1. ¹Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY, USA
2. ²Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
3. ³Department of Surgery, Columbia University College of Physicians and Surgeons, New York, NY, USA
4. ⁴Department of Biomedical Informatics, Columbia University College of Physicians and Surgeons, New York, NY, USA
5. ⁵Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY, USA

Correspondence: Dr CA Powell, Division of Pulmonary, Allergy and Critical Care Medicine, Columbia University Medical Center, 630 West 168th Street, Box 91, New York, NY 10032, USA. E-mail: cap6@columbia.edu

Received 2 April 2007; Revised 31 May 2007; Accepted 7 June 2007; Published online 23 July 2007.

Abstract

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- receptor (TGFRII), 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- signaling important for lung adenocarcinoma invasion. We specifically hypothesized that RANTES is required for lung cancer invasion and progression in TGFRII-repressed cells. We examined invasion in TGFRII-deficient cells treated with two inhibitors of RANTES activity, Met-RANTES and a CCR5 receptor-blocking antibody. Both treatments blocked invasion induced by TGFRII 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 TGFRII-deficient cells and suggest a role for CCR5 inhibition in lung adenocarcinoma prevention and treatment.