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 highest mortality rates worldwide. However, relevant mouse models that recapitulated genetic alterations found in RCC have been lacking. In this study, we crossed Trp53 and Pten conditional knockout mice Ggt1-Cre to generate a Ggt1-Cre; Trp53LoxP/LoxP; PtenLoxP/LoxP; YFPLoxP/LoxP (GPPY) model, which resulted formation dysplastic lesions involving kidney tubular epithelial cells (TEC), only approximately 25% developing at an advanced age. Combining CRISPR/Cas9-mediated Vhl these increased frequency dysplasia, but failed increase incidence RCC. Assessments whether ischemic injury TECs GPPY without influences emergence revealed predominantly emerged contralateral, noninjured 100% penetrance younger age, rarely injured due severely damaged TEC. Injured TEC released CXCL1 into microenvironment traveled systemically activate fibroblasts recruit neutrophils enable contralateral kidney. Fibroblasts responded via CXCR2 recruited tumor-associated neutrophils, turn mediated tumor-promoting inflammation angiogenesis. Treatment anti-CXCR2 antibodies abolished malignant Collectively, results demonstrate defining functional role systemic cancer from preestablished precursor lesions. Significance: These identify for CXCL1/CXCR2 tumor development