| First Author | Nguyen TN | Year | 2022 |
| Journal | Cancer Res | Volume | 82 |
| Issue | 15 | Pages | 2716-2733 |
| PubMed ID | 35666812 | Mgi Jnum | J:326991 |
| Mgi Id | MGI:7327477 | Doi | 10.1158/0008-5472.CAN-21-3749 |
| Citation | Nguyen TN, et al. (2022) IL6 and CCL18 Mediate Cross-talk between VHL-Deficient Kidney Cells and Macrophages during Development of Renal Cell Carcinoma. Cancer Res 82(15):2716-2733 |
| abstractText | Loss of the von Hippel-Lindau (VHL) tumor suppressor gene function accounts for 70% to 80% of all clear-cell renal cell carcinoma (ccRCC) cases, the most prevalent form of RCC. Accumulating evidence has indicated that ccRCC arises from sites of chronic inflammation, yet how ccRCC tumor cells interact with immune components of the microenvironment has not been fully elucidated. In this study, we used unbiased proteomic and genomic analyses on components of the tumor microenvironment under different conditions, identifying the molecular and cellular mechanisms that underlie the cross-talk between VHL-deficient kidney tubule cells and macrophages. In vitro and in a Vhlh conditional knockout mouse model, VHL-deficient noncancerous kidney epithelial cells, representing the early stage of ccRCC initiation, secreted IL6 that induced macrophage infiltration and polarization toward the protumorigenic M2 phenotype. Activated human macrophages secreted CCL18 and TGFbeta1 to stimulate epithelial-to-mesenchymal transition (EMT) of the kidney tubule cells. Treatment with IL6-neutralizing antibody rescued inflammatory, proliferative, and EMT phenotypes of kidney epithelial cells in Vhlh conditional knockout mice. Furthermore, in a human ccRCC xenograft model, exogenous human primary or cultured macrophages significantly promoted primary tumor growth and metastasis in a CCL18-dependent manner. These findings identify specific factors involved in reciprocal cross-talk between tumor cells and immune components in the microenvironment, thus providing an avenue for early intervention in ccRCC. SIGNIFICANCE: The identification of VHL-deficient kidney tubule cell cross-talk with macrophages regulated by IL6 and CCL18 reveals potential targets for the prevention and treatment of ccRCC. |
