CXCL1型
PTEN公司
肾
条件基因敲除
肾细胞癌
癌症研究
肾癌
医学
病理
癌症
趋化因子受体
发育不良
基因剔除小鼠
肿瘤微环境
急性肾损伤
生物
炎症
免疫学
内科学
细胞凋亡
趋化因子
PI3K/AKT/mTOR通路
表型
受体
趋化因子受体
生物化学
基因
作者
Xi Zhou,Fei Xiao,Hikaru Sugimoto,Bingrui Li,Kathleen M. McAndrews,Raghu Kalluri
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2021-02-08
卷期号:81 (10): 2690-2702
被引量:11
标识
DOI:10.1158/0008-5472.can-20-2930
摘要
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 Trp53 and Pten conditional knockout mice with Ggt1-Cre mice to generate a Ggt1-Cre; Trp53LoxP/LoxP; PtenLoxP/LoxP; YFPLoxP/LoxP (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 Vhl 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 Vhl 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.
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