Acute Kidney Injury Instigates Malignant Renal Cell Carcinoma via CXCR2 in Mice with Inactivated <i>Trp53</i> and <i>Pten</i> in Proximal Tubular Kidney Epithelial Cells.

Abstract

Renal cell carcinoma (RCC) is one of the most common urologic malignancies with the highest mortality rates worldwide. However, relevant mouse models that recapitulated the genetic alterations found in RCC have been lacking. In this study, we crossed <i>Trp53</i> and <i>Pten</i> conditional knockout mice with <i>Ggt1-Cre</i> mice to generate a <i>Ggt1-Cre</i>; <i>Trp53^LoxP/LoxP</i> ; <i>Pten^LoxP/LoxP</i> ; <i>YFP^LoxP/LoxP</i> (GPPY) mouse model, which resulted in the formation of dysplastic lesions involving kidney tubular epithelial cells (TEC), with only approximately 25% of mice developing RCC at an advanced age. Combining CRISPR/Cas9-mediated <i>Vhl</i> knockout in these mice increased the frequency of dysplasia, but failed to increase the incidence of RCC. Assessments of whether ischemic injury of TECs in the GPPY kidney without <i>Vhl</i> knockout influences the emergence of RCC revealed that advanced RCC predominantly emerged in the contralateral, noninjured kidney with 100% penetrance at a younger age, but rarely in the injured kidney due to severely damaged ischemic TEC. Injured TEC released CXCL1 into the microenvironment that traveled systemically to activate fibroblasts and recruit neutrophils to enable emergence of RCC in the contralateral kidney. Fibroblasts responded to CXCL1 via CXCR2 and recruited tumor-associated neutrophils, which in turn mediated tumor-promoting inflammation and angiogenesis. Treatment with anti-CXCR2 antibodies abolished the emergence of malignant RCC. Collectively, these results demonstrate a defining functional role of systemic inflammation and microenvironment in the emergence of malignant cancer from preestablished dysplastic precursor lesions. SIGNIFICANCE: These results identify a role for CXCL1/CXCR2 and the tumor microenvironment in the development of RCC. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/10/2690/F1.large.jpg.<i>See related commentary by Kusmartsev, p. 2584</i>.