Interleukin-8 and Its Role During EMT

Human epithelial breast cancer MCF7 cells were left untreated or incubated with recombinant IL-8 and analyzed for expression of epithelial E-cadherin (green) and mesenchymal Fibronectin (green) by immunofluorescence. The nuclei were stained with DAPI (blue). Treatment with IL-8 induced down-regulation of E-cadherin and up-regulation of Fibronectin, characteristics of an EMT.

Human epithelial breast cancer MCF7 cells were left untreated or incubated with recombinant IL-8 and analyzed for expression of epithelial E-cadherin (green) and mesenchymal Fibronectin (green) by immunofluorescence. The nuclei were stained with DAPI (blue). Treatment with IL-8 induced down-regulation of E-cadherin and up-regulation of Fibronectin, characteristics of an EMT.

The switch of cancer cells from an epithelial to a mesenchymal-like phenotype, designated as epithelial-to-mesenchymal transition or EMT, is known to induce cell motility and invasiveness and appears to be critical for the dissemination of solid tumors and drug resistance. An understanding of the signaling events that induce tumor EMT could lead to novel ways to prevent metastasis.

Romaine Fernando, Ph.D., and others in the CCR’s Laboratory of Tumor Immunology and Biology (LTIB), working under the direction of Claudia Palena, Ph.D., head of the LTIB’s Immunoregulation Group, previously identified the transcription factor Brachyury as a driver of EMT in human tumors.  Following this discovery, the same team recently reported in Cancer Research that lung, breast, and pancreatic cancer cells undergoing EMT that involves Brachyury over-expression, all secrete multiple factors, including cytokines, chemokines, and angiogenic factors that could create an environment for metastasis. In particular, Brachyury over-expression induced the secretion of the chemokine interleukin-8 (IL-8), together with the up-regulation of its receptors.

The Palena team demonstrated that the soluble factors secreted by tumor cells undergoing the epithelial-mesenchymal switch are able to induce other epithelial cancer cells into EMT, an effect that is, at least in part, mediated by IL-8. Their results also showed that IL-8 signaling is critical for maintaining the mesenchymal characteristics of human tumor cells. Inhibition of IL-8 signaling resulted in decreased tumor invasiveness together with a reversion into an epithelial phenotype.

While these results were obtained in vitro with tumor cell lines, the findings may have implications for cancer therapy. Possibly, blockade of IL-8 signaling might be a new way to target mesenchymal-like, invasive carcinoma cells, therefore interfering with tumor dissemination and metastasis.

These studies represent an extension of previous work by the same laboratory, demonstrating the specific expression of Brachyury in tumors compared to normal tissues, and the development of T-cell immune responses against Brachyury. Those studies led to the current development of Brachyury-based vaccines for the treatment of human carcinomas.

Summary Posted: 12/2011

Reference

IL-8 signaling plays a critical role in the epithelial-mesenchymal transition of human carcinoma cells. Fernando RI, Castillo MD, Litzinger M, Hamilton DH, Palena C. Cancer Res. 2011;71(15):5296-306. Reviewed by Donna Kerrigan PubMed Link