Tumor-stroma interaction between RCC cell lines and lung stroma in mouse xenografts

The leading cause of death in human patients with metastatic renal cell carcinoma (RCC) and malignant cancer in general is the dissemination of the primary tumor to secondary sites. The mechanisms by which RCC colonize the lung microenvironment during metastasis remain largely unknown. To investigate the mechanisms of lung colonization by tumor cells, we grafted human RCC cells with different lung metastatic activities in mice. Gene expression profiling of the mouse lung stromal compartment revealed a gene signature enriched for neutrophil-specific functions, induced preferentially by poorly metastatic cells. Analysis of the gene expression patterns in tumor cells and clinical specimens showed an inverse correlation between metastatic activity and the levels of a number of chemokines, including CXL5 ad IL8. Enforced depletion of CXCL5 and IL8 in tumor cells allowed us to establish a functional link between lung neutrophil infiltration, the secretion of chemokines by cancer cells and metastatic activity. Finally, we showed that human neutrophils displayed a higher cytotoxic activity toward poorly metastatic cells relative to highly metastatic cells. Together, these results support a model in which neutrophils recruited to the lung by tumor-secreted chemokines build an antimetastatic barrier and loss of those neutrophil chemokines in tumor cells is a critical rate-limiting step during lung metastatic seeding.

12

López-Lago MA, Posner S, Thodima VJ, Molina AM, Motzer RJ, Chaganti RS