 

[1] Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel; E-Mails:;Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel; E-Mails:

关键词: Ras hyper-activation;    p53dysfunction;    cluster of cancer-related chemokines;    inflammatory cytokines;    TNFα;    IL-1β;   

DOI  :  10.3390/cancers4010055

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2012 by the authors; licensee MDPI, Basel, Switzerland.