Inflammation has been associated with metastatic progression in clear cell renal cell carcinoma (ccRCC). Blocking chemokine expression in cancer cells through the inhibition of chromatin remodelling might attenuate inflammatory processes and reduce metastatic spread, according to a preclinical study by Kohei Miyazono and Shogo Ehata.

The researchers demonstrated that, in an orthotopic xenograft mouse model, the use of highly aggressive inflammatory human ccRCC (iRCC) cells (derived through serial orthotopic inoculation in mice) increased the infiltration of primary tumours and lungs by Ly6G+ neutrophils, compared with the parental RCC (paRCC) cells. An anti-Ly6G antibody not only reduced the number of neutrophils in this model but also decreased the metastatic burden; primary tumour size was not affected.

In vitro, neutrophil migration and survival were enhanced in the presence of supernatants from iRCC cells but not those from paRCC cells, suggesting that iRCC cells might contribute to inflammation by releasing soluble mediators that modulate neutrophil phenotypes. Epigenetic analyses revealed that genes encoding proteins associated with responses to hypoxia, such as hypoxia-inducible factor (HIF), and inflammation, such as nuclear factor-κB (NF-κB) and CCAAT/enhancer-binding protein (C/EBP), were transcriptionally active in iRCC cells. Compared with paRCC cells, expression of CXC chemokines was also increased in iRCC cells, and chromatin precipitation analysis suggested that CXCL8 expression was controlled by a super-enhancer (SE) in these cells.

“Surprisingly, a bromodomain and extra-terminal (BET) inhibitor, which blocks SE-driven transcription, broadly reduced the expression of several chemokines,” remarks Ehata. “In vivo, this inhibitor decreased both neutrophil infiltration and lung metastasis.”

“BET inhibitors or related compounds might therapeutically target inflammation-driven metastatic spread in patients with advanced RCC,” adds Ehata.