dc.description.abstract | Clear-cell renal cell carcinoma (ccRCC), the most prevalent subtype of renal cell carcinoma (up to 70% of all RCC types), is characterized by malignant tubule epithelial cells with clear cytoplasm. There is a very close causal correlation between ccRCC and inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) located on chromosome 3p25‐26. Up
to 80% of sporadic ccRCC carry genomic mutations or epigenetic inactivation of VHL, and nearly 100% of familial ccRCC (in VHL disease) are VHL mutant. Accumulating evidence has indicated that ccRCC arises at the site of chronic inflammation, and this solid tumor contains a substantial number of infiltrated immune cells. This suggests that ccRCC may be induced by the interaction between kidney tubule cells carrying inactivated VHL gene and the inflammatory
microenvironment.
Monocyte-derived tissue effector cells, macrophages, are a crucial player in linking inflammation and cancer formation. Macrophage infiltration in the inflammatory microenvironment has been observed in previous studies of ccRCC models containing VHL mutations. However, the mechanism by which VHL loss-of-function cells activate macrophages during ccRCC formation has remained unclear.
In this study, we characterized the interaction between VHL-deficient kidney tubule cells and macrophages with relevance to tumor-associated inflammation and ccRCC formation.
The study demonstrated that the VHL-deficient kidney epithelial cells, representing the early stage of cancer initiation, secreted IL-6 to induce macrophage infiltration and subsequent polarization toward the pro-tumorigenic tumor-associated macrophage (TAM) phenotype both in vitro and in vivo. In the reciprocal action, the induced macrophages promote tumor development by secreting CCL18 and TGF-β1 to induce epithelial-to-mesenchymal transition (EMT) of the kidney tubule cells. Blockade of the IL-6 significantly inhibited macrophage extravasation and polarization, and reduced the inflammatory and proliferative phenotypes of the Vhlh conditional kidney knockout mouse. On the other hand, blockade of the macrophage secreted CCL18 and TGF-β inhibited the EMT-like phenotype in the VHL-deficient cells.
Specially, knocking down the expression of CCL18 in macrophages reduces tumor growth and cell metastasis in the xenograft model. The findings identified specific factors involved in a reciprocal mechanism that established the crosstalk between the tumor cells and the immune
components such as macrophages in the microenvironment. These results suggest an avenue for early detection and treatment of ccRCC. | en_US |