Lung adenocarcinoma invasion in TGFbRII-deficient cells is mediated by CCL5/RANTES

Recently, we identified a lung adenocarcinoma signature that segregated tumors into three clades distinguished by histological invasiveness. Among the genes differentially expressed was the type II transforming growth factor-beta receptor (TGF beta RII), which was lower in adenocarcinoma mixed subtype and solid invasive subtype tumors compared with bronchioloalveolar carcinoma. We used a tumor cell invasion system to identify the chemokine CCL5 (RANTES, regulated on activation, normal T-cell expressed and presumably secreted) as a potential downstream mediator of TGF-beta signaling important for lung adenocarcinoma invasion. We specifically hypothesized that RANTES is required for lung cancer invasion and progression in TGFbRII-repressed cells. We examined invasion in TGFbRII-deficient cells treated with two inhibitors of RANTES activity, Met-RANTES and a CCR5 receptor-blocking antibody. Both treatments blocked invasion induced by TGFbRII knockdown. In addition, we examined the clinical relevance of the RANTES-CCR5 pathway by establishing an association of RANTES and CCR5 immunostaining with invasion and outcome in human lung adenocarcinoma specimens. Moderate or high expression of both RANTES and CCR5 was associated with an increased risk for death, P = 0.014 and 0.002, respectively. In conclusion, our studies indicate RANTES signaling is required for invasion in TGFbRII-deficient cells and suggest a role for CCR5 inhibition in lung adenocarcinoma prevention and treatment.