Abstract 4681: Characterization of pulmonary hypertension in lung cancer.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Introduction: Approximately 60%-70% of patients with lung cancer have dyspnea at presentation, and 90% experience it just prior to death. Considering case reports describing the formation of pulmonary hypertension (PH) via pulmonary tumor microemboli from gastric and gallbladder cancer, we analyzed the involvement of PH in the development of dyspnea in lung cancer using different mouse models and human lung tumor samples. Methods: Three murine lung cancer models have been used: C57BL/6N-mice that received an injection of Lewis-lung-carcinoma-cells (LLC1) via tail vein, K-rasLA2 knock-in-mice and SP-C-c-raf-1-BxB-23 transgene mice. They underwent echocardiographic analyses at different time points and hemodynamic measurements to assess the right ventricular systolic pressure (RVSP) and systemic arterial pressure. Histological evaluation was performed to determine the pulmonary vascular morphometry in the tumor-area as well as the total collagen of the right ventricle. Identical histological analyses have been done in human lung tumor samples. In addition, to understand the contribution of immune cells to the development of PH in lung cancer setting, pulmonary vascular walls were analyzed in human lung tumor tissue and quantified for macrophages (CD68+), T-lymphocytes (CD3+) and dendritic cells (CD209+). Results: For each mouse model, echocardiography reveals an impaired systolic, diastolic and global function of the right ventricle, as well as a dilated right ventricle. Hemodynamics show an increased RVSP. Murine and human lung tumor samples demonstrate vascular remodeling, affecting both wall thickness and the degree of muscularization in the tumor-area. The quantification of total collagen enables to prove a right ventricular fibrosis. Higher incidences of T-lymphocytes and macrophages in pulmonary vascular walls were demonstrated in the tumor-area of human lung section. Conclusion: This study provides clear evidence for the existence of PH in human as well as animal models affected by lung cancer. Repeated echocardiographic analyses show that the detected PH represents an end-stage phenomenon. The increased content of T-lymphocytes and macrophages in the vascular walls leads us to the hypothesis that these cell types might be involved in the remodeling of small pulmonary vessels in tumors. Citation Format: Samantha Storn, Soni Savai Pullamsetti, Baktybek Kojonazarov, Ralph Theo Schermuly, Friedrich Grimminger, Ulf R. Rapp, Werner Seeger, Rajkumar Savai. Characterization of pulmonary hypertension in lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4681. doi:10.1158/1538-7445.AM2013-4681